Nivolumab and Ipilimumab Combination Treatment in Advanced Ovarian and Endometrial Clear Cell Cancers: A Nonrandomized Clinical Trial.

Importance Gynecological clear cell cancers (CCCs) are aggressive malignant neoplasms with low response rate to chemotherapy. The treatment of patients with metastatic disease remains an area of significant unmet need.

To evaluate the efficacy of combined anti–programmed cell death 1 protein (PD-1)/cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blockade using nivolumab and ipilimumab in advanced gynecological CCCs. Design, Setting, and Participants The MoST-CIRCUIT prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced selected rare cancers. Patients with advanced clear cell ovarian cancer (CCOC)/clear cell endometrial cancer (CCEC) with a maximum of 1 course of prior systemic therapy were enrolled from August 2021 to February 2024 across 17 Australian and New Zealand sites. Interventions Patients received nivolumab, 3 mg/kg, and ipilimumab, 1 mg/kg, every 3 weeks for 4 doses followed by nivolumab, 480 mg, every 4 weeks for 96 weeks until disease progression or the development of unacceptable toxic effects. Main Outcomes and Measures Coprimary end points were objective response rate (ORR) and 6-month progression-free survival (PFS) as assessed by RECIST version 1.1 criteria, with the secondary end points being median overall survival, PFS, and treatment-related toxic effects.

Of 28 included patients, the median (range) age was 55 (34-77) years. A total of 24 had CCOC and 4 had CCEC; 19 (68%) had a previous course of therapy. Overall ORR was 54% (95% CI, 35-71), with 3 (12%) with complete response and 12 (42%) with partial response; the ORR was 55% (95% CI, 35-73) in the CCOC group and 50% (95% CI, 9-91) in the CCEC group. The median duration of response has not been reached, with all responses ongoing. The 6-month PFS was 58% (95% CI, 39-74), and the median overall survival has not been reached. A total of 9 patients (35%) experienced a grade 3 or 4 immune-related adverse event, and a grade 5 myocarditis occurred in 1 patient.

and Relevance In this nonrandomized clinical trial, immunotherapy using combined anti–PD-1/CTLA-4 blockade demonstrated encouraging activity with a high rate of durable responses in patients with advanced gynecological CCCs. This regimen should be further investigated in this patient population with unmet medical need. Trial Registration ClinicalTrials.gov Identifier: NCT04969887

Clear cell carcinomas (CCC) of the female genital tract are rare tumors, accounting for 5% to 20% of epithelial ovarian cancers (EOCs) and 5% to 10% of endometrial carcinomas. They are a clinically distinct entity with specific clinicopathological features, such as a higher prevalence in Asian populations and its association with thromboembolic complications and paraneoplastic hypercalcemia.1,2 There is strong molecular evidence that ovarian CCCs arise in foci of endometriosis, such that CCCs of the female genital tract can be regarded as a single entity of endometrial origin.3 Due to their anatomical origin and rarity, however, patients with clear cell malignant neoplasms have historically been included in ovarian-specific and endometrial-specific clinical trials. Patients with advanced-stage disease have a poor prognosis due to inherent resistance to platinum-based and non–platinum-based chemotherapy, resulting in dismal survival compared with other subtypes of ovarian and endometrial cancers.4,5 The genomic profile of CCOC is characterized by a high frequency of ARID1A and PIK3CA variants that define next to other recurrent genomic aberrations molecular subgroups.6 CCEC has a similar molecular profile to CCOC, although ARID1A and PIK3CA variants occur at a lower frequency.7,8 Together, relapsed CCOC and CCEC represent a patient population with limited therapeutic options, resulting in an urgent need to develop novel therapeutic strategies. Immune checkpoint blockade has recently emerged at the forefront of gynecologic cancer therapy apart from EOC, in which clinical trials using anti–programmed cell death 1 protein (PD-1)/programmed cell death 1 protein ligand 1 (PD-L1) blockade were overall disappointing.9 Subgroup analyses of these trials, however, suggest that immune checkpoint blockade may offer benefits to patients with clear cell histology.10,11 Immunotherapy using combined anti–PD-1/cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blockade has demonstrated increased efficacy compared with anti–PD-1 monotherapy across a range of advanced malignant neoplasms, including melanoma and kidney CCC.12,13 We previously conducted a clinical trial with combined checkpoint blockade using the anti–PD-1 antibody nivolumab and the anti–CTLA-4 antibody ipilimumab in patients with rare gynecological malignant neoplasms demonstrating durable responses in 3 of 8 patients with CCC.14 The MoST-CIRCUIT nonrandomized clinical trial subsequently investigated the same treatment regimen in a larger patient cohort, the results of which are reported here.

Study Design, Treatment, and Participants MoST-CIRCUIT was a multicenter open-label phase 2 study conducted at 17 Australian and New Zealand sites that enrolled 240 patients with selected advanced rare cancers. Eligible patients were 18 years or older with histologically confirmed, protocol-defined advanced rare cancer types, including an ovarian or uterine CCC. Patients had at least 1 measurable lesion according to Response Evaluation Criteria In Solid Tumour (RECIST) version 1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Patients could either be treatment naive or have received 1 prior systemic therapy for metastatic disease with a minimum washout period of 28 days before initiation of study treatment. Other inclusion criteria were a life expectancy of 3 months or more and adequate organ function. Key exclusion criteria were active brain metastases and a history of autoimmune conditions. Archival tumor tissue, or a fresh tumor biopsy during screening, was required for explorative biomarker analysis. All participants were synchronously referred for targeted panel genomic profiling using Trusight Oncology 500 (TSO500; Illumina), FoundationOneCDx (Foundation Medicine), and AVENIO (Roche Diagnostics) assays under the Garvan Institute of Medical Research Molecular Screening and Therapeutics Clinical Trials and Immunotherapy (MoST) framework until December 30, 2023, then subsequently referred to the Garvan Institute of Medical Research Cancer Screening Program (CaSP). Additional details are provided in the trial protocol (Supplement 1). The clinical trial protocol was reviewed and approved by the Institutional Review Board at Austin Health and was undertaken in accordance with the Declaration of Helsinki and the guidelines of Good Clinical Practice. Written informed consent was obtained from all participants prior to enrollment into the study. Nivolumab, 3 mg/kg, over 60 minutes and ipilimumab, 1 mg/kg, over 90 minutes were administered intravenously every three 3 for 4 doses (induction phase), followed by nivolumab monotherapy at a dose of 480 mg every 4 weeks (maintenance phase). Treatment continued until progressive disease, unacceptable toxic effects, withdrawal of consent, or a maximum of 2 years after enrollment. Dose reductions were not permitted; however, study treatment could be interrupted to enable recovery from adverse reactions for up to 6 weeks. If treatment was discontinued, patients were followed-up until disease progression or initiation of a new therapy. Tumor assessments were performed by radiological assessment (computer tomography of brain, chest, abdomen, and pelvis) at baseline and then every 12 weeks during treatment or follow-up. Tumor response was assessed according to RECIST version 1.1 criteria.15 Safety analyses were performed on all patients who received at least 1 dose of study treatment. Laboratory monitoring and safety assessments were performed at baseline and every 3 to 4 weeks prior to treatment according to the study protocol. Adverse events were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and collected during treatment and for 100 days after the last dose received. The coprimary end points were the proportion of patients with an objective response (complete or partial response) according to RECIST version 1.1 criteria and the proportion of patients alive and free of disease progression at 6 months. The secondary end points were median overall survival and progression-free survival (PFS) and treatment-related toxic effects. Tumor Profiling Archival formalin-fixed paraffin-embedded tumor tissue was tested locally for the expression of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry. Tumor genomic profiling was performed using formalin-fixed paraffin-embedded material by the MoST or CaSP programs, using comprehensive next-generation sequencing panels, including FoundationOne CDx (n = 15), Trusight Oncology 500 (n = 7), or other (n = 4). Profiling of single-nucleotide and indel variants (short variants) was then performed by assessing for variants in the 289 genes that were common to all 3 panels. Only those short variants that were marked as either likely pathogenic or pathogenic were included in analysis. Statistical Analysis The primary objective of the MOST-CIRCUIT study was to confirm the clinical efficacy of ipilimumab and nivolumab observed in the CA209-538 trial (30% ORR).14 A prospective sample size calculation indicated that a minimum of 58 patients should be enrolled in each rare cancer subgroup in the MoST-CIRCUIT study, assuming a significance level of 5% and power of 80% to ensure sufficient probability of detecting a true event compared with an approximate 10% response to standard care. Within the eligible rare gynecological cancer patients enrolled, the 28 participants with CCOC or CCEC are described herein. Descriptive statistics (medians and confidence intervals) were performed using GraphPad Prism version 10.0.0 software (GraphPad). 95% CIs were calculated using the modified Wilson interval. Survival proportions were estimated using the Kaplan-Meier method. Association between response and median tumor mutational burden (TMB) was assessed using the nonparametric Mann-Whitney U test. Hierarchical clustering of genomic profiling was performed using the Ward D method. Significance was set at P < .05, and all P values were 2-tailed.

Patient Characteristics and Disposition From August 2021 through to February 2024, a total of 28 patients with gynecological CCC (median [range] age, 55 [34-77] years) were enrolled into MoST-CIRCUIT and received at least 1 dose of ipilimumab and nivolumab (Figure 1). Most patients had CCOC (24 [86%]), while the remainder had CCEC (4 [14%]). The disease characteristics of the patient population are outlined in Table 1. A total of 9 patients (32%) were treatment naive and 19 (68%) had received 1 course of chemotherapy for metastatic disease prior to enrollment into the trial. Two patients with CCOC had a mismatch repair protein–deficient (dMMR) tumor (isolated PMS-2 and concomitant MLH1/PMS2 loss, respectively) with tumors of the remaining patients being mismatch repair protein proficient and/or microsatellite stable. Table 1. Demographic Characteristics. | Characteristic | No. (%) | |---|---| | Total, No. | 28 | | Age, median (range), y | 55 (34-77) | | ECOG Performance Status score | | | 0 | 16 (57) | | 1 | 12 (43) | | Tumor type | | | Ovarian | 24 (86) | | Uterine | 4 (14) | | Prior systemic regimens | | | 0 | 9 (32) | | 1 | 19 (68) | | Microsatellite status | | | MSS/pMMR | 26 (93) | | MSI-H/dMMR | 2 (7) | Abbreviations: dMMR, mismatch repair protein deficient; ECOG, Eastern Cooperative Oncology Group; MSI-H, microsatellite unstable; MSS, microsatellite stable; pMMR, mismatch repair protein proficient. A total of 14 patients (54%) completed the induction treatment with 4 doses of nivolumab and ipilimumab; 5 (19%) patients progressed clinically and 1 patient with a dMMR tumor withdrew from the study during the induction phase prior to the first radiological assessment. Three patients (7%) discontinued treatment during the induction period due to immune-related adverse events and subsequently switched to single-agent nivolumab therapy. One patient died of immune-mediated myocarditis after 3 doses. Of 14 patients who completed induction treatment, 12 patients entered into the maintenance phase with monthly nivolumab infusions and 2 patients discontinued study drugs because of progressive disease at their first radiological assessment at week 12. Efficacy The objective response rate (ORR) of the evaluable population was 14 of 26 (54%; 95% CI, 35-71), including 3 complete remissions, with the ORR being 55% (95% CI, 35-73) for the CCOC subgroup and 50% (95% CI, 9-91) for the CCEC subgroup (Figure 2A). The 6-month PFS was 58% (95% CI, 39-74) for the entire cohort. All 14 responses were ongoing at the time of data cutoff (range, 9-33 months) (Figure 2B). The response rate did not significantly differ between chemotherapy-naive and pretreated patients (4 of 9 [44%] vs 10 of 17 [58%]). An additional 2 patients had stable disease, leading to a disease control rate of 62% (95% CI, 43-78). Five patients (19%) progressed rapidly prior to the first restaging scan and were discontinued from the study. A total of 5 patients (19%) had progressive disease at their first restaging scan at week 12 (Table 2). The median overall survival has not been reached, with the median PFS being 10 months (95% CI, 2-17) with a median follow-up 11.2 months (95% CI, 1.05-17.3) (Figure 2C-D). Table 2. Antitumor Activity. | Response | No. (%) | || |---|---|---|---| | Total (n = 26)a | CCOC (n = 22) | CCEC (n = 4) | | | ORR, % (95% CI) | 54 (35-71)b | 55 (35-73) | 50 (9-91) | | Best overall response | ||| | CR | 3 (12) | 3 (14) | 0 | | PR | 11 (42) | 9 (41) | 2 (50) | | SD | 2 (8) | 1 (5) | 1 (25) | | PD | 5 (19) | 5 (23) | 0 | | No radiological assessmentc | 5 (19) | 4 (18) | 1 (25) | | DCR, % (95% CI) | 62 (43-78) | 59 (39-77) | 75 (30-99) | Abbreviations: CCEC, clear cell endometrial cancer; CCOC, clear cell ovarian cancer; DCR, disease control rate; CR, complete response; PD, progressive disease; PR, partial response; ORR, objective response rate; SD, stable disease. One patient withdrew and 1 patient experienced grade 5 myocarditis prior to first assessment. Includes 1 patient with a mismatch repair protein–deficient tumor (PMS2 mutation). Five patients clinically progressed prior to their first radiological assessment and were discontinued from the study. Safety A total of 22 patients (78%) experienced immune–related adverse events of any grade; grade 3 or higher immune-related toxic effects occurred in 10 patients (35%), with the most frequent being hepatitis. One patient sustained a severe immune-mediated myocarditis, leading to high-grade ventricular arrythmias and death (eTable in Supplement 2). Exploratory Biomarker Analyses Targeted panel tumor DNA sequencing was performed on the tumors of all 26 evaluable patients; TMB could not be determined for 3 patients due to the low tumor purity of the submitted specimen. Overall, TMB was low, with the median (range) being 3.1 (0-13.9) somatic variants per megabase (MB), with only 3 tumors demonstrating a TMB of more than 10 variants per MB, including 1 dMMR tumor. The median (range) TMB was significantly higher in responders vs nonresponders for the 22 patients with CCOC (4.7 vs 1.8 variants per MB) (Figure 3A). The most frequent detected genomic aberrations were variants in ARID1A (11 of 22 [50%]), PIK3CA (10 of 22 [45%]), SPOP (6 of 22 [27%]), and ZNF217 gene amplifications (5 of 22 [23%]) (Figure 3B-C). All 4 patients with tumors harboring a TERT promoter mutation obtained an objective response. ARID1A variants were limited to patients with CCOC and were detected in 11 of 22 patients (50%; 5 with ARID1A-mutated tumors and 6 with wild-type tumors) and were not associated with objective response (Figure 3B).

In this phase 2 study, we demonstrated high efficacy of combined immunotherapy with nivolumab and ipilimumab followed by maintenance nivolumab for advanced gynecological CCCs, with an ORR of 54% (95% CI, 35-71) for the overall study population and 55% (95% CI, 35-73) for the CCOC cohort, which represented most patients. Additionally, responses were durable, with all currently being ongoing and a 6-month PFS of 58% (95% CI, 39-74). The safety profiles of nivolumab and ipilimumab were consistent with those seen in prior studies using the same dosing regimen in other malignant neoplasms.13,16 Our study results support anti–PD-1/CTLA-4 combination immunotherapy as a potential treatment option for women with these rare and aggressive cancers. Advanced gynecological CCCs are a chemotherapy-resistant disease with lower ORR to first-line platinum-based chemotherapy compared with high-grade serous ovarian cancer or uterine endometrioid carcinoma, resulting in poorer 5-year stage-adjusted disease-specific survival.4,5 On disease recurrence, the response rate to second-line chemotherapy has been reported to be only 6% to 9%, and best supportive care is frequently recommended. These poor outcomes underscore the need for further drug discovery to treat this resistant disease. Transcriptomic analyses exploring the immune landscape of CCOC have demonstrated overexpression of a number of immune-related genes including PD-1 and CTLA-4, leading to the identification of transcriptional subtypes and supporting investigation of immunotherapy using checkpoint blockade in this tumor type.17,18 Clinical trials investigating immunotherapy using single-agent anti–PD-1/PD-L1 blockade in advanced EOC have shown limited efficacy, with responses ranging from 8% to 10% and median PFS just over 2 months.10 However, subgroup analyses suggested that immune checkpoint blockade may offer superior benefit to patients with clear cell histology.10,11 However, a recent trial comparing the anti–PD-L1 antibody durvalumab with chemotherapy in patients with relapsed CCOC demonstrated a poor outcome in both treatment arms.19 A potential explanation for these discordant observations may be that PD-L2 and not PD-L1 is the main ligand expressed in ovarian CCC, suggesting a preferred treatment approach with anti–PD-1–based immunotherapy.20 It also highlights the importance of exploring combination immunotherapy to enhance antitumor activity compared with PD-1/PD-L1 inhibition alone, an approach which is supported by translational research demonstrating that tumor-infiltrating lymphocytes in ovarian cancer require CD28 costimulation next to anti–PD-1 blockade to be effectively activated.21 In recently presented results of the BrUOG354 study in women with gynecologic CCC, the ORR was higher when nivolumab was given in combination with ipilimumab vs as a single agent (33.3% vs 14.3%).22 The DART SWOG S1609 trial demonstrated a response rate of 21.1% and 36.8% (including unconfirmed responses), respectively, in recurrent CCOC using the same treatment regimen.23 The outcome of our trial is in keeping with the results of these studies, with the response rate in this study being numerically higher than reported for the combination arm of the BrUOG354 and DART SWOG S1609 studies. This may be due to the overall limited number of patients enrolled into these studies or the different ipilimumab scheduling. In our trial, nivolumab, 3 mg/kg, and ipilimumab, 1 mg/kg, every 3 weeks was chosen as an induction treatment followed by nivolumab monotherapy as maintenance treatment. Rationale for this is the observation in advanced melanoma, where equivalent efficacy was demonstrated between ipilimumab, 1 mg/kg, and ipilimumab, 3 mg/kg, dosing, with a better safety profile for the former.16 In contrast, ongoing combination treatment using nivolumab, 240 mg, once every 2 weeks plus ipilimumab, 1 mg/kg, once every 6 weeks, as investigated in the BrUOG345 and DART S1609 studies, has failed to show superiority to anti–PD-1 monotherapy in melanoma and head and neck cancer trials.24,25 In addition, combination therapies of anti–PD-1 antibodies and antiangiogenic agents, such as the anti–vascular endothelial growth factor A antibody bevacizumab or the multityrosine kinase inhibitor lenvatinib have recently shown encouraging activity in patients with advanced CCOC.26,27 The Keynote755 trial that compared combination treatment of the anti–PD-1 antibody pembrolizumab and lenvatinib to chemotherapy in patients with recurrent endometrial carcinoma also demonstrated substantial benefits of the combination therapy in the CCC subgroup.28 The above studies support anti–PD-1–based combination therapies with either an anti–CTLA-4 antibody or an antiangiogenic agent in this patient population resembling treatment approaches used in advanced kidney CCC, which shares genomic features with gynecological CCCs.29 The underrepresentation of patients with endometrial CCC in our trial cohort is most likely due to alternative access pathways to checkpoint inhibitors, as the trial was open to enrollment when pembrolizumab and lenvatinib combination treatment has been established as the new standard of care in patients with recurrent endometrial cancer.28 In keeping with prior analyses, we found in the tumors of our study cohort frequent variants in the ARID1A gene next to other genomic aberrations.6 ARID1A forms a component of the canonical BRG1-associated factors complex as part of the mammalian switch/sucrose-nonfermentable complex involved with DNA repair and transcription, and preclinical research has demonstrated that ARID1A loss in tumors leads to increased immunogenicity and sensitivity to checkpoint inhibition.30 In keeping with these findings, ARID1A variants were correlated with response to anti–PD-1/PD-L1 checkpoint blockade in a pancancer analysis.31 Wild-type and variant ARID1A CCOCs are also characterized by distinct immune microenvironments, with the former being characterized by a higher frequency of CD8 and CD4 T cells and the later by a greater immune cell diversity, including B cells and plasma cells.20 Surprisingly, in view of the above findings, ARID1 tumor mutation status did not discriminate for response in our study population, with responses being seen in both wild-type and variant subgroups. All 4 patients with tumors harboring TERT promoter mutations that lead to TERT overexpression obtained an objective response, a finding that merits further analyses in larger datasets, as TERT is a well-recognized tumor-associated antigen that can induce T-cell responses and serve as tumor rejection antigen.32 High TMB has previously been shown to predict response to checkpoint inhibitor therapy in metastatic melanoma and non–small cell lung cancer, with subsequent trials suggesting that high TMB can serve as a tumor-agnostic biomarker for response to anti–PD-1 blockade.33 However, subsequent analyses demonstrated that TMB does not have predictive value in all tumor types and that the TMB threshold determining response differs across tumor types.34 The TMB in this patient cohort was overall low, in keeping with prior analyses in EOC.34 However, the median TMB of patients with CCOC in our cohort was significantly associated with response, a finding that will require confirmation in future studies. The median TMB of the CCOC responders in our study also aligned well with the threshold for response to anti–PD-1 checkpoint blockade that has been determined in a large retrospective analysis of patients with EOC.34 The frequency of severe immune-related adverse events was in keeping with clinical trials using the same nivolumab and ipilimumab dosing regimen in other malignant neoplasms, with one-third of patients experiencing high-grade immune-related toxic effects.13,16 Immune-related toxic effects were well managed with steroid therapy and drug discontinuation according to established guidelines. Rare lethal immune-related adverse effects, such as the observed grade 5 myocarditis, can nevertheless occur, and therefore vigilance and close surveillance of patients is critical as these treatments are introduced in the management of new tumor types.

This study has limitations. This trial investigated anti–PD-1/CTLA-4 combination immunotherapy in a limited number of patients with CCOC. Further investigations in a larger patient population will be required to confirm efficacy.

In this nonrandomized clinical trial, combination immunotherapy with the anti–PD-1 antibody nivolumab and the anti–CTLA-4 antibody ipilimumab showed significant clinical activity in gynecological CCCs and represents a promising treatment option. Further clinical trials are needed to confirm the efficacy of anti–PD-1/CTLA-4 combination immunotherapy in a larger patient population with recurrent disease and to compare it with combination therapies of anti–PD-1 blockade and an antiangiogenic agent. Ongoing biomarker research is currently underway to better define the patient population that is responsive to this treatment regimen and define the mechanism of treatment resistance.

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