Metronomic vinorelbine combined with durvalumab plus tremelimumab dual immunotherapy in patients with metastatic prostate cancer

Metronomic vinorelbine combined with durvalumab plus tremelimumab dual immunotherapy in patients with metastatic prostate cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Metronomic vinorelbine combined with durvalumab plus tremelimumab dual immunotherapy in patients with metastatic prostate cancer Elodie Coquan, Alice Hervieu, Claire Cropet, Esma Saada–Bouzina, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6062361/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Immune checkpoint inhibitors (ICI) are a class of immunotherapy drugs that have shown significant success in treating various types of cancers. However, their effectiveness in treating prostate cancer (PC) has been more challenging due to an immunosuppressive tumor microenvironment. Low-dose metronomic chemotherapy have immunomodulatory properties that could enhance immunotherapy and is well-tolerated. MOVIE was a phase 1/2 multi-cohort study with a Bayesian design that evaluated the antitumor activity and safety of metronomic vinorelbine with durvalumab plus tremelimumab. Here, we report the results of the PC cohort during phase 2. Fifteen patients with locally advanced or metastatic PC, resistant to conventional therapies, presenting a measurable disease according to RECISTv1.1, and a performance status (PS)≤1, received metronomic oral vinorelbine 40mg three times a week, and durvalumab 1500mg plus tremelimumab 75mg intravenously at day 1 of 28-day cycles. Primary endpoint was the clinical benefit rate (CBR) evaluated using a Bayesian design. Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mean estimated CBR according to a non-informative prior distribution was 12.5% (95% credible interval: 1.7-31.9). One patient achieved PR leading to an ORR of 7.7%, and 4 SD<24 weeks. Median PFS was 1.9 months (95% confidence interval [CI]: 1.7-3.8), and median OS 5.4 months (95%CI: 2.4-12.2). Most frequent treatment-related G≥3 AEs were anemia (13.3%) for vinorelbine, and colitis (20.0%) and diarrhea (13.3%) for ICI. One treatment-related G5 AE (sepsis) was observed. The study outcomes highlighted the complexities of treating advanced PC with ICI, even when combined with metronomic vinorelbine. Prostate cancer (PC) metronomic chemotherapy (MCT) vinorelbine durvalumab tremelimumab Figures Figure 1 INTRODUCTION In 2022, prostate cancer (PC) was the fourth most common cancer and the eighth leading cause of cancer death worldwide [ 1 ]. It remains a significant clinical challenge, particularly in its castration resistant form, when traditional therapeutic options fail to provide long-term control. Indeed, while androgen deprivation therapy, chemotherapy, androgen receptor pathway inhibitors, PARP inhibitors, and radioligand therapy can initially suppress tumor growth and prolong survival, they are often limited by the development of resistance, leading to disease progression and suboptimal long-term outcomes [ 2 ]. In recent years, immune checkpoint inhibitors (ICI) have revolutionized the treatment of several malignancies [3 4]. These agents, which target key immune regulatory pathways such as the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) axis and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), have demonstrated the ability to generate potent anti-tumor immune responses by overcoming tumor-induced immunosuppression [ 5 ]. In PC, the role of ICI has yet to be clarified, especially since PC is typically considered a "cold" tumor due to its low mutational burden, low number of neoantigens, and limited immune infiltration [ 6 ]. Blockade of PD-1 with nivolumab or pembrolizumab in patients with metastatic castration-resistant PC (mCRPC) demonstrated no significant clinical benefits indicating that using PD-1 inhibitors as single agents are inadequate for treating advanced PC cases [7 8]. Also, ipilimumab, an anti-CTLA-4, showed no improvement in terms of objective response rate combined to radiotherapy in mCRPC patients and in patients who had previously undergone chemotherapy [ 9 ]. Similarly, two phase-3 trials evaluating ipilimumab versus placebo in patients with docetaxel-resistant (CA184-043) and chemotherapy-naïve mCRPC (CA184-095) failed to improve overall survival (OS) [10 11]. Since ICI monotherapy is being modestly effective in these tumors, combination therapies that pair anti-PD-L1 with anti-CTLA-4 and immunotherapy with other modalities, are currently being explored in an effort to boost the immune response against PC. In search of alternatives cancer strategies, the use of metronomic chemotherapy (MCT) has also been investigated with some success in advanced tumors. MCT, which consists in the administration of low-dose chemotherapy at regular, frequent intervals, without interruption, was initially designed to target tumor angiogenesis, exploiting the extreme sensitivity of rapidly renewing endothelial cells in growing tumors. However, immunomodulation also occurs, shifting the immunological balance from immunosuppression to immunostimulation through various mechanisms including induction of immunogenic cell death, enhancement of antigen-presentation by modulation of dendritic cells, increased immunogenicity of cancer cells, depletion of regulatory T cells, enhancement of the cytotoxic activity of immune effector cells, such as tumor-specific T cells and γδT cells [ 12 – 15 ]. Notably, MCT induces less acquired therapeutic resistance and its lower toxicity profile allows for longer treatment durations [ 16 ]. Several chemotherapeutic agents, alone or in combination with various targeted therapies, have been evaluated using metronomic schedules in solid tumors [17 18]. Among the MCT tested, metronomic vinorelbine has demonstrated a low toxicity profile with some anti-tumoral activity in mCRPC [ 19 ]. Combine to ICI, it may have the potential to improve patient outcomes by synergistically enhancing both the direct anti-tumor effects of chemotherapy and the immune-mediated tumor destruction achieved through checkpoint inhibition [ 20 ]. In this context, the MOVIE trial was designed to assess the antitumor activity and safety of metronomic oral vinorelbine combined to anti-PD-L1 durvalumab and anti-CTLA-4 tremelimumab dual immunotherapy. MOVIE was a phase 1/2 multiple cohort study, and we present herein the results obtained in the prostate cohort during the phase 2 part of the trial. METHODS Study design and participants The MOVIE trial was a phase 1/2, multiple cohort, French, multicentre, open-label, non-randomised and non-comparative study that aimed to evaluate the activity and safety of metronomic oral vinorelbine with durvalumab plus tremelimumab in patients with advanced solid tumors including head and neck, prostate, cervix, breast cancers, as well as miscellaneous malignancies with high mutational load and/or MSI-High. The study was divided into two successive parts: a phase 1 dose-escalation expanded to a phase 2 to assess the activity and safety of the combination under the previously defined Recommended Phase II Dose (RP2D). MOVIE phase 1 was conducted from July 2018 to May 2019 and results were previously reported [ 21 ]. Patients treated at RP2D during phase 1 were considered evaluable for phase 2. Patients included in the prostate cohort were men ≥ 18 years old with histologically confirmed locally advanced or metastatic prostate tumors, resistant to conventional therapies, and candidate to experimental therapy according to local clinical board. Eligible patients were required to have a measurable disease by RECIST v1.1, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, normal hematological (ANC ≥ 1.5 x 10 9 /L; platelets count ≥ 100 x 10 9 /L; hemoglobin ≥ 9.0 g/dL), hepatic (total bilirubin ≤ 1.5 upper limit of normal [ULN] unless documented Gilbert’s syndrome; ASAT and ALAT ≤ 2.5 ULN / ≤5 ULN in the presence of liver metastases), and cardiac functions (LVEF ≥ 50%), measured creatinine clearance (Cockcroft and Gault) ≥ 40 mL/min or creatinine ≤ 1.5 times ULN, and an estimated life expectancy of at least 3 months. Key exclusion criteria included other concurrent malignancies, active brain metastases, spinal cord compression, or leptomeningeal disease (except local meningeal disease due to local recurrence), previous treatment with an anti-PD-(L)1 antibody or an anti-CTLA-4 therapy or vinorelbine (in advanced settings), current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab, prior anticancer therapy within the last 3 weeks, major surgery within 28 days prior to the first dose of study treatment, and participation in another clinical trial with an investigational product within 21 days of inclusion. Procedures RP2D was defined during the phase I of the MOVIE study at oral vinorelbine 40mg three times a week (3QW), and durvalumab 1500mg plus tremelimumab 75mg via intravenous infusion at day 1 of 28-day cycles (Q4W) [ 21 ]. Patients received vinorelbine until disease progression, and up to 26 cycles of durvalumab and 4 cycles of tremelimumab. Dose reductions of durvalumab and tremelimumab were not permitted. Vinorelbine could be reduced to 30mg then 20mg. Patients were treated until progression of their disease, unacceptable toxicity, intercurrent conditions that precluded continuation of treatment, or patient refusal. During durvalumab plus tremelimumab combination, dose interruptions always applied to both compounds. Clinical disease and radiologic assessments were performed at baseline, at D28 every 2 cycles during treatment phase, then at the end of treatment visit, and every 12 weeks for up to 2 years thereafter. Radiological response was assessed by investigators according to RECIST v1.1. Tumor evaluation had to be continued during the post-treatment period if withdrawal was not related to disease progression and should have been continued and documented every 8 weeks (or every 12 weeks after the first 12 months of treatment phase) until disease progression or initiation of an antineoplastic treatment. Adverse events (AEs) were recorded from the time of signature of informed consent, throughout the treatment period and including the follow-up period (30 days after the last administration of vinorelbine or for 90 days after the last administration of durvalumab and tremelimumab, whichever period was longer). AEs were graded according to the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0. Endpoints The primary endpoint of the phase II part of the MOVIE study was the clinical benefit rate (CBR) defined as the rate of complete response (CR), partial response (PR), or stabilized disease (SD) lasting at least 24 weeks according to RECIST. Secondary objectives included safety, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The assessment of safety rested on the frequency and severity of AEs based on the common toxicity criteria grade (NCI-CTCAE-V5.0), ORR as the percentage of CR or PR as the best response measured according to RECIST, DoR as the time period from documented tumor response (CR/PR) to disease progression by RECIST or death from any cause. PFS was measured from first administration of the combination immunotherapy until first documented progression by RECIST or death from any cause. OS was measured from first administration of the combination immunotherapy until death from any cause. For time-to-event endpoints, patients who had not experienced the event of interest at the time of analysis were censored at the time of last evaluation. Evaluation of PDL1 expression Formalin-Fixed Paraffin-Embedded tumor specimens were collected to monitor PD-L1 expression by immunohistochemistry using IHC 22C3 pharmDx assay (Agilent Technologies). The evaluation of PD-L1 expression was performed by independent pathologists, who were blinded to the clinicopathological data, including the therapeutic response and survival time. Statistical analysis The analysis of the primary endpoint (CBR) was carried out sequentially using a Bayesian approach with a beta-binomial model. Interim analyses were planned after a 24-week follow-up of the first 10 patients of each cohort and then every 5 patients until a maximum sample size of 30 patients. Inclusions were not suspended between interim analyses, except in case of an important accrual rate. The Bayesian approach was based on an update, at each interim analysis, of our baseline knowledge of the CBR, which was prior to the beginning of the study. Three “prior” probability models (distributions) for the CBR were defined in the protocol (1-a non-informative prior, 2-an informative optimistic prior centered on a CBR of 30%, and 3-a less informative optimistic prior centered on a CBR of 30%). A stopping criterion for inefficacity was also defined and stopping the prostate cohort could have been recommended if there was a high probability (≥ 0.75) that the estimated CBR was less than or equal to the futility bound p0 = 20%. ORR were presented with the associated 95% confidence intervals (CIs). PFS, OS, and DoR were estimated using the Kaplan-Meier method and described in terms of medians with the associated 95%CI. The analysis was performed on the full analysis set (FAS) population consisting of all included patients having received at least one cycle of study treatment or discontinued the treatment before the end of the first cycle for progression or toxicity (treatment failures) and no major protocol violation that could have biased primary endpoint evaluation. The safety analysis was performed on all patients having received at least one dose of the study drugs. RESULTS Patient characteristics Between February 2019 and March 2020, 15 patients were included in the prostate cohort of the MOVIE trial. Patient characteristics are described in Table 1. All the patients were considered for the efficacy and the safety analyses. The median age of the population was 73 years (range: 59–79). ECOG at baseline was 0 for 6 (40.0%) patients and 2 (13.3%) patients had gleason score > 8. All the patients had metastatic adenocarcinoma at inclusion. In total, 40.0% (n = 6) patients had visceral metastases at inclusion, and 46.7% (n = 7) patients prior prostatectomy. All patients were castration-resistant and median of previous metastatic lines was 4 (min-max: 1–6). Efficacy A swimmer plot of patient responses and a summary of the efficacy data are presented in Fig. 1 and Table 2. Among the FAS population, one patient was not evaluable for the Bayesian analysis (treatment stopped for toxicity after 2 months and no further evaluation was performed), one patient was in success (PR), and 13 patients were in failure. According to the prior distributions 1-(non-informative prior), 2-(informative optimistic prior), and 3-(less informative optimistic prior), CBR was respectively 12.5% (95% credible interval: 1.7–31.9), 14.0% (2.9–31.8), and 10.6% (1.1–28.8). Based on these distributions, there was a probability > 75% that the CBR was lower than the futility bound of 20% and the stopping criterion for inefficacy was met. Best overall response was PR for 1 patient, SD (< 24 weeks) for 4 (30.8%) patients, and PD for 8 (61.5%) patients including 1 death due to PD before any tumoral evaluation), leading to an ORR of 7.7%. DoR for the PR patient was 3.9 months. Median follow-up for PFS was 1.8 months (Q1-Q3: 0.9–2.8), PFS events were reported for 13 patients (11 progression and 2 deaths), and median PFS was 1.9 months (95%CI: 1.7–3.8; Supplementary Fig. 1). At data cut-off, median follow-up for OS was 5.7 months (Q1-Q3: 3.7–7.8) and 13 (86.7%) patients had died following disease progression (n = 11; 73.3%), one patient died from a treatment-related grade (G)5 AE (sepsis), and one for unknown reason (patient was in progression but had hemorrhagic stroke). Median OS was 5.4 months (95%CI: 2.4–12.2; Supplementary Fig. 2). Compliance and safety Median number of cycles administered was 2 (range: 1–8) for vinorelbine, 2 (1–5) for tremelimumab, and 2 (1–8) for durvalumab. At the time of the analysis, all the patients had definitely discontinued the study treatments due to disease progression (n = 9; 60.0%), toxicity (n = 5; 33.3%), and physician decision (n = 1; 6.7%). Out of 5 treatment-related toxicities leading to treatment discontinuations, one was vinorelbine- and ICI-related and 3 ICI-related, and one was due to concomitant disease. The summary of the AEs reported during the study in the prostate cohort is presented in Table 3. In the safety population, 40.0% patients reported at least one treatment-related G ≥ 3 AEs, 26.7% reported vinorelbine-related G ≥ 3 AEs and 33.3% ICI-related G ≥ 3 AEs. Most frequent vinorelbine- and ICI-related G ≥ 3 AEs were anemia (13.3%), and colitis (20.0%) and diarrhea (13.3%), respectively (Table 4). One AE resulting in death (sepsis) were considered related to all the treatments of the study according to the investigator. PD-L1 expression Among the 13 patients analyzed for PD-L1 expression, 92.3% (n = 12) were PD-L1 CPS < 1. The one patient with CPS ≥ 20 had a progressive disease from C2. The patient who experienced a partial response was not evaluable for PD-L1. DISCUSSION In the MOVIE trial, dual blockade of PD-L1 and CTLA-4 pathways with durvalumab and tremelimumab combined to metronomic vinorelbine was intended to improve efficacy by modifying the tumor microenvironment and enhancing tumor immunogenicity. The association was explored in five different cohorts of advanced solid tumors. Here, we report the results obtained during phase 2 in the prostate cohort. With a CBR of 12.5% and an ORR of 7.7%, these results underscore the difficulty of achieving significant anti-tumor activity in advanced PC using ICI. They align with historical reports where ORR were ranging from 0–5% for anti-PD-(L)1 or anti-CTLA-4 used as single agents [7 8 22 23]. A single-arm pilot study (NCT03204812) of durvalumab plus tremelimumab combination also demonstrated an ORR of 5% in mCRPC patients with evidence of metastatic disease to the bone [ 24 ]. Remarkably, preliminary results from the phase 2 Checkmate 650 (NCT02985957) study reported a better effect of the dual blockade of the PD-L1 and CTLA-4 pathways with nivolumab and ipilimumab, and ORR of 25% and 10% in pre- and post-chemotherapy cohorts, respectively [ 25 ]. It is typical in mCRPC trials to distinguish such cohorts, as differential outcomes are observed in patients receiving treatment before or after chemotherapy. Of note, the NCT03204812 study tested the durvalumab plus tremelimumab in chemotherapy-naive mCRPC patients, while in MOVIE, the association of the same ICI combination with vinorelbine may have given a therapeutic advantage to the heavily pre-treated advanced PC patients. The use of vinorelbine as monotherapy has formerly demonstrated safety and durable clinical benefit, such as improvement in pain and performance status, in PC [26 27]. Here, to ensure fewest toxic effects as it was combined to two immune agents, and indirectly boost immunomodulation, vinorelbine was given in metronomic schedules. Metronomic vinorelbine has previously shown favorable activity and a low toxicity profile in association with dexamethasone in mCRPC patients [ 19 ]. However, despite its theoretical advantage over a maximum tolerated dose approach, in the elderly and heavily pre-treated MOVIE prostate patients, its combination to durvalumab plus tremelimumab demonstrated limited improvement in clinical outcomes, with a median PFS of 1.9 months and median OS of 5.4 months. Our data suggest that while MCT may modulate the tumor microenvironment, it might not be sufficient to entirely overcome the robust immunosuppressive mechanisms in this setting. PC have a relatively "cold" immune environment characterized by a lack of immune cell infiltration necessary for ICI to be effective, and phase 3 key clinical trials have failed to show a significant improvement in unselected populations. For instance, the Keynote-921 (NCT03834506) study did not demonstrate an OS benefit of pembrolizumab (anti-PD-L1) in combination with docetaxel in chemotherapy-naive mCRPC patients [ 28 ]. Similarly, the Checkmate 7DX trial, assessing nivolumab plus docetaxel, did not meet the primary endpoint of PFS at final analysis [ 29 ]. Also, the Keynote-991 (NCT04191096) and IMbassador250 (NCT03016312) trials, which respectively assessed the activity of the androgen receptor enzalutamide with atezolizumab (anti-PD-L1) and pembrolizumab, did not show an improvement in terms of OS over control [30 31]. Nevertheless, emerging data suggest that some PC patients may benefit from ICI as monotherapy or in combination with other treatment modalities. For example, in the above mentioned study of durvalumab plus tremelimumab in chemotherapy-naive mCRPC patients with bone metastases (NCT03204812), a potential antitumor activity was reported in a specific subset [ 24 ]. Likewise, in the IMbassador250 trial, a pre-planned subgroup analysis showed superior PFS in tumors with high levels of PD-L1 expression or high levels of intra-tumoral CD8 + T-cell infiltration [ 31 ]. In line with these results, mCRPC patients with high intra-tumoral CD8 + T-cell density were shown to respond better to CTLA-4-targeting antibodies, indicating that enhanced CD8 + activation may offer clinical benefits [ 32 ]. Furthermore, a long-term follow-up study of mCRPC patients showed that ipilimumab may have the potential to generate durable responses and long-term survival with OS rates at 3, 4, and 5 years approximately two to three times higher than those in the control group [ 9 ]. Altogether, these data suggest that ICI is active in certain subtypes of PC that may harbor intrinsic or acquired vulnerabilities to immune checkpoint blockade. Interestingly, while PD-L1 was approved for the treatment of any type of tumor exhibiting high microsatellite instability (MSI), including PC in which it was associated with durable response [ 33 ], a phase 2 study reported potentially enhanced and durable response to pembrolizumab plus enzalutamide in specific subsets of men with mCRPC whose tumors appear to lack MSI, DNA-repair defects, or PD-L1 expression. Further research are needed to validate predictive biomarkers since their identification is a crucial key in determining which advanced PC patients may benefit from ICI [ 34 ]. In terms of safety, both ICI- and chemotherapy-related toxicities were observed in the MOVIE trial. Interestingly, although the incidence of colitis and diarrhea was increased with 20% and 13%, respectively, compared to 8% in the NCT03204812 study, likely due to the addition of chemotherapy to dual immunotherapy, the incidence of other AEs did not appear to occur at an increased rate and was consistent with previous observations, as was the incidence of treatment-related G ≥ 3 AEs (40%) [ 24 ]. However, one AE resulting in death was considered to be related to all the treatments and 4 discontinuations due to treatment-related AEs were reported. The toxicity was therefore more significant than in a previous trial where the combination was deemed safe and well tolerated in chemotherapy-naïve mCRPC patients [ 24 ]. Of note, the median age in the latter study was 68 (range: 48–89) years. MOVIE PC patients were elderly with a median age of 73 years (range: 59–79), heavily pre-treated (100% had prior chemotherapy), and potentially frailer with more comorbidities. In the MOVIE trial, patient demographics were not comparable and the prostate cohort consisted of older patients in whom drug-related toxicities may be more clinically relevant. The limitations of the MOVIE trial included the heterogeneous unselected study population and the small sample size having been designed as a basket study including different cohorts of advanced tumor types with various sensitivity to immunotherapy, to explore the efficacy and safety of MC with dual immunotherapy. In conclusion, despite the theoretical benefits of the MOVIE approach, the study outcomes highlighted the complexities of treating advanced PC with ICI, even when combined with MCT. The modest clinical benefits observed underscore the need for further research to overcome the inherent resistance of PC to immunotherapy. Future strategies may involve different combination therapies, the use of predictive biomarkers, and novel approaches to modulate the tumor microenvironment. Ongoing research will be critical in refining these approaches and improving outcomes for patients with advanced PC or in specific sub-populations that could benefit from immunotherapy. Declarations Funding This study was funded by the French Ministry of Health (PHRC-K_2016-078), La Ligue Nationale Contre le Cancer (no grant number), AstraZeneca [grant number #2018-00706/ESR-16-12287], and Pierre Fabre [grant number #2018-00603]. Competing interests EC is employed by Astra Zeneca since October 1 st , 2024, has received speaker and consultant honoraria from BMS, MSD, Janssen, Merck, Ipsen, Astra Zeneca, and Astellas, and has received support for attending meetings and/or travel from Pfizer, Astra Zeneca, Novartis, Ipsen, MSD, and Merck outside the submitted work. ESB has received grant from Merck and Astra Zeneca, speaker and consultant honoraria from Merck and MSD, and travel accommodation from Merck, Novartis, and MSD, outside the submitted work. TDLMR has received research funding from Seagen outside of the submitted work, and has received speaker and consultant honoraria from Abbvie, Astra Zeneca, GSK, Roche, Sanofi, Pfizer, Regeneron, Novartis, Gilead, Menarini, Eisai, and has received support for attending meeting and/or travel from MSD, Gilead, Pfizer, and Eisai outside of the submitted work. PL has received travel accommodation from IPSEN, Mundi Pharma, JANSSEN, Astellas, Pfizer, Sanofi, Daichi, and Takeda. PL has also received speaker and consultant Honoria from Astellas, AZ, Sanofi, BMS, and Takeda. DB has received grants from BMS and Pfizer, has received speaker and consultant honoraria from Accord HealthCare, Astellas, Astra-Zeneca, Bayer, BMS, Janssen, Ipsen, Merck, MSD, Novartis, and Pfizer, support for attending meetings and/or travel Astellas, Bayer, BMS, Janssen, Ipsen, MSD, Novartis, and Pfizer, outside the submitted work. LC has received support for attending meeting and/or travel from Janssen, Astellas, IPSEN, and BMS, and participated on a datasafety monitoring board or advisory board of BMS. GG has received research funding from BMS and Janssen outside of the submitted work. GG has received speaker honoraria from BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Sanofi, MSD, Ipsen, Astra Zeneca, Astellas, Eisai, Amgen, and Bayer outside of the submitted work. GG has also received support for attending meeting and/or travel from BMS, Janssen, Pfizer, MSD, Ipsen, Astra Zeneca, and Bayer, and declared participation on a Data Safety Monitoring Board or Advisory Board for BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Ipsen, Astra Zeneca, Eisai, and Bayer, outside the submitted work. AG has received research funding from Roche/Genentech, Astra Zeneca, Daiichi Sankyo, MSD, Gilead, and Novartis outside of the submitted work. AG has also received speaker and consultant honoraria from Novartis, Astra Zeneca, MSD, and Gilead outside of the submitted work. All other authors declare they have no relevant financial or non-financial interests to disclose. Author contributions AG was the principal investigator for the study. AG, EC, and Unicancer designed the trial. All the authors contributed to the acquisition, trial management, analysis, and interpretation of the data. All the authors had access and verified the underlying data in the study. ED wrote the article on behalf of Unicancer and all the other authors critically reviewed and revised the manuscript. Data Availability The datasets used and/or analyzed during the current study are available upon reasonable request addressed to the sponsor (Unicancer). Ethics approval and consent to participate The study was sponsored by Unicancer and conducted in the rigorous standards set out in the Good Clinical Practice guidelines and in accordance with the principles in the Declaration of Helsinki. The study protocol was approved by the French Ethical Committee CPP Sud-Méditerranée I and by the French regulatory authorities. Patients had to confirm their consent in writing before starting the study and before any study-related procedures. It is registered at ClinicalTrials.gov (identifier: NCT03518606). Consent to publish All authors approved the final version of the manuscript before submission. Acknowledgments: The authors thank the patients and their families as well as all of the investigators and their staff involved in the MOVIE trial. This work was funded by the French Ministry of Health, La Ligue Nationale Contre le Cancer, AstraZeneca, and Pierre Fabre. 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Curr Oncol 30(4):4246–4256. 10.3390/curroncol30040323 [published Online First: Epub Date]| Tables Table 1 : Patient and disease characteristics PROSTATE CANCER N=15 Age Median (min; max) 73 (59; 79) ECOG performance status at baseline; n (%) 0 6 (40.0%) 1 9 (60.0%) Disease status at inclusion Metastatic 15 (100.0%) Histologic type Adenocarcinoma 15 (100.0%) Gleason score ≤ 7 9 (60.0%) ≥ 8 3 (40.0%) Metastatic sites Lymphatic system 14 (93.3%) Bone 12 (80.0%) Lung 4 (26.7%) Liver 2 (13.3%) Other 4 (26.7%) Number of previous metastatic lines Mean (Std) 4.0 (1.8) Median (min; max) 4.0 (1.0; 6.0) Chemotherapy 15 (100.0%) Docetaxel 12 (80.0%) Carboplatin 2 (13.3%) Cabazitaxel 14 (93.3%) Other 15 (100.0%) Number of previous chemotherapy lines (metastatic setting) N 15 Mean (Std) 2.2 (1.0) Median (min ;max) 2.0 (0.0; 4.0) Androgen receptor pathway inhibitor (ARPI) 13 (86.7%) Abiraterone 13 (86.7%) Enzalutamide 12 (80.0%) Radiotherapy 12 (80.0%) Local radiotherapy 10 (66.7%) Radiotherapy at metastatic sites 6 (40.0%) Surgery 10 (66.7%) Prostatectomy 7 (46.7%) Other 6 (40.0%) Table 2 : Summary of efficacy endpoints Prostate cohort N=15 CBR (Bayesian estimation / Mean estimated success rate [95% credible interval]) Success* (CR+PR+SD≥24weeks) 1 / 15 Prior distribution 1 Prior non-informative distribution = beta (1,1) 12.5% [1.7% ; 31.9%] (p=0.83) Prior distribution 2 Prior informative optimistic distribution = beta (1.8-4.2) 14.0% [2.9% ; 31.8%] (p=0.80) Prior distribution 3 Prior less informative optimistic distribution = beta (0.75-1.75) 10.6% [1.1% ; 28.8%] (p=0.89) Best overall response (N [%]) PR 1 (7.7%) SD<24 weeks 4 (30.8%) PD** 8 (61.5%) Not evaluable 2*** ORR (CR+PR) 1 (7.7%) *The CBR was estimated based on a binary variable (success/failure) defined as follows: Success : Patients with CR or PR as best response status obtained until 24 weeks after inclusion Patients with SD as best response status obtained until 24 weeks after starting treatment: Success : If no RECIST progression, nor definite treatment discontinuation for progression or death at the time of the analysis, and the duration between inclusion and the last tumoral evaluation was ≥ 22 weeks. Success : If a RECIST progression occurred more than 26 weeks after inclusion. Failure : If a RECIST progression occurred within 26 weeks after inclusion. Failure : If treatment was discontinued for progression or death within 26 weeks after inclusion, and no tumoral evaluation performed after treatment discontinuation. Failure : Patients with Progressive Disease (PD) as best response status obtained until 24 weeks after inclusion Failure : Patients having definitely discontinued treatment for progression or death before any tumoral evaluation. **including 1 death from progressive disease before any planned tumoral evaluation ***2 patient did not have any tumoral evaluation (1 had treatment stopped following physician decision and died from PD, and 1 from intercurrent disease [sepsis]) Table 3 : Summary of AEs* Prostate cohort N=30 AEs 15 (100.0%) Vinorelbine-related AEs 11 (73.3%) ICI-related AEs 8 (53.3%) Treatment-related AEs 11 (73.3%) Grade ≥2 AEs 15 (100.0%) Grade ≥2 vinorelbine-related AEs 11 (73.3%) Grade ≥2 ICI-related AEs 8 (53.3%) Grade ≥2 treatment-related AEs 11 (73.3%) Grade ≥3 AEs 11 (73.3%) Grade ≥3 vinorelbine-related AEs 4 (26.7%) Grade ≥3 ICI-related AEs 5 (33.3%) Grade ≥3 treatment-related AEs 6 (40.0%) Grade ≥5 AEs 1 (6.7%) Grade ≥5 vinorelbine-related AEs 1 (6.7%) Grade ≥5 ICI-related AEs 1 (6.7%) Grade ≥5 treatment-related AEs 1 (6.7%) SAEs** 11 (73.3%) Vinorelbine-related SAEs 3 (20.0%) ICI-related SAEs 5 (33.3%) Treatment-related SAEs 6 (40.0%) *AEs = adverse events **SAEs = serious adverse events Table 4 : Description of treatment-related G≥2 AEs Prefer Term Name Grade max N=15 Vinorelbine-related G≥2 AEs Blood and lymphatic system disorders Anaemia Total 4 (26.7%) 2 2 (13.3%) 3 2 (13.3%) Febrile neutropenia Total 1 (6.7%) 3 1 (6.7%) Thrombocytopenia Total 1 (6.7%) 2 1 (6.7%) Gastrointestinal disorders Constipation Total 1 (6.7%) 2 1 (6.7%) Diarrhoea Total 1 (6.7%) 2 1 (6.7%) Dysphagia Total 1 (6.7%) 2 1 (6.7%) Nausea Total 4 (26.7%) 2 4 (26.7%) Vomiting Total 3 (20.0%) 2 3 (20.0%) General disorders and administration site conditions Asthenia Total 3 (20.0%) 2 3 (20.0%) Fatigue Total 2 (13.3%) 2 2 (13.3%) Gait disturbance Total 1 (6.7%) 2 1 (6.7%) Mucosal inflammation Total 1 (6.7%) 3 1 (6.7%) Infections and infestations Erysipelas Total 1 (6.7%) 2 1 (6.7%) Sepsis Total 1 (6.7%) 5 1 (6.7%) Investigations Blood creatinine increased Total 1 (6.7%) 2 1 (6.7%) Neutrophil count decreased Total 1 (6.7%) 2 1 (6.7%) Metabolism and nutrition disorders Acidosis Total 1 (6.7%) 2 1 (6.7%) Decreased appetite Total 4 (26.7%) 2 3 (20.0%) 3 1 (6.7%) Hypokalaemia Total 1 (6.7%) 3 1 (6.7%) Starvation Total 1 (6.7%) 2 1 (6.7%) Nervous system disorders Neuropathy peripheral Total 1 (6.7%) 2 1 (6.7%) Renal and urinary disorders Renal failure Total 2 (13.3%) 2 2 (13.3%) Skin and subcutaneous tissue disorders Rash Total 1 (6.7%) 2 1 (6.7%) ICI-related G≥2 AEs Gastrointestinal disorders Colitis Total 3 (20.0%) 3 3 (20.0%) Diarrhoea Total 3 (20.0%) 2 1 (6.7%) 3 2 (13.3%) Dysphagia Total 1 (6.7%) 2 1 (6.7%) Vomiting Total 1 (6.7%) 2 1 (6.7%) General disorders and administration site conditions Asthenia Total 3 (20.0%) 2 3 (20.0%) Fatigue Total 1 (6.7%) 2 1 (6.7%) Pyrexia Total 1 (6.7%) 2 1 (6.7%) Infections and infestations Sepsis Total 1 (6.7%) 5 1 (6.7%) Investigations Aspartate aminotransferase increased Total 1 (6.7%) 3 1 (6.7%) Blood creatinine increased Total 1 (6.7%) 2 1 (6.7%) Metabolism and nutrition disorders Acidosis Total 1 (6.7%) 2 1 (6.7%) Decreased appetite Total 2 (13.3%) 2 2 (13.3%) Hypokalaemia Total 1 (6.7%) 3 1 (6.7%) Renal and urinary disorders Renal failure Total 2 (13.3%) 2 2 (13.3%) Skin and subcutaneous tissus disorders Pruritis Total 1 (6.7%) 2 1 (6.7%) Additional Declarations Competing interest reported. EC is employed by Astra Zeneca since October 1st, 2024, has received speaker and consultant honoraria from BMS, MSD, Janssen, Merck, Ipsen, Astra Zeneca, and Astellas, and has received support for attending meetings and/or travel from Pfizer, Astra Zeneca, Novartis, Ipsen, MSD, and Merck outside the submitted work. ESB has received grant from Merck and Astra Zeneca, speaker and consultant honoraria from Merck and MSD, and travel accommodation from Merck, Novartis, and MSD, outside the submitted work. TDLMR has received research funding from Seagen outside of the submitted work, and has received speaker and consultant honoraria from Abbvie, Astra Zeneca, GSK, Roche, Sanofi, Pfizer, Regeneron, Novartis, Gilead, Menarini, Eisai, and has received support for attending meeting and/or travel from MSD, Gilead, Pfizer, and Eisai outside of the submitted work. PL has received travel accommodation from IPSEN, Mundi Pharma, JANSSEN, Astellas, Pfizer, Sanofi, Daichi, and Takeda. PL has also received speaker and consultant Honoria from Astellas, AZ, Sanofi, BMS, and Takeda. DB has received grants from BMS and Pfizer, has received speaker and consultant honoraria from Accord HealthCare, Astellas, Astra-Zeneca, Bayer, BMS, Janssen, Ipsen, Merck, MSD, Novartis, and Pfizer, support for attending meetings and/or travel Astellas, Bayer, BMS, Janssen, Ipsen, MSD, Novartis, and Pfizer, outside the submitted work. LC has received support for attending meeting and/or travel from Janssen, Astellas, IPSEN, and BMS, and participated on a datasafety monitoring board or advisory board of BMS. GG has received research funding from BMS and Janssen outside of the submitted work. GG has received speaker honoraria from BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Sanofi, MSD, Ipsen, Astra Zeneca, Astellas, Eisai, Amgen, and Bayer outside of the submitted work. GG has also received support for attending meeting and/or travel from BMS, Janssen, Pfizer, MSD, Ipsen, Astra Zeneca, and Bayer, and declared participation on a Data Safety Monitoring Board or Advisory Board for BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Ipsen, Astra Zeneca, Eisai, and Bayer, outside the submitted work. AG has received research funding from Roche/Genentech, Astra Zeneca, Daiichi Sankyo, MSD, Gilead, and Novartis outside of the submitted work. AG has also received speaker and consultant honoraria from Novartis, Astra Zeneca, MSD, and Gilead outside of the submitted work. All other authors declare they have no relevant financial or non-financial interests to disclose. 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EC is employed by Astra Zeneca since October 1st, 2024, has received speaker and consultant honoraria from BMS, MSD, Janssen, Merck, Ipsen, Astra Zeneca, and Astellas, and has received support for attending meetings and/or travel from Pfizer, Astra Zeneca, Novartis, Ipsen, MSD, and Merck outside the submitted work. ESB has received grant from Merck and Astra Zeneca, speaker and consultant honoraria from Merck and MSD, and travel accommodation from Merck, Novartis, and MSD, outside the submitted work. TDLMR has received research funding from Seagen outside of the submitted work, and has received speaker and consultant honoraria from Abbvie, Astra Zeneca, GSK, Roche, Sanofi, Pfizer, Regeneron, Novartis, Gilead, Menarini, Eisai, and has received support for attending meeting and/or travel from MSD, Gilead, Pfizer, and Eisai outside of the submitted work. PL has received travel accommodation from IPSEN, Mundi Pharma, JANSSEN, Astellas, Pfizer, Sanofi, Daichi, and Takeda. PL has also received speaker and consultant Honoria from Astellas, AZ, Sanofi, BMS, and Takeda. DB has received grants from BMS and Pfizer, has received speaker and consultant honoraria from Accord HealthCare, Astellas, Astra-Zeneca, Bayer, BMS, Janssen, Ipsen, Merck, MSD, Novartis, and Pfizer, support for attending meetings and/or travel Astellas, Bayer, BMS, Janssen, Ipsen, MSD, Novartis, and Pfizer, outside the submitted work. LC has received support for attending meeting and/or travel from Janssen, Astellas, IPSEN, and BMS, and participated on a datasafety monitoring board or advisory board of BMS. GG has received research funding from BMS and Janssen outside of the submitted work. GG has received speaker honoraria from BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Sanofi, MSD, Ipsen, Astra Zeneca, Astellas, Eisai, Amgen, and Bayer outside of the submitted work. GG has also received support for attending meeting and/or travel from BMS, Janssen, Pfizer, MSD, Ipsen, Astra Zeneca, and Bayer, and declared participation on a Data Safety Monitoring Board or Advisory Board for BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Ipsen, Astra Zeneca, Eisai, and Bayer, outside the submitted work. AG has received research funding from Roche/Genentech, Astra Zeneca, Daiichi Sankyo, MSD, Gilead, and Novartis outside of the submitted work. AG has also received speaker and consultant honoraria from Novartis, Astra Zeneca, MSD, and Gilead outside of the submitted work. All other authors declare they have no relevant financial or non-financial interests to disclose.","formattedTitle":"Metronomic vinorelbine combined with durvalumab plus tremelimumab dual immunotherapy in patients with metastatic prostate cancer","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eIn 2022, prostate cancer (PC) was the fourth most common cancer and the eighth leading cause of cancer death worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It remains a significant clinical challenge, particularly in its castration resistant form, when traditional therapeutic options fail to provide long-term control. Indeed, while androgen deprivation therapy, chemotherapy, androgen receptor pathway inhibitors, PARP inhibitors, and radioligand therapy can initially suppress tumor growth and prolong survival, they are often limited by the development of resistance, leading to disease progression and suboptimal long-term outcomes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, immune checkpoint inhibitors (ICI) have revolutionized the treatment of several malignancies [3 4]. These agents, which target key immune regulatory pathways such as the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) axis and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), have demonstrated the ability to generate potent anti-tumor immune responses by overcoming tumor-induced immunosuppression [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In PC, the role of ICI has yet to be clarified, especially since PC is typically considered a \"cold\" tumor due to its low mutational burden, low number of neoantigens, and limited immune infiltration [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Blockade of PD-1 with nivolumab or pembrolizumab in patients with metastatic castration-resistant PC (mCRPC) demonstrated no significant clinical benefits indicating that using PD-1 inhibitors as single agents are inadequate for treating advanced PC cases [7 8]. Also, ipilimumab, an anti-CTLA-4, showed no improvement in terms of objective response rate combined to radiotherapy in mCRPC patients and in patients who had previously undergone chemotherapy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Similarly, two phase-3 trials evaluating ipilimumab versus placebo in patients with docetaxel-resistant (CA184-043) and chemotherapy-na\u0026iuml;ve mCRPC (CA184-095) failed to improve overall survival (OS) [10 11]. Since ICI monotherapy is being modestly effective in these tumors, combination therapies that pair anti-PD-L1 with anti-CTLA-4 and immunotherapy with other modalities, are currently being explored in an effort to boost the immune response against PC.\u003c/p\u003e \u003cp\u003eIn search of alternatives cancer strategies, the use of metronomic chemotherapy (MCT) has also been investigated with some success in advanced tumors. MCT, which consists in the administration of low-dose chemotherapy at regular, frequent intervals, without interruption, was initially designed to target tumor angiogenesis, exploiting the extreme sensitivity of rapidly renewing endothelial cells in growing tumors. However, immunomodulation also occurs, shifting the immunological balance from immunosuppression to immunostimulation through various mechanisms including induction of immunogenic cell death, enhancement of antigen-presentation by modulation of dendritic cells, increased immunogenicity of cancer cells, depletion of regulatory T cells, enhancement of the cytotoxic activity of immune effector cells, such as tumor-specific T cells and γδT cells [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Notably, MCT induces less acquired therapeutic resistance and its lower toxicity profile allows for longer treatment durations [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Several chemotherapeutic agents, alone or in combination with various targeted therapies, have been evaluated using metronomic schedules in solid tumors [17 18]. Among the MCT tested, metronomic vinorelbine has demonstrated a low toxicity profile with some anti-tumoral activity in mCRPC [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Combine to ICI, it may have the potential to improve patient outcomes by synergistically enhancing both the direct anti-tumor effects of chemotherapy and the immune-mediated tumor destruction achieved through checkpoint inhibition [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, the MOVIE trial was designed to assess the antitumor activity and safety of metronomic oral vinorelbine combined to anti-PD-L1 durvalumab and anti-CTLA-4 tremelimumab dual immunotherapy. MOVIE was a phase 1/2 multiple cohort study, and we present herein the results obtained in the prostate cohort during the phase 2 part of the trial.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThe MOVIE trial was a phase 1/2, multiple cohort, French, multicentre, open-label, non-randomised and non-comparative study that aimed to evaluate the activity and safety of metronomic oral vinorelbine with durvalumab plus tremelimumab in patients with advanced solid tumors including head and neck, prostate, cervix, breast cancers, as well as miscellaneous malignancies with high mutational load and/or MSI-High. The study was divided into two successive parts: a phase 1 dose-escalation expanded to a phase 2 to assess the activity and safety of the combination under the previously defined Recommended Phase II Dose (RP2D). MOVIE phase 1 was conducted from July 2018 to May 2019 and results were previously reported [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Patients treated at RP2D during phase 1 were considered evaluable for phase 2.\u003c/p\u003e \u003cp\u003ePatients included in the prostate cohort were men\u0026thinsp;\u0026ge;\u0026thinsp;18 years old with histologically confirmed locally advanced or metastatic prostate tumors, resistant to conventional therapies, and candidate to experimental therapy according to local clinical board. Eligible patients were required to have a measurable disease by RECIST v1.1, an Eastern Cooperative Oncology Group (ECOG) performance status (PS)\u0026thinsp;\u0026le;\u0026thinsp;1, normal hematological (ANC\u0026thinsp;\u0026ge;\u0026thinsp;1.5 x 10\u003csup\u003e9\u003c/sup\u003e/L; platelets count\u0026thinsp;\u0026ge;\u0026thinsp;100 x 10\u003csup\u003e9\u003c/sup\u003e/L; hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;9.0 g/dL), hepatic (total bilirubin\u0026thinsp;\u0026le;\u0026thinsp;1.5 upper limit of normal [ULN] unless documented Gilbert\u0026rsquo;s syndrome; ASAT and ALAT\u0026thinsp;\u0026le;\u0026thinsp;2.5 ULN / \u0026le;5 ULN in the presence of liver metastases), and cardiac functions (LVEF\u0026thinsp;\u0026ge;\u0026thinsp;50%), measured creatinine clearance (Cockcroft and Gault)\u0026thinsp;\u0026ge;\u0026thinsp;40 mL/min or creatinine\u0026thinsp;\u0026le;\u0026thinsp;1.5 times ULN, and an estimated life expectancy of at least 3 months. Key exclusion criteria included other concurrent malignancies, active brain metastases, spinal cord compression, or leptomeningeal disease (except local meningeal disease due to local recurrence), previous treatment with an anti-PD-(L)1 antibody or an anti-CTLA-4 therapy or vinorelbine (in advanced settings), current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab, prior anticancer therapy within the last 3 weeks, major surgery within 28 days prior to the first dose of study treatment, and participation in another clinical trial with an investigational product within 21 days of inclusion.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003eRP2D was defined during the phase I of the MOVIE study at oral vinorelbine 40mg three times a week (3QW), and durvalumab 1500mg plus tremelimumab 75mg via intravenous infusion at day 1 of 28-day cycles (Q4W) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Patients received vinorelbine until disease progression, and up to 26 cycles of durvalumab and 4 cycles of tremelimumab. Dose reductions of durvalumab and tremelimumab were not permitted. Vinorelbine could be reduced to 30mg then 20mg. Patients were treated until progression of their disease, unacceptable toxicity, intercurrent conditions that precluded continuation of treatment, or patient refusal. During durvalumab plus tremelimumab combination, dose interruptions always applied to both compounds. Clinical disease and radiologic assessments were performed at baseline, at D28 every 2 cycles during treatment phase, then at the end of treatment visit, and every 12 weeks for up to 2 years thereafter. Radiological response was assessed by investigators according to RECIST v1.1. Tumor evaluation had to be continued during the post-treatment period if withdrawal was not related to disease progression and should have been continued and documented every 8 weeks (or every 12 weeks after the first 12 months of treatment phase) until disease progression or initiation of an antineoplastic treatment. Adverse events (AEs) were recorded from the time of signature of informed consent, throughout the treatment period and including the follow-up period (30 days after the last administration of vinorelbine or for 90 days after the last administration of durvalumab and tremelimumab, whichever period was longer). AEs were graded according to the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of the phase II part of the MOVIE study was the clinical benefit rate (CBR) defined as the rate of complete response (CR), partial response (PR), or stabilized disease (SD) lasting at least 24 weeks according to RECIST. Secondary objectives included safety, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The assessment of safety rested on the frequency and severity of AEs based on the common toxicity criteria grade (NCI-CTCAE-V5.0), ORR as the percentage of CR or PR as the best response measured according to RECIST, DoR as the time period from documented tumor response (CR/PR) to disease progression by RECIST or death from any cause. PFS was measured from first administration of the combination immunotherapy until first documented progression by RECIST or death from any cause. OS was measured from first administration of the combination immunotherapy until death from any cause. For time-to-event endpoints, patients who had not experienced the event of interest at the time of analysis were censored at the time of last evaluation.\u003c/p\u003e\n\u003ch3\u003eEvaluation of PDL1 expression\u003c/h3\u003e\n\u003cp\u003eFormalin-Fixed Paraffin-Embedded tumor specimens were collected to monitor PD-L1 expression by immunohistochemistry using IHC 22C3 pharmDx assay (Agilent Technologies). The evaluation of PD-L1 expression was performed by independent pathologists, who were blinded to the clinicopathological data, including the therapeutic response and survival time.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe analysis of the primary endpoint (CBR) was carried out sequentially using a Bayesian approach with a beta-binomial model. Interim analyses were planned after a 24-week follow-up of the first 10 patients of each cohort and then every 5 patients until a maximum sample size of 30 patients. Inclusions were not suspended between interim analyses, except in case of an important accrual rate. The Bayesian approach was based on an update, at each interim analysis, of our baseline knowledge of the CBR, which was prior to the beginning of the study. Three \u0026ldquo;prior\u0026rdquo; probability models (distributions) for the CBR were defined in the protocol (1-a non-informative prior, 2-an informative optimistic prior centered on a CBR of 30%, and 3-a less informative optimistic prior centered on a CBR of 30%). A stopping criterion for inefficacity was also defined and stopping the prostate cohort could have been recommended if there was a high probability (\u0026ge;\u0026thinsp;0.75) that the estimated CBR was less than or equal to the futility bound p0\u0026thinsp;=\u0026thinsp;20%. ORR were presented with the associated 95% confidence intervals (CIs). PFS, OS, and DoR were estimated using the Kaplan-Meier method and described in terms of medians with the associated 95%CI. The analysis was performed on the full analysis set (FAS) population consisting of all included patients having received at least one cycle of study treatment or discontinued the treatment before the end of the first cycle for progression or toxicity (treatment failures) and no major protocol violation that could have biased primary endpoint evaluation. The safety analysis was performed on all patients having received at least one dose of the study drugs.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eBetween February 2019 and March 2020, 15 patients were included in the prostate cohort of the MOVIE trial. Patient characteristics are described in Table\u0026nbsp;1. All the patients were considered for the efficacy and the safety analyses. The median age of the population was 73 years (range: 59\u0026ndash;79). ECOG at baseline was 0 for 6 (40.0%) patients and 2 (13.3%) patients had gleason score\u0026thinsp;\u0026gt;\u0026thinsp;8. All the patients had metastatic adenocarcinoma at inclusion. In total, 40.0% (n\u0026thinsp;=\u0026thinsp;6) patients had visceral metastases at inclusion, and 46.7% (n\u0026thinsp;=\u0026thinsp;7) patients prior prostatectomy. All patients were castration-resistant and median of previous metastatic lines was 4 (min-max: 1\u0026ndash;6).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eA swimmer plot of patient responses and a summary of the efficacy data are presented in Fig.\u0026nbsp;1 and Table\u0026nbsp;2. Among the FAS population, one patient was not evaluable for the Bayesian analysis (treatment stopped for toxicity after 2 months and no further evaluation was performed), one patient was in success (PR), and 13 patients were in failure. According to the prior distributions 1-(non-informative prior), 2-(informative optimistic prior), and 3-(less informative optimistic prior), CBR was respectively 12.5% (95% credible interval: 1.7\u0026ndash;31.9), 14.0% (2.9\u0026ndash;31.8), and 10.6% (1.1\u0026ndash;28.8). Based on these distributions, there was a probability\u0026thinsp;\u0026gt;\u0026thinsp;75% that the CBR was lower than the futility bound of 20% and the stopping criterion for inefficacy was met. Best overall response was PR for 1 patient, SD (\u0026lt;\u0026thinsp;24 weeks) for 4 (30.8%) patients, and PD for 8 (61.5%) patients including 1 death due to PD before any tumoral evaluation), leading to an ORR of 7.7%. DoR for the PR patient was 3.9 months. Median follow-up for PFS was 1.8 months (Q1-Q3: 0.9\u0026ndash;2.8), PFS events were reported for 13 patients (11 progression and 2 deaths), and median PFS was 1.9 months (95%CI: 1.7\u0026ndash;3.8; Supplementary Fig.\u0026nbsp;1). At data cut-off, median follow-up for OS was 5.7 months (Q1-Q3: 3.7\u0026ndash;7.8) and 13 (86.7%) patients had died following disease progression (n\u0026thinsp;=\u0026thinsp;11; 73.3%), one patient died from a treatment-related grade (G)5 AE (sepsis), and one for unknown reason (patient was in progression but had hemorrhagic stroke). Median OS was 5.4 months (95%CI: 2.4\u0026ndash;12.2; Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCompliance and safety\u003c/h2\u003e \u003cp\u003eMedian number of cycles administered was 2 (range: 1\u0026ndash;8) for vinorelbine, 2 (1\u0026ndash;5) for tremelimumab, and 2 (1\u0026ndash;8) for durvalumab. At the time of the analysis, all the patients had definitely discontinued the study treatments due to disease progression (n\u0026thinsp;=\u0026thinsp;9; 60.0%), toxicity (n\u0026thinsp;=\u0026thinsp;5; 33.3%), and physician decision (n\u0026thinsp;=\u0026thinsp;1; 6.7%). Out of 5 treatment-related toxicities leading to treatment discontinuations, one was vinorelbine- and ICI-related and 3 ICI-related, and one was due to concomitant disease. The summary of the AEs reported during the study in the prostate cohort is presented in Table\u0026nbsp;3. In the safety population, 40.0% patients reported at least one treatment-related G\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs, 26.7% reported vinorelbine-related G\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs and 33.3% ICI-related G\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs. Most frequent vinorelbine- and ICI-related G\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs were anemia (13.3%), and colitis (20.0%) and diarrhea (13.3%), respectively (Table\u0026nbsp;4). One AE resulting in death (sepsis) were considered related to all the treatments of the study according to the investigator.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePD-L1 expression\u003c/h2\u003e \u003cp\u003eAmong the 13 patients analyzed for PD-L1 expression, 92.3% (n\u0026thinsp;=\u0026thinsp;12) were PD-L1 CPS\u0026thinsp;\u0026lt;\u0026thinsp;1. The one patient with CPS\u0026thinsp;\u0026ge;\u0026thinsp;20 had a progressive disease from C2. The patient who experienced a partial response was not evaluable for PD-L1.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn the MOVIE trial, dual blockade of PD-L1 and CTLA-4 pathways with durvalumab and tremelimumab combined to metronomic vinorelbine was intended to improve efficacy by modifying the tumor microenvironment and enhancing tumor immunogenicity. The association was explored in five different cohorts of advanced solid tumors. Here, we report the results obtained during phase 2 in the prostate cohort. With a CBR of 12.5% and an ORR of 7.7%, these results underscore the difficulty of achieving significant anti-tumor activity in advanced PC using ICI. They align with historical reports where ORR were ranging from 0\u0026ndash;5% for anti-PD-(L)1 or anti-CTLA-4 used as single agents [7 8 22 23]. A single-arm pilot study (NCT03204812) of durvalumab plus tremelimumab combination also demonstrated an ORR of 5% in mCRPC patients with evidence of metastatic disease to the bone [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Remarkably, preliminary results from the phase 2 Checkmate 650 (NCT02985957) study reported a better effect of the dual blockade of the PD-L1 and CTLA-4 pathways with nivolumab and ipilimumab, and ORR of 25% and 10% in pre- and post-chemotherapy cohorts, respectively [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. It is typical in mCRPC trials to distinguish such cohorts, as differential outcomes are observed in patients receiving treatment before or after chemotherapy. Of note, the NCT03204812 study tested the durvalumab plus tremelimumab in chemotherapy-naive mCRPC patients, while in MOVIE, the association of the same ICI combination with vinorelbine may have given a therapeutic advantage to the heavily pre-treated advanced PC patients. The use of vinorelbine as monotherapy has formerly demonstrated safety and durable clinical benefit, such as improvement in pain and performance status, in PC [26 27]. Here, to ensure fewest toxic effects as it was combined to two immune agents, and indirectly boost immunomodulation, vinorelbine was given in metronomic schedules. Metronomic vinorelbine has previously shown favorable activity and a low toxicity profile in association with dexamethasone in mCRPC patients [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, despite its theoretical advantage over a maximum tolerated dose approach, in the elderly and heavily pre-treated MOVIE prostate patients, its combination to durvalumab plus tremelimumab demonstrated limited improvement in clinical outcomes, with a median PFS of 1.9 months and median OS of 5.4 months. Our data suggest that while MCT may modulate the tumor microenvironment, it might not be sufficient to entirely overcome the robust immunosuppressive mechanisms in this setting.\u003c/p\u003e \u003cp\u003e PC have a relatively \"cold\" immune environment characterized by a lack of immune cell infiltration necessary for ICI to be effective, and phase 3 key clinical trials have failed to show a significant improvement in unselected populations. For instance, the Keynote-921 (NCT03834506) study did not demonstrate an OS benefit of pembrolizumab (anti-PD-L1) in combination with docetaxel in chemotherapy-naive mCRPC patients [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Similarly, the Checkmate 7DX trial, assessing nivolumab plus docetaxel, did not meet the primary endpoint of PFS at final analysis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Also, the Keynote-991 (NCT04191096) and IMbassador250 (NCT03016312) trials, which respectively assessed the activity of the androgen receptor enzalutamide with atezolizumab (anti-PD-L1) and pembrolizumab, did not show an improvement in terms of OS over control [30 31]. Nevertheless, emerging data suggest that some PC patients may benefit from ICI as monotherapy or in combination with other treatment modalities. For example, in the above mentioned study of durvalumab plus tremelimumab in chemotherapy-naive mCRPC patients with bone metastases (NCT03204812), a potential antitumor activity was reported in a specific subset [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Likewise, in the IMbassador250 trial, a pre-planned subgroup analysis showed superior PFS in tumors with high levels of PD-L1 expression or high levels of intra-tumoral CD8\u0026thinsp;+\u0026thinsp;T-cell infiltration [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In line with these results, mCRPC patients with high intra-tumoral CD8\u0026thinsp;+\u0026thinsp;T-cell density were shown to respond better to CTLA-4-targeting antibodies, indicating that enhanced CD8\u0026thinsp;+\u0026thinsp;activation may offer clinical benefits [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Furthermore, a long-term follow-up study of mCRPC patients showed that ipilimumab may have the potential to generate durable responses and long-term survival with OS rates at 3, 4, and 5 years approximately two to three times higher than those in the control group [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Altogether, these data suggest that ICI is active in certain subtypes of PC that may harbor intrinsic or acquired vulnerabilities to immune checkpoint blockade. Interestingly, while PD-L1 was approved for the treatment of any type of tumor exhibiting high microsatellite instability (MSI), including PC in which it was associated with durable response [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], a phase 2 study reported potentially enhanced and durable response to pembrolizumab plus enzalutamide in specific subsets of men with mCRPC whose tumors appear to lack MSI, DNA-repair defects, or PD-L1 expression. Further research are needed to validate predictive biomarkers since their identification is a crucial key in determining which advanced PC patients may benefit from ICI [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn terms of safety, both ICI- and chemotherapy-related toxicities were observed in the MOVIE trial. Interestingly, although the incidence of colitis and diarrhea was increased with 20% and 13%, respectively, compared to 8% in the NCT03204812 study, likely due to the addition of chemotherapy to dual immunotherapy, the incidence of other AEs did not appear to occur at an increased rate and was consistent with previous observations, as was the incidence of treatment-related G\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs (40%) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, one AE resulting in death was considered to be related to all the treatments and 4 discontinuations due to treatment-related AEs were reported. The toxicity was therefore more significant than in a previous trial where the combination was deemed safe and well tolerated in chemotherapy-na\u0026iuml;ve mCRPC patients [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Of note, the median age in the latter study was 68 (range: 48\u0026ndash;89) years. MOVIE PC patients were elderly with a median age of 73 years (range: 59\u0026ndash;79), heavily pre-treated (100% had prior chemotherapy), and potentially frailer with more comorbidities. In the MOVIE trial, patient demographics were not comparable and the prostate cohort consisted of older patients in whom drug-related toxicities may be more clinically relevant.\u003c/p\u003e \u003cp\u003eThe limitations of the MOVIE trial included the heterogeneous unselected study population and the small sample size having been designed as a basket study including different cohorts of advanced tumor types with various sensitivity to immunotherapy, to explore the efficacy and safety of MC with dual immunotherapy.\u003c/p\u003e \u003cp\u003eIn conclusion, despite the theoretical benefits of the MOVIE approach, the study outcomes highlighted the complexities of treating advanced PC with ICI, even when combined with MCT. The modest clinical benefits observed underscore the need for further research to overcome the inherent resistance of PC to immunotherapy. Future strategies may involve different combination therapies, the use of predictive biomarkers, and novel approaches to modulate the tumor microenvironment. Ongoing research will be critical in refining these approaches and improving outcomes for patients with advanced PC or in specific sub-populations that could benefit from immunotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the French Ministry of Health (PHRC-K_2016-078), La Ligue Nationale Contre le Cancer (no grant number), AstraZeneca [grant number #2018-00706/ESR-16-12287], and Pierre Fabre [grant number #2018-00603].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEC is employed by Astra Zeneca since October 1\u003csup\u003est\u003c/sup\u003e, 2024, has received speaker and consultant honoraria from BMS, MSD, Janssen, Merck, Ipsen, Astra Zeneca, and Astellas, and has received support for attending meetings and/or travel from Pfizer, Astra Zeneca, Novartis, Ipsen, MSD, and Merck outside the submitted work. ESB has received grant from Merck and Astra Zeneca, speaker and consultant honoraria from Merck and MSD, and travel accommodation from Merck, Novartis, and MSD, outside the submitted work. TDLMR has received research funding from Seagen outside of the submitted work, and has received speaker and consultant honoraria from Abbvie, Astra Zeneca, GSK, Roche, Sanofi, Pfizer, Regeneron, Novartis, Gilead, Menarini, Eisai, and has received support for attending meeting and/or travel from MSD, Gilead, Pfizer, and Eisai outside of the submitted work. PL has received travel accommodation from IPSEN, Mundi Pharma, JANSSEN, Astellas, Pfizer, Sanofi, Daichi, and Takeda. PL has also received speaker and consultant Honoria from Astellas, AZ, Sanofi, BMS, and Takeda. DB has received grants from BMS and Pfizer, has received speaker and consultant honoraria from Accord HealthCare, Astellas, Astra-Zeneca, Bayer, BMS, Janssen, Ipsen, Merck, MSD, Novartis, and Pfizer, support for attending meetings and/or travel Astellas, Bayer, BMS, Janssen, Ipsen, MSD, Novartis, and Pfizer, outside the submitted work. LC has received support for attending meeting and/or travel from Janssen, Astellas, IPSEN, and BMS, and participated on a datasafety monitoring board or advisory board of BMS. GG has received research funding from BMS and Janssen outside of the submitted work. GG has received speaker honoraria from BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Sanofi, MSD, Ipsen, Astra Zeneca, Astellas, Eisai, Amgen, and Bayer outside of the submitted work. GG has also received support for attending meeting and/or travel from BMS, Janssen, Pfizer, MSD, Ipsen, Astra Zeneca, and Bayer, and declared participation on a Data Safety Monitoring Board or Advisory Board for BMS, Janssen, Pfizer, Alliance Merck-Pfizer, AAA, Ipsen, Astra Zeneca, Eisai, and Bayer, outside the submitted work. AG has received research funding from Roche/Genentech, Astra Zeneca, Daiichi Sankyo, MSD, Gilead, and Novartis outside of the submitted work. AG has also received speaker and consultant honoraria from Novartis, Astra Zeneca, MSD, and Gilead outside of the submitted work. All other authors declare they have no relevant financial or non-financial interests to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAG was the principal investigator for the study. AG, EC, and Unicancer designed the trial. All the authors contributed to the acquisition, trial management, analysis, and interpretation of the data. All the authors had access and verified the underlying data in the study. ED wrote the article on behalf of Unicancer and all the other authors critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available upon reasonable request addressed to the sponsor (Unicancer).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was sponsored by Unicancer and conducted in the rigorous standards set out in the Good Clinical Practice guidelines and in accordance with the principles in the Declaration of Helsinki. The study protocol was approved by the French Ethical Committee CPP Sud-M\u0026eacute;diterran\u0026eacute;e I and by the French regulatory authorities. Patients had to confirm their consent in writing before starting the study and before any study-related procedures. It is registered at ClinicalTrials.gov (identifier: NCT03518606).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors approved the final version of the manuscript before submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe authors thank the patients and their families as well as all of the investigators and their staff involved in the MOVIE trial. This work was funded by the French Ministry of Health, La Ligue Nationale Contre le Cancer, AstraZeneca, and Pierre Fabre.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229\u0026ndash;263 [published Online First: Epub Date]|\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtiq M, Chandran E, Karzai F, Madan RA, Aragon-Ching JB (2023) Emerging treatment options for prostate cancer. Expert Rev Anticancer Ther 23(6):625\u0026ndash;631 [published Online First: Epub Date]|\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrivas P, Monk BJ, Petrylak D et al (2019) Immune Checkpoint Inhibitors as Switch or Continuation Maintenance Therapy in Solid Tumors: Rationale and Current State. 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J Immunother Cancer 8(2). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/jitc-2020-001065\u003c/span\u003e\u003cspan address=\"10.1136/jitc-2020-001065\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e[published Online First: Epub Date]|\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanka SM, Zorko NA, Antonarakis ES, Barata PC (2023) Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond. Curr Oncol 30(4):4246\u0026ndash;4256. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/curroncol30040323\u003c/span\u003e\u003cspan address=\"10.3390/curroncol30040323\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e[published Online First: Epub Date]|\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e: Patient and disease characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePROSTATE CANCER\u003c/p\u003e\n \u003cp\u003eN=15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Median (min; max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e73\u0026nbsp;(59;\u0026nbsp;79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eECOG performance status at baseline; n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDisease status at inclusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Metastatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHistologic type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGleason score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026le; 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u0026ge; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eMetastatic sites\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Lymphatic system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e(93.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e(80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e(26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e(26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of previous metastatic lines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Mean (Std)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Median (min; max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(1.0;\u0026nbsp;6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Docetaxel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Cabazitaxel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(93.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of previous chemotherapy lines (metastatic setting)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Mean (Std)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Median (min ;max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(0.0; 4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAndrogen receptor pathway inhibitor (ARPI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(86.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Abiraterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(86.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Enzalutamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRadiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Local radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Radiotherapy at metastatic sites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Prostatectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;: Summary of efficacy endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProstate cohort\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 604px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCBR\u003c/strong\u003e (Bayesian estimation / Mean estimated success rate [95% credible interval])\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003eSuccess* (CR+PR+SD\u0026ge;24weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e1 / 15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Prior distribution 1\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ePrior non-informative distribution = beta (1,1)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 232px;\"\u003e\n \u003cp\u003e12.5% [1.7% ; 31.9%] (p=0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Prior distribution 2\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ePrior informative optimistic distribution = beta (1.8-4.2)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 232px;\"\u003e\n \u003cp\u003e14.0% [2.9% ; 31.8%] (p=0.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Prior distribution 3\u003c/p\u003e\n \u003cp\u003e\u003cem\u003ePrior less informative optimistic distribution = beta (0.75-1.75)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 232px;\"\u003e\n \u003cp\u003e10.6% [1.1% ; 28.8%] (p=0.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBest overall response\u0026nbsp;\u003c/strong\u003e(N [%])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; PR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e1 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; SD\u0026lt;24 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e4 (30.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; PD**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e8 (61.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Not evaluable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e2***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 372px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eORR\u003c/strong\u003e (CR+PR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e1 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*The CBR was estimated based on a binary variable (success/failure) defined as follows:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSuccess\u003c/u\u003e: Patients with CR or PR as best response status obtained until 24 weeks after inclusion\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Patients with SD as best response status obtained until 24 weeks after starting treatment:\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cu\u003eSuccess\u003c/u\u003e: If no RECIST progression, nor definite treatment discontinuation for progression or death at the time of the analysis, and the duration between inclusion and the last tumoral evaluation was \u0026ge; 22 weeks.\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eSuccess\u003c/u\u003e: If a RECIST progression occurred more than 26 weeks after inclusion.\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eFailure\u003c/u\u003e: If a RECIST progression occurred within 26 weeks after inclusion.\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eFailure\u003c/u\u003e: If treatment was discontinued for progression or death within 26 weeks after inclusion, and no tumoral evaluation performed after treatment discontinuation.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cu\u003eFailure\u003c/u\u003e: Patients with Progressive Disease (PD) as best response status obtained until 24 weeks after inclusion\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFailure\u003c/u\u003e: Patients having definitely discontinued treatment for progression or death before any tumoral evaluation.\u003c/p\u003e\n\u003cp\u003e**including 1 death from progressive disease before any planned tumoral evaluation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e***2 patient did not have any tumoral evaluation (1 had treatment stopped following physician decision and died from PD, and 1 from intercurrent disease [sepsis])\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;: Summary of AEs*\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProstate cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=30\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003eAEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Vinorelbine-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; ICI-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Treatment-related AEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003eGrade \u0026ge;2 AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;2 vinorelbine-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;2 ICI-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;2 treatment-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003eGrade \u0026ge;3 AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;3 vinorelbine-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;3 ICI-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;3 treatment-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003eGrade \u0026ge;5 AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;5 vinorelbine-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;5 ICI-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Grade \u0026ge;5 treatment-related AEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003eSAEs**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Vinorelbine-related SAEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; ICI-related SAEs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 468px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Treatment-related SAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e(40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*AEs = adverse events\u003c/p\u003e\n\u003cp\u003e**SAEs = serious adverse events\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;: Description of treatment-related G\u0026ge;2 AEs\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrefer Term Name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade\u0026nbsp;max\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVinorelbine-related G\u0026ge;2 AEs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eAnaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFebrile neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"10\" valign=\"top\"\u003e\n \u003cp\u003eGastrointestinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eDiarrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAsthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eGait disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMucosal inflammation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eInfections and infestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eErysipelas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSepsis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eInvestigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eBlood creatinine increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNeutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"9\" valign=\"top\"\u003e\n \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAcidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eHypokalaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eStarvation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNervous system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNeuropathy peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eRenal and urinary disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eRenal failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eICI-related G\u0026ge;2 AEs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"9\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eGastrointestinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eColitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eDiarrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eAsthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003ePyrexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eInfections and infestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eSepsis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eInvestigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eAspartate aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eBlood creatinine increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eAcidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eHypokalaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eRenal and urinary disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eRenal failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eSkin and subcutaneous tissus disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003ePruritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e(6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Prostate cancer (PC), metronomic chemotherapy (MCT), vinorelbine, durvalumab, tremelimumab","lastPublishedDoi":"10.21203/rs.3.rs-6062361/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6062361/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eImmune checkpoint inhibitors (ICI) are a class of immunotherapy drugs that have shown significant success in treating various types of cancers. However, their effectiveness in treating prostate cancer (PC) has been more challenging due to an immunosuppressive tumor microenvironment. Low-dose metronomic chemotherapy have immunomodulatory properties that could enhance immunotherapy and is well-tolerated. MOVIE was a phase 1/2 multi-cohort study with a Bayesian design that evaluated the antitumor activity and safety of metronomic vinorelbine with durvalumab plus tremelimumab. Here, we report the results of the PC cohort during phase 2. Fifteen patients with locally advanced or metastatic PC, resistant to conventional therapies, presenting a measurable disease according to RECISTv1.1, and a performance status (PS)≤1, received metronomic oral vinorelbine 40mg three times a week, and durvalumab 1500mg plus tremelimumab 75mg intravenously at day 1 of 28-day cycles. Primary endpoint was the clinical benefit rate (CBR) evaluated using a Bayesian design. Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mean estimated CBR according to a non-informative prior distribution was 12.5% (95% credible interval: 1.7-31.9). One patient achieved PR leading to an ORR of 7.7%, and 4 SD\u0026lt;24 weeks. Median PFS was 1.9 months (95% confidence interval [CI]: 1.7-3.8), and median OS 5.4 months (95%CI: 2.4-12.2). Most frequent treatment-related G≥3 AEs were anemia (13.3%) for vinorelbine, and colitis (20.0%) and diarrhea (13.3%) for ICI. One treatment-related G5 AE (sepsis) was observed. The study outcomes highlighted the complexities of treating advanced PC with ICI, even when combined with metronomic vinorelbine.\u003c/p\u003e","manuscriptTitle":"Metronomic vinorelbine combined with durvalumab plus tremelimumab dual immunotherapy in patients with metastatic prostate cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-27 05:37:34","doi":"10.21203/rs.3.rs-6062361/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"77e4a428-ac83-44f5-997d-31aa18631f13","owner":[],"postedDate":"February 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-30T14:53:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-27 05:37:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6062361","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6062361","identity":"rs-6062361","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}