Randomized Study of Apatinib plus Ifosfamide and Etoposide versus Ifosfamide and Etoposide in Patients With Advanced Osteosarcomas (OAIE/PKUPH-sarcoma 11)

Randomized Study of Apatinib plus Ifosfamide and Etoposide versus Ifosfamide and Etoposide in Patients With Advanced Osteosarcomas (OAIE/PKUPH-sarcoma 11) | 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 Article Randomized Study of Apatinib plus Ifosfamide and Etoposide versus Ifosfamide and Etoposide in Patients With Advanced Osteosarcomas (OAIE/PKUPH-sarcoma 11) Xiaodong Tang, Lu Xie, Jie Xu, Xin Sun, Kuisheng Liu, Kunkun Sun, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5641573/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Background: Retrospective analysis have indicated potential benefits of combining apatinib, a multi-targeted tyrosine kinase inhibitor, with ifosfamide and etoposide (IE) for advanced osteosarcoma. This study aims to compare the efficacy of apatinib plus IE versus IE alone in patients with relapsed or refractory osteosarcoma. Methods: This multicenter, randomized controlled trial (NCT05277480) involved patients with relapsed or refractory osteosarcoma, who had progressed on first-line chemotherapy, typically comprising high-dose methotrexate, doxorubicin, cisplatin with or without ifosfamide (MAP/I). Participants were randomized in a 2:1 ratio to receive either apatinib plus IE or IE alone. The apatinib plus IE group received 500 mg of oral apatinib daily, along with ifosfamide (1.8 g/m²/day) and etoposide (100 mg/m²/day) d 1-3 q3w. The IE group received the same daily regimen d 1-5 q3w. The primary endpoint was median progression-free survival (mPFS). Results: From April 2022 to August 2023, 81 patients were enrolled, with 53 receiving apatinib plus IE and 28 receiving IE alone. With median follow-up of 19.9 months, the mPFS was 5.5 months (95% confidence interval [CI], 3.9 to 6.4) for the apatinib+IE, compared to 3.4 months (95% CI, 1.4 to 4.6) for single IE (hazard ratio, 0.60; 95% CI, 0.37 to 0.98; P=0.0402). The median OS was 18.2 months (95% confidence interval [CI], 13.7 to 25.2) for apatinib+IE, compared to 22.9 months (95% CI, 19.3 to NE) for single IE (hazard ratio, 1.48; 95% CI, 0.76 to 2.89; P=0.2493). The incidence of neutropenia and thrombocytopenia was similar between two groups. Quality of life assessments revealed significant improvements in global health status in apatinib+IE. Conclusion: Combining apatinib with IE significantly enhances PFS in patients with relapsed or refractory osteosarcoma post MAP/I chemotherapy, maintaining an acceptable safety profile. Health sciences/Oncology/Cancer/Sarcoma Health sciences/Oncology/Cancer/Paediatric cancer Figures Figure 1 Figure 2 INTRODUCTION The prognosis for patients with inoperable, metastatic osteosarcoma that is resistant to first-line chemotherapy remains poor. Previous studies have demonstrated that multi-targeted tyrosine kinase inhibitor (TKIs) can induce varying degrees of objective responses and prolong progression-free survival (PFS) ( 1 – 5 ). However, the efficacy of TKIs is often compromised by factors such as large tumor volumes, poor performance status, and the axial location of lesions ( 4 , 5 ) and so on. Additionally, clinical trials involving TKIs alone are typically with median PFS ranging from 4 to 6 months accompanied with inevitable development of secondary drug resistance ( 1 – 5 ). Specifically, TKIs often exhibit limited and short-lived efficacy in controlling musculoskeletal lesions besides other metastasis outside the lung ( 4 – 6 ), the underlying mechanism of which remains poorly understood. Osteosarcoma is characterized by significant genomic instability and genetic heterogeneity ( 7 ), necessitating treatments that have traditionally focused on cytotoxic and cytostatic drugs. These treatments often require combination strategy to address the intra- and inter-tumoral heterogeneity effectively. In this context, classic second-line chemotherapy regimen, such as ifosfamide and etoposide (IE), might complement the activity of TKIs. It might be possible to achieve better overall disease control by combining IE with TKIs, especially for those with multiple metastatic lesions in different organs. Apatinib, a multi-targeted TKI utilized in the treatment of gastric, non-small cell lung, and esophageal cancers ( 8 ), has demonstrated efficacy in inhibiting the proliferation, migration, and invasion of osteosarcoma in both preclinical and clinical trials ( 4 , 6 ). IE are chemotherapeutic agents that induce DNA damage: ifosfamide acts as an alkylating agent, whereas etoposide inhibits topoisomerase II ( 9 ). Since the 1990s, the combination of IE has been employed in multiple pediatric clinical settings, with a phase II trial reporting a response rate of 48% and acceptable toxicity inrelapsed or refractory pediatric osteogenic sarcomas ( 10 ). The rationale for combining TKIs with IE, including lenvatinib plus IE, was initially proposed by Gaspar et al ( 11 – 13 ) with the idea of inhibition of angiogenesis may increase uptake of IE into tumor tissue through vascular normalization. In the current study, this combination strategy is based on the premise that adding chemotherapy can mitigate the limitations of the cytostatic properties of TKIs, particularly in managing extra-pulmonary lesions ( 14 ). Furthermore, in heavily pretreated patients with inoperable lesions, managing adverse events (AEs) to a tolerable level is crucial since the therapy may need to be administered over a life-long period. By utilizing off-label doses for these combinations, we developed a suitable metronomic chemotherapy regimen in combination with apatinib in our previous study, allowing for a longer duration of chemotherapy compared to the OLIE/ITCC-082 study ( 14 , 15 ). Thus, this randomized controlled trial aims to evaluate the efficacy of combining apatinib with IE versus IE alone in patients with unresectable, recurrent or refractory osteosarcoma. METHODS Study design and patients This multicenter, randomized controlled trial (OAIE/PKUPH-sarcoma 11) was conducted across four centers in China under the auspices of the Chinese Sarcoma Study Group. The study enrolled adolescents and adults aged 12 to 65 years, with body surface areas exceeding 1.0 m². Participants were required to have histologically or pathologically confirmed locally advanced or metastatic high-grade osteosarcoma that had either progressed following at least one line of prior chemotherapy. Enrollment criteria mandated that the disease be measurable according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ( 16 ). Eligible patients needed to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, an expected survival of more than three months, and satisfactory organ function. Exclusion criteria included previous treatment with any TKIs such as apatinib, anlotinib, regorafenib, cabozantinib, or sorafenib, or those treated solely with IE chemotherapy. Additionally, patients with symptomatic central nervous system metastasis or uncontrolled comorbid conditions that could interfere with protocol adherence were excluded. Detailed inclusion and exclusion criteria are provided in the study protocol. The trial received ethical approval from the Ethical Review Committee of Peking University People’s Hospital and other participating centers, and it was conducted in accordance with the Declaration of Helsinki and applicable local regulatory requirements and laws. Informed consents were obtained from all participants, with minors providing assent alongside consents from their legal guardians. The trial is registered on ClinicalTrials.gov (NCT05277480). Procedure Eligible patients were randomized in a 2:1 ratio to receive either the combination of apatinib and IE (Apa + IE group) or IE alone (IE group). Participants in the Apa + IE group received 500 mg of apatinib orally once daily, combined with ifosfamide (1.8 g/m²/day d 1 − 3 ) and etoposide (100 mg/m²/day d 1 − 3 ), administered every three weeks (Q3W) with appropriate hydration and mesna for cytoprotection. The IE group received the same daily dose of ifosfamide and etoposide, albeit on an extended schedule (d 1 − 5 Q3W) ( 14 ). Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, initiation of non-protocol cancer therapies, or death. Additionally, apatinib was administered for a maximum of one year, while IE was administered for up to 10 cycles. Dose adjustments were permitted for toxicity management according to protocol; however, if treatment was postponed for over four weeks beyond a planned cycle, discontinuation was mandated. Both groups underwent tumor evaluations using computed tomography or magnetic resonance imaging at baseline and subsequently every two cycles according to RECIST 1.1 criteria. AEs were recorded and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Furthermore, all participants completed the European Organization for Research and Treatment of Cancer (EORTC) 30-item core Quality of Life (QoL) questionnaire (QLQ-C30) ( 17 ) prior to initiating treatment, with follow-up QoL assessments conducted every two cycles. Endpoints In this study, the primary endpoint was PFS, as assessed by the investigators using RECIST 1.1 criteria. PFS was defined as the time from randomization to disease progression or death from any cause, whichever occurred first. Secondary endpoints included 4-month PFS rate; 6-month PFS rate; overall survival (OS), measured from randomization to death from any cause; objective response rate (ORR), defined as the proportion of patients achieving a complete response (CR) or partial response (PR); disease control rate (DCR), which encompassed the percentage of patients with either CR, PR, or stable disease (SD); duration of response (DoR), calculated from the first occurrence of CR or PR to progressive disease (PD) or death; time to response (TTR), the interval from randomization to the first CR or PR; time to progression (TTP), defined as the time from randomization to disease progression; and safety assessments throughout the study duration. The exploratory endpoints included QoL, assessed using the EORTC QLQ-C30 questionnaire, and event-free survival (EFS). Duing the treatment, some patients received local therapy, such as local radiation or sugery, which was not allowed for this trial. And we calculated these cases as censoring for PFS, however at the same time we also use EFS to describe the time from randomization to the first occurrence of disease progression, local or distant recurrence, initiation of subsequent anti-tumor therapy, or death, of which the local therapy was permitted in this course, so to comparing the result to other trials. Statistical analysis Assuming a median PFS of 5.0 months in the IE group and 11.0 months in the Apa + IE group ( 14 ), detecting a hazard ratio (HR) of 0.45 with 80% power at a two-sided significance level of 0.05 required 69 PFS events. Considering a 2:1 randomization ratio and anticipating an 18-month enrollment period followed by a 12-month follow-up, the study aimed to enroll 46 patients in the Apa + IE group and 23 patients in the IE group to observe sufficient PFS events by the study's conclusion. Factoring in a 10% dropout rate, the total required sample size was adjusted to 52 patients in the Apa + IE group and 26 patients in the IE group, culminating in a total enrollment of 78 patients. The full analysis set (FAS) included all participants who received at least one dose of the study treatment and served as the primary efficacy analysis dataset. The safety analysis set (SS) encompassed all patients who received at least one dose of the study treatment. The Kaplan-Meier method was utilized to estimate the median PFS for each treatment group, and the 95% confidence intervals (CIs) of median PFS were calculated using the Brookmeyer and Crowley method. Differences in PFS between the Apa + IE group and the IE group were evaluated using an unstratified log-rank test. Additionally, an unstratified Cox proportional hazards regression model estimated the HR and its associated 95% CI. Subgroup analyses were performed according to baseline factors. The median values for OS, DoR, TTP, and TTR for each group were also estimated using the Kaplan-Meier method, with 95% CIs calculated by the Brookmeyer and Crowley method. The 95% CIs for the 4- and 6-month PFS rate, ORR and DCR were estimated using the Clopper-Pearson method. QoL assessments, as measured by the subscales of the EORTC QLQ-C30, were scored according to the EORTC scoring manual. Each scale was transformed so that scores ranged from 0 to 100, with higher scores indicating better functioning and lower scores indicating worse symptoms. Scale scores were summarized as continuous variables for baseline and each scheduled post-baseline visit by treatment group, with mean values and standard deviations reported for each time point. The Friedman test was used to assess significant changes in QoL scores over time. All statistical analyses were performed using SAS version 9.3 or higher. A P-value < 0.05 was considered statistically significant. RESULTS Baseline characteristics of patients Between April 2022 and August 2023, 89 patients were assessed for eligibility, with 81 patients subsequently enrolled. Of these, 53 were randomized to the Apa + IE group and 28 to the IE group. All enrolled patients received treatment and were included in both the FAS and the SS (Fig. 1 ). As shown in Table 1 , baseline characteristics were generally balanced between the two groups. The proportion of participants younger than 18 was comparable, accounting for 54.7% in the Apa + IE group and 53.6% in the IE group. The median time since initial diagnosis was slightly shorter in the Apa + IE group at 12.1 months (interquartile range [IQR] 5.4–18.8) compared to 15.1 months (IQR 8.6–22.7) in the IE group. Approximately 30% of patients had an ECOG PS of 0. Lung-only metastasis was observed in 66.0% of patients in the Apa + IE group and 71.4% in the IE group. All patients had received prior anthracyclines while 88.7% of the Apa + IE group and 92.9% of the IE group had received prior ifosfamide treatment in combination with other chemo-agents. 71.7% of patients in the Apa + IE group had undergone prior one surgery, compared to 64.3% in the IE group, while 22.6% and 32.1% respectively had two or more surgeries. With final analysis, we had 13.6% (11/81) patients censored due to local therapy of selected lesions, of which usually the biggest lesion that had been radiated to avoid secondary drug resistance. Table 1 Baseline characteristics of patients Variables Apa + IE group (n = 53) IE group (n = 28) Age, years, n (%) < 18 29 (54.7) 15 (53.6) ≥ 18 24 (45.3) 13 (46.4) Sex, n (%) Male 34 (64.2) 21 (75.0) Female 19 (35.8) 7 (25.0) Time since initial diagnosis, months, median (IQR) 12.1 (5.4, 18.8) 15.1 (8.6, 22.7) ECOG PS*, n (%) 0 14 (26.4) 10 (35.7) 1 32 (60.4) 16 (57.1) 2 3 (5.7) 0 3 4 (7.5) 2 (7.1) Location of primary tumor, n (%) Limbs 37 (69.8) 14 (50.0) Non-extremities 16 (30.2) 14 (50.0) Metastatic sites, n (%) 1 19 (35.8) 10 (35.7) 2 9 (17.0) 6 (21.4) ≥ 3 25 (47.2) 12 (42.9) Sites of metastasis, n (%) Only lung 35 (66.0) 20 (71.4) Others 18 (34.0) 8 (28.6) Targeted tumor burden, mm, median (range) 33.2 (10.0, 225.9) 36.5 (10.0, 138.7) Previous lines of therapy, n (%) 1 40 (75.5) 22 (78.6) ≥ 2 13 (24.5) 6 (21.4) Previous chemotherapy, n (%) Anthracyclines 53 (100.0) 28 (100.0) Ifosfamide 47 (88.7) 26 (92.9) Best overall response to previous ifosfamide, n (%) Partital response 4 (7.5) 4 (14.3) Stable disease 23 (43.4) 15 (53.6) Progressive disease 20 (37.7) 7 (25.0) Previous surgery, n (%) 1 38 (71.7) 18 (64.3) ≥ 2 12 (22.6) 9 (32.1) Previous radiotherapy, n (%) 4 (7.5) 0 *Only patients with an ECOG PS of 2–3 for amputation surgery were included. IQR, interquartile range; ECOG PS, Eastern Cooperative Oncology Group performance status. Efficacy By the cut-off date of October 8, 2024, median follow-up was 19.9 months (95% CI: 19.1, 21.8). Treatment was ongoing for three patients in the Apa + IE group and one patient in the IE group with last follow-up. The Apa + IE group exhibited a median PFS of 5.5 months (95% CI: 3.9, 6.4), compared to 3.4 months (95% CI: 1.4, 4.6) in the IE group, with a HR of 0.60 (95% CI: 0.37, 0.98; P = 0.0402) (Fig. 2 A). The 4-month and 6-month PFS rates were 65.8% (95% CI: 50.3, 77.5) and 36.7% (95% CI: 22.5, 50.9) in the Apa + IE group, versus 41.6% (95% CI: 22.4, 59.8) and 15.9% (95% CI: 4.2, 34.3) in the IE group, respectively. If we calucated all those censoring data which were due to local therapy, the median EFS was 5.5 months (95% CI: 3.9, 5.9) for the Apa + IE group, compared to 3.4 months (95% CI: 1.4, 4.6) for the IE group (HR, 0.64; 95% CI: 0.40, 1.02, P = 0.0598) (Figure S1 ). The median OS was 18.1 months (95% CI: 13.7, 25.2) for the Apa + IE group, compared to 22.9 months (95% CI: 19.3, not estimated [NE]) for the IE group (HR, 1.48; 95% CI: 0.76, 2.89) (Fig. 2 B). The ORR was 32.1% in the Apa + IE group and 25.0% in the IE group. The DCR was observed at 90.6% in the Apa + IE group, while the IE group had a DCR of 60.7%. The median TTP was 5.1 months (95% CI: 3.7, 5.7) in the Apa + IE group and 2.5 months (95% CI: 1.4, 4.1) in the IE group (Table 2 ). However, the median TTR was almost the same, with 1.4 months (95% CI: 1.2, 3.1) in the Apa + IE group while 1.5 months (95% CI: 1.3, 2.0) in the IE group. The DoR was also nearly the same between these two groups, with 3.9 months (95% CI: 1.9, 7.8) for the Apa + IE group and 4.1 months (95% CI: 1.7, NE) for the IE group. The percentage changes from baseline in target lesions for all patients are shown in Figure S2 A, and treatment exposure along with DoR is presented in Figure S2 B. Table 2 Efficacy endpoints Outcomes Apa + IE group (n = 53) IE group (n = 28) Best overall response, n (%) Complete response 1 (1.9) 0 Partial response 16 (30.2) 7 (25.0) Stable disease 31 (58.5) 10 (35.7) Progressive disease 3 (5.7) 10 (35.7) Not evaluable 2 (3.8) 1 (3.6) Objective response rate, n (%) 17 (32.1) 7 (25.0) 95% CI (19.9, 46.3) (10.7, 44.9) Disease control rate, n (%) 48 (90.6) 17 (60.7) 95% CI (79.3, 96.9) (40.6, 78.5) Time to response, months, median (95% CI) 1.4 (1.2, 3.1) 1.5 (1.3, 2.0) Duration of response, months, median (95% CI) 3.9 (1.9, 7.8) 4.1 (1.7, NE) Time to progress, months, median (95% CI) 5.1 (3.7, 5.7) 2.5 (1.4, 4.1) Progression-free survival, median (95% CI) 5.4 (4.9, 6.4) 3.4 (1.4, 4.6) 4 months, % (95% CI) 65.8 (50.3, 77.5) 41.6 (22.4, 59.8) 6 months, % (95% CI) 36.7 (22.5, 50.9) 15.9 (4.2, 34.3) Overall survival, median (95% CI) NR (12.3, NE) NR (12.0, NE) 6 months, % (95% CI) 96.2 (85.6, 99.0) 92.7 (73.9, 98.1) 12 months, % (95% CI) 70.3 (54.1, 81.7) 82.2 (58.3, 93.1) 18 months, % (95% CI) 57.9 (35.6, 74.9) 58.1 (28.8, 78.9) CI, confidence interval; NE, not estimable. Following disease progression, patients’ general condition seemed to be better and later treatment options seemed to be more in the IE group. In the Apa + IE group, 30.2% had no further treatment (OS events) compared to 18.9% in the IE group. The most common subsequent therapies in the Apa + IE group were multiple other chemotherapy plus TKIs (18.9%), chemotherapy alone (17.0%), and other TKI monotherapy (9.4%). In the IE group, chemotherapy alone (21.4%), chemotherapy plus TKI (14.3%) and antibody-drug conjugates (14.3%) were primarily used (Table S1 ). Safety profiles Treatment-related adverse events (TRAEs) were reported in 98.1% of patients in the Apa+IE group and 89.3% of patients in the IE group. Grade 3 or higher TRAEs occurred in 69.8% of the Apa+IE group compared to 64.3% in the IE group. Serious adverse events (SAEs) were observed in 11.3% of patients receiving Apa+IE and 10.7% of those in the IE group. For combination group, indeed more toxicities occurred, like hand and foot syndrome, pneumothorax and so on. However neutropenia and thrombocytopenia did not seem to be more severe in the apa+IE group because the dose of the chemotherapy had been reduced in the combination group (Table 3). In the Apa+IE group, there were no dose interruptions or reductions with chemotherapy, whereas in the IE group, one patient (3.6%) discontinued treatment because of severe myelosuppression. For apatinib, dose interruptions occurred in seven patients (13.2%), dose reductions in 16 patients (30.2%), and discontinuation in one patient (1.9%) within the Apa+IE group. Table 3. Treatment related adverse events (TRAEs) in at least 10% of patients in either group. Events, n (%) Apa+IE group (n=53) IE group (n=28) Any grade Grade ≥3 Any grade Grade ≥3 Any TRAE 52 (98.1) 37 (69.8) 25 (89.3) 18 (64.3) Platelet count decreased 39 (73.6) 21 (39.6) 15 (53.6) 8 (28.6) White blood cell decreased 37 (69.8) 27 (50.9) 19 (67.9) 17 (60.7) Anemia 35 (66.0) 17 (32.1) 21 (75.0) 15 (53.6) Neutrophil count decreased 32 (60.4) 26 (49.1) 19 (67.9) 15 (53.6) Hypothyroidism 32 (60.4) 3 (5.7) 4 (14.3) 0 Proteinuria 18 (34.0) 2 (3.8) 2 (7.1) 0 Hypoproteinemia 10 (18.9) 0 3 (10.7) 1 (3.6) Diarrhea 9 (17.0) 0 0 0 Hypertension 8 (15.1) 0 4 (14.3) 0 Hypocalcemia 8 (15.1) 0 2 (7.1) 0 Thyrotropin increased 7 (13.2) 3 (5.7) 0 0 Pneumothorax 6 (11.3) 3 (5.7) 0 0 Hypokalemia 5 (9.4) 0 3 (10.7) 0 Lymphocyte count decreased 3 (5.7) 0 3 (10.7) 2 (7.1) Quality of life Throughout the treatment course, patients in the Apa+IE group reported a statistically significant improvement in global health status, with the mean score increasing from 47.12 at baseline to 56.67 by cycle 9 (P=0.042). Conversely, the IE group did not exhibit a statistically significant change in QoL over the course of treatment (Table S2). DISCUSSION This randomized, multicenter, phase II trial successfully met its primary endpoint, demonstrating a significantly longer median PFS for Apa + IE compared to IE alone. However, unlike our retrospective study where local therapy was permitted ( 14 ), current study failed to achieve a median PFS for 11 months or longer, but with only 5.5 months in the Apa + IE while 3.4 months in the IE group. For patients with unresectable and refractory osteosarcoma following first-line chemotherapy, the prognosis has remained dismal over the past 30 years, with a 5-year post-relapse survival rate of less than 20% ( 18 , 19 ). Although multi-targeted TKIs can induce responses (as evidenced by similar ORR in the present study), long-term disease control remains to be a critical challenge ( 1 , 4 – 6 , 13 , 14 , 20 ). In this study, the combination of apatinib and IE demonstrated superior PFS compared to IE alone in osteosarcoma progressed upon MAP + I first-line chemotherapy (Figure S3 ), particularly those with multiple metastatic sites and substantial tumor burden. However, as for lesions outside the lungs, it still seems to be challenging to be controlled by this combination, which partly might be due to the lower daily dose of IE. However in real world practice, we had ever tried higher daily dose in combination like OLIE/ITCC-082 did, there were rarely anyone could tolerate more than 5 cycles of chemotherapy since these patients had been heavily pretreated by first-line chemotherapy for a year or even more. In this study, the addition of metronomic chemotherapy did not effectively overcome rapid secondary resistance, prolonging PFS as we previously expected. But it did successfully prolong the mPFS compared to IE alone. The rationale for combining apatinib with IE in this study is grounded by the hypothesis that integrating traditional, effective second-line chemotherapy can enhance the overall disease control for both pulmonary and extrapulmonary lesions, which, especially the later, are often poorly controlled by apatinib alone ( 4 ). Nathalie Gaspar et al. previously explored the combination of lenvatinib with IE in patients with refractory or relapsed osteosarcoma, achieving a median PFS of 8.7 months (95% CI 4.5–12.0) in the phase 1/2 study of ITCC-050 ( 12 ). Their approach was predicated on the synergistic mechanism of cytotoxic agents and VEGF pathway inhibition, which can slow tumor growth through angiogenesis suppression and indue more cytoxic reactions ( 11 ). However, results from the phase II randomized controlled study of OLIE/ITCC-082 did not demonstrate statistical superior survival benefit, even for PFS only (6.5 months vs. 5.5 months, respectively) ( 13 ). Our study, by contrast, has shown that the combination of apatinib with IE prolongs PFS in patients progressed upon MAP + I chemotherapy, which might mostly be due to a higher percentage of participants in our study had progressed following ifosfamide-containing combination chemo-protocol (Figure S3 ) (90.1% compared to 46.9% in the OLIE/ITCC-082 study) ( 13 ), which likely weakened the efficacy of the control group. Although single IE intensified the intensity and density of ifosphamide than first-line MAP + I, which could induce some responses or control disease for some time in our study, it was less effective in the ifosfamide-pretreated population other than in the ifosfamide-naïve population. Thus we did not have such powerful control as OLIE/ITCC-082 did, our study group won the control. This factor may account for the numerically shorter median PFS observed in both groups of our study compared to OLIE/ITCC-082. In the meanwhile, there are some other differences between the OLIE/ITCC-082 and present study ( 13 ). Most notably, local therapy, which could be performed after 18 weeks of treatment in the lenvatinib plus IE, was not permitted in this study, which might partly explain why the mPFS seems to be longer in the OLIE/ITCC-082 than in our trial. For patients with advanced osteosarcoma, even when lesions are not fully resectable at baseline, local therapies such as radiotherapy for large tumor burdens can significantly delay secondary drug resistance and prolong EFS. This is exemplified in our retrospective study ( 14 ), where despite patients being in more advanced stages of their disease, the median EFS could reach 11 months. The restriction on localized treatment in the current study created a complex scenario. Although the trial targeted inoperable osteosarcomas, treatment led to downstaging in many cases after 3–4 cycles of treatment, potentially converting inoperable tumors to operable ones. Consequently, some patients opted for local therapies, primarily radiotherapy, to reduce tumor burden and maintain longer disease stability, thus leading to data censoring (13.6%) in the present trial. Thus when we calculated all those censoring data to compare the mEFS between the two groups, it was interesting to notice that the P value seemed not to be so significant by 0.0598, which might also be deemed as a confounding factor in OLIE/ITCC-082. While not recommended within the study protocol, this real-world adjustment highlights the ethical dilemmas faced in balancing trial guidelines with patient best interests. As a result, the tumor burden in this study was expectedly higher compared to other trials where local therapies allowed, as we included a larger proportion of patients with late-stage disease, further complicating analysis and comparability of these trials Furthermore, the two trials employed different TKIs, making it challenging to directly compare the efficacy of lenvatinib and apatinib given the varied patient populations. Additionally, there were discrepancies in the daily dose and duration of the IE chemotherapy between the trials. Our study utilized a lower daily dose of ifosfamide (1.8 g/m²/day compared to 3 g/m²/day in ITCC-050 and OLIE/ITCC-082) but extended the chemotherapy regimen to 10 cycles, compared to five cycles in the ITCC-050 and OLIE/ITCC-082 studies ( 12 , 13 ). This approach was informed by our retrospective findings indicating that Asian patients experienced significant myelosuppression after 3–4 cycles of the higher ifosfamide dose ( 14 ), and almost all progressions in the ITCC-050 study occurred after the cessation of IE chemotherapy ( 12 ). Therefore, to balance toxicity and efficacy, we reduced the daily dose and prolonged the duration of chemotherapy. Further investigations should be tried and conducted by managing the toxicities without compromsig the effectiveness of the chemotherapy in these kinds of combinations. In our previous retrospective study, the most prominent AEs associated with combination therapy were ifosfamide-induced encephalitis, which occurred more frequently and with greater severity than typically reported ( 14 ). This complication was partly attributed to hypoalbuminemia and hypertension induced by apatinib ( 15 ). However, in this trial, careful patient selection and preconditioning measures effectively mitigated the incidence of grade 3 or higher encephalitis. Another significant AE impacting patients' QoL was pneumothorax, likely due to necrosis within pulmonary lesions. All patients with pneumothorax were managed by chemical or mechanical pleurodesis in this trial. This procedure, though typically arduous and accompanied by chest pain and fevers, allowed for the continuation of treatment without interruption( 15 ). This study has several limitations. Firstly, we did not include any biomarker analysis, which could have provided insights into the mechanisms underlying the efficacy of the combination. Secondly while our combination cohort demonstrated superior efficacy compared to IE alone, we did not evaluate the benefits of apa + IE against apatinib monotherapy or apatinib combined with anti-PD-1 therapy. This omission leaves an open question regarding which strategy might provide the most benefit for heavily pretreated populations. In summary, for patients with unresectable or refractory osteosarcomas that have progressed following ifosfamide-included chemotherapy, the combination of apatinib and IE demonstrated superior PFS compared to IE alone, with an acceptable toxicity profile. Prophylactic measures should be prioritized to mitigate serious AEs and improve patients' QoL. Declarations Author Contributions Conception and design: Wei Guo, Xiaodong Tang and Lu Xie; Financial support: Lu Xie and Xiaodong Tang; Administrative support: Lu Xie; Provision of study materials or patients: Lu Xie, Xin Sun, Jie Xu, Guangxin Zhou, Sujia Wu, Yingqi Hua, Haiyan Hu, Yi Yang, Tao Ji; Collection and assembly of data: All authors; Data analysis and interpretation: All authors; Manuscript writing: All authors; Final approval of manuscript: All authors; Accountable for all aspects of the work: All authors. Conflict of Interest Disclosures Du Wang, Shurong Shao, Zhongjiang Chen and Zheng Pang are employees of Jiangsu Hengrui Pharmaceuticals. The other authors declare no competing interests. Funding/Support OAIE/PKUPH-sarcoma 11 was funded by Jiangsu Hengrui Pharmaceuticals Co, Ltd. Apatinib as well as ifosfamide and etoposide in this trial were all provided free of charge by Jiangsu Hengrui Pharmaceuticals Co, Ltd. The first author LX also received Research and Development Fund of Peking University People’s Hospital (Clinical research incubation program, No. RDL2022-37) and Beijing Natural Science Foundation-Changping Innovation Collaborative Fund (No. L234041) to support this trial. Role of the Funding Source The funder of the study was involved in the study design, data collection, data analysis, data interpretation, and writing of the report. All authors had full access to all the data in this study and take final responsibility for the decision to submit the manuscript for publication. Meeting Presentation Preliminary findings from this study were presented at the 2024 ASCO Annual Meeting and the 2024 CTOS Annual Meeting. Data Sharing Statement Deidentified participant data from this study will be made available to qualified researchers upon reasonable request. Requests should be directed to the corresponding author via email and will require approval from the study sponsor. Data access will be provided starting two years after the study's completion. Additional Contributions We extend our deepest gratitude to the patients and their families for their invaluable participation. We also acknowledge the dedicated efforts of all investigators and study staff who contributed to the execution of this trial. References Grignani G, Palmerini E, Dileo P, Asaftei SD, D'Ambrosio L, Pignochino Y, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23(2):508-16. Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, et al. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019;37(16):1424-31. Duffaud F, Mir O, Boudou-Rouquette P, Piperno-Neumann S, Penel N, Bompas E, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2019;20(1):120-33. Xie L, Xu J, Sun X, Tang X, Yan T, Yang R, et al. Apatinib for Advanced Osteosarcoma after Failure of Standard Multimodal Therapy: An Open Label Phase II Clinical Trial. Oncologist. 2019;24(7):e542-e50. Gaspar N, Campbell-Hewson Q, Gallego Melcon S, Locatelli F, Venkatramani R, Hecker-Nolting S, et al. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)(☆). ESMO Open. 2021;6(5):100250. Xie L, Xu J, Sun X, Guo W, Gu J, Liu K, et al. Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial. J Immunother Cancer. 2020;8(1). Schott C, Shah AT, Sweet-Cordero EA. Genomic Complexity of Osteosarcoma and Its Implication for Preclinical and Clinical Targeted Therapies. Adv Exp Med Biol. 2020;1258:1-19. Scott LJ. Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers. Drugs. 2018;78(7):747-58. Blackledge G, Steward WP, Verweij J, Mouridsen H, Bramwell V, Schutte J, et al. Experience with ifosfamide in the EORTC Soft Tissue and Bone Sarcoma Group. Semin Oncol. 1992;19(1 Suppl 1):14-8. Gentet JC, Brunat-Mentigny M, Demaille MC, Pein F, Avet-Loiseau H, Berger C, et al. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. Eur J Cancer. 1997;33(2):232-7. Gaspar N, Campbell-Hewson Q, Huang J, Okpara CE, Bautista F. OLIE, ITCC-082: a Phase II trial of lenvatinib plus ifosfamide and etoposide in relapsed/refractory osteosarcoma. Future Oncol. 2021;17(32):4249-61. Gaspar N, Venkatramani R, Hecker-Nolting S, Melcon SG, Locatelli F, Bautista F, et al. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. 2021;22(9):1312-21. Gaspar N, Hung G-Y, Strauss S, Campbell-Hewson Q, Dela Cruz F, Glade Bender J, et al. A multicenter, open-label, randomized, phase 2 study of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. 2022 Connective Tissue Oncology Society (CTOS) Annual Meeting. 2022. Xie L, Xu J, Sun X, Li X, Liu K, Liang X, et al. Apatinib plus ifosfamide and etoposide for relapsed or refractory osteosarcoma: A retrospective study in two centres. Oncol Lett. 2021;22(1):552. Xie L, Xu J, Guo W, Wang Z, Yao Y, Li J, et al. Management of Apatinib-Related Adverse Events in Patients With Advanced Osteosarcoma From Four Prospective Trials: Chinese Sarcoma Study Group Experience. Front Oncol. 2021;11:696865. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76. Lagmay JP, Krailo MD, Dang H, Kim A, Hawkins DS, Beaty O, 3rd, et al. Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward. J Clin Oncol. 2016;34(25):3031-8. van Ewijk R, Cleirec M, Herold N, le Deley MC, van Eijkelenburg N, Boudou-Rouquette P, et al. A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design? Cancer Treat Rev. 2023;120:102625. Schulte B, Mohindra N, Milhem M, Attia S, Robinson S, Monga V, et al. Phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas. Br J Cancer. 2021;125(4):528-33. Additional Declarations There is NO Competing Interest. Supplementary Files Supplement.pdf Supplementary figures and tables Protocol.pdf Trial protocol CONSORT2010Checklist.doc consort checklist SAP.docx Statistical Analysis Plan for STS-II-010 Cite Share Download PDF Status: Published Journal Publication published 25 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5641573","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":402477963,"identity":"ffa3d6b3-9507-4761-8d37-845b5a859183","order_by":0,"name":"Xiaodong 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post-treatment, while others received palliative surgery or radiotherapy. FAS, full analysis set, SS, safety analysis set.\u003c/p\u003e","description":"","filename":"Binder11.png","url":"https://assets-eu.researchsquare.com/files/rs-5641573/v1/96cab9605d5937e0ee9603f8.png"},{"id":73942994,"identity":"da0ce312-89b8-47eb-a4e6-5dbc6e3e769b","added_by":"auto","created_at":"2025-01-16 08:14:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97591,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of (A) progression-free survival and (B) overall survival. NE, not estimated; HR, hazard ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Binder12.png","url":"https://assets-eu.researchsquare.com/files/rs-5641573/v1/2f1980bf90d534a26863d9dc.png"},{"id":96798851,"identity":"ade83241-3c23-40c2-b59e-fd05b98701e6","added_by":"auto","created_at":"2025-11-26 08:13:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":916476,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5641573/v1/d03b3645-bdc1-4fb9-8d06-6fe4f13e08f7.pdf"},{"id":73942998,"identity":"74268e41-597b-4de3-a94b-adffaaeff5c1","added_by":"auto","created_at":"2025-01-16 08:14:03","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":285534,"visible":true,"origin":"","legend":"Supplementary figures and tables","description":"","filename":"Supplement.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5641573/v1/5f4d177e8f8b0422d95d5263.pdf"},{"id":73942997,"identity":"ba4f2177-3ad5-4384-b062-dac5a96bb938","added_by":"auto","created_at":"2025-01-16 08:14:03","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1036004,"visible":true,"origin":"","legend":"Trial protocol","description":"","filename":"Protocol.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5641573/v1/da682fb7d75ce569b22d8f7e.pdf"},{"id":73943334,"identity":"f0cf829c-2dda-473d-87a1-67dece32ea01","added_by":"auto","created_at":"2025-01-16 08:22:03","extension":"doc","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":221184,"visible":true,"origin":"","legend":"consort checklist","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-5641573/v1/acac3b30a08ae8147fb96edc.doc"},{"id":73943335,"identity":"5978dd35-132f-4bb3-9b5c-f7af3da1d059","added_by":"auto","created_at":"2025-01-16 08:22:03","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":101707,"visible":true,"origin":"","legend":"Statistical Analysis Plan for STS-II-010","description":"","filename":"SAP.docx","url":"https://assets-eu.researchsquare.com/files/rs-5641573/v1/65a56098815e8132c64dfec1.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Randomized Study of Apatinib plus Ifosfamide and Etoposide versus Ifosfamide and Etoposide in Patients With Advanced Osteosarcomas (OAIE/PKUPH-sarcoma 11)","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe prognosis for patients with inoperable, metastatic osteosarcoma that is resistant to first-line chemotherapy remains poor. Previous studies have demonstrated that multi-targeted tyrosine kinase inhibitor (TKIs) can induce varying degrees of objective responses and prolong progression-free survival (PFS) (\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, the efficacy of TKIs is often compromised by factors such as large tumor volumes, poor performance status, and the axial location of lesions (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and so on. Additionally, clinical trials involving TKIs alone are typically with median PFS ranging from 4 to 6 months accompanied with inevitable development of secondary drug resistance (\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Specifically, TKIs often exhibit limited and short-lived efficacy in controlling musculoskeletal lesions besides other metastasis outside the lung (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), the underlying mechanism of which remains poorly understood. Osteosarcoma is characterized by significant genomic instability and genetic heterogeneity (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), necessitating treatments that have traditionally focused on cytotoxic and cytostatic drugs. These treatments often require combination strategy to address the intra- and inter-tumoral heterogeneity effectively. In this context, classic second-line chemotherapy regimen, such as ifosfamide and etoposide (IE), might complement the activity of TKIs. It might be possible to achieve better overall disease control by combining IE with TKIs, especially for those with multiple metastatic lesions in different organs.\u003c/p\u003e \u003cp\u003eApatinib, a multi-targeted TKI utilized in the treatment of gastric, non-small cell lung, and esophageal cancers (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), has demonstrated efficacy in inhibiting the proliferation, migration, and invasion of osteosarcoma in both preclinical and clinical trials (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). IE are chemotherapeutic agents that induce DNA damage: ifosfamide acts as an alkylating agent, whereas etoposide inhibits topoisomerase II (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Since the 1990s, the combination of IE has been employed in multiple pediatric clinical settings, with a phase II trial reporting a response rate of 48% and acceptable toxicity inrelapsed or refractory pediatric osteogenic sarcomas (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The rationale for combining TKIs with IE, including lenvatinib plus IE, was initially proposed by Gaspar et al (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) with the idea of inhibition of angiogenesis may increase uptake of IE into tumor tissue through vascular normalization. In the current study, this combination strategy is based on the premise that adding chemotherapy can mitigate the limitations of the cytostatic properties of TKIs, particularly in managing extra-pulmonary lesions (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Furthermore, in heavily pretreated patients with inoperable lesions, managing adverse events (AEs) to a tolerable level is crucial since the therapy may need to be administered over a life-long period. By utilizing off-label doses for these combinations, we developed a suitable metronomic chemotherapy regimen in combination with apatinib in our previous study, allowing for a longer duration of chemotherapy compared to the OLIE/ITCC-082 study (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Thus, this randomized controlled trial aims to evaluate the efficacy of combining apatinib with IE versus IE alone in patients with unresectable, recurrent or refractory osteosarcoma.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis multicenter, randomized controlled trial (OAIE/PKUPH-sarcoma 11) was conducted across four centers in China under the auspices of the Chinese Sarcoma Study Group. The study enrolled adolescents and adults aged 12 to 65 years, with body surface areas exceeding 1.0 m\u0026sup2;. Participants were required to have histologically or pathologically confirmed locally advanced or metastatic high-grade osteosarcoma that had either progressed following at least one line of prior chemotherapy. Enrollment criteria mandated that the disease be measurable according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Eligible patients needed to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0\u0026ndash;1, an expected survival of more than three months, and satisfactory organ function. Exclusion criteria included previous treatment with any TKIs such as apatinib, anlotinib, regorafenib, cabozantinib, or sorafenib, or those treated solely with IE chemotherapy. Additionally, patients with symptomatic central nervous system metastasis or uncontrolled comorbid conditions that could interfere with protocol adherence were excluded. Detailed inclusion and exclusion criteria are provided in the study protocol.\u003c/p\u003e \u003cp\u003e The trial received ethical approval from the Ethical Review Committee of Peking University People\u0026rsquo;s Hospital and other participating centers, and it was conducted in accordance with the Declaration of Helsinki and applicable local regulatory requirements and laws. Informed consents were obtained from all participants, with minors providing assent alongside consents from their legal guardians. The trial is registered on ClinicalTrials.gov (NCT05277480).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eEligible patients were randomized in a 2:1 ratio to receive either the combination of apatinib and IE (Apa\u0026thinsp;+\u0026thinsp;IE group) or IE alone (IE group). Participants in the Apa\u0026thinsp;+\u0026thinsp;IE group received 500 mg of apatinib orally once daily, combined with ifosfamide (1.8 g/m\u0026sup2;/day d\u003csub\u003e1\u0026thinsp;\u0026minus;\u0026thinsp;3\u003c/sub\u003e) and etoposide (100 mg/m\u0026sup2;/day d\u003csub\u003e1\u0026thinsp;\u0026minus;\u0026thinsp;3\u003c/sub\u003e), administered every three weeks (Q3W) with appropriate hydration and mesna for cytoprotection. The IE group received the same daily dose of ifosfamide and etoposide, albeit on an extended schedule (d\u003csub\u003e1\u0026thinsp;\u0026minus;\u0026thinsp;5\u003c/sub\u003e Q3W) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, initiation of non-protocol cancer therapies, or death. Additionally, apatinib was administered for a maximum of one year, while IE was administered for up to 10 cycles. Dose adjustments were permitted for toxicity management according to protocol; however, if treatment was postponed for over four weeks beyond a planned cycle, discontinuation was mandated.\u003c/p\u003e \u003cp\u003eBoth groups underwent tumor evaluations using computed tomography or magnetic resonance imaging at baseline and subsequently every two cycles according to RECIST 1.1 criteria. AEs were recorded and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Furthermore, all participants completed the European Organization for Research and Treatment of Cancer (EORTC) 30-item core Quality of Life (QoL) questionnaire (QLQ-C30) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) prior to initiating treatment, with follow-up QoL assessments conducted every two cycles.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eIn this study, the primary endpoint was PFS, as assessed by the investigators using RECIST 1.1 criteria. PFS was defined as the time from randomization to disease progression or death from any cause, whichever occurred first. Secondary endpoints included 4-month PFS rate; 6-month PFS rate; overall survival (OS), measured from randomization to death from any cause; objective response rate (ORR), defined as the proportion of patients achieving a complete response (CR) or partial response (PR); disease control rate (DCR), which encompassed the percentage of patients with either CR, PR, or stable disease (SD); duration of response (DoR), calculated from the first occurrence of CR or PR to progressive disease (PD) or death; time to response (TTR), the interval from randomization to the first CR or PR; time to progression (TTP), defined as the time from randomization to disease progression; and safety assessments throughout the study duration. The exploratory endpoints included QoL, assessed using the EORTC QLQ-C30 questionnaire, and event-free survival (EFS). Duing the treatment, some patients received local therapy, such as local radiation or sugery, which was not allowed for this trial. And we calculated these cases as censoring for PFS, however at the same time we also use EFS to describe the time from randomization to the first occurrence of disease progression, local or distant recurrence, initiation of subsequent anti-tumor therapy, or death, of which the local therapy was permitted in this course, so to comparing the result to other trials.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAssuming a median PFS of 5.0 months in the IE group and 11.0 months in the Apa\u0026thinsp;+\u0026thinsp;IE group (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), detecting a hazard ratio (HR) of 0.45 with 80% power at a two-sided significance level of 0.05 required 69 PFS events. Considering a 2:1 randomization ratio and anticipating an 18-month enrollment period followed by a 12-month follow-up, the study aimed to enroll 46 patients in the Apa\u0026thinsp;+\u0026thinsp;IE group and 23 patients in the IE group to observe sufficient PFS events by the study's conclusion. Factoring in a 10% dropout rate, the total required sample size was adjusted to 52 patients in the Apa\u0026thinsp;+\u0026thinsp;IE group and 26 patients in the IE group, culminating in a total enrollment of 78 patients.\u003c/p\u003e \u003cp\u003eThe full analysis set (FAS) included all participants who received at least one dose of the study treatment and served as the primary efficacy analysis dataset. The safety analysis set (SS) encompassed all patients who received at least one dose of the study treatment. The Kaplan-Meier method was utilized to estimate the median PFS for each treatment group, and the 95% confidence intervals (CIs) of median PFS were calculated using the Brookmeyer and Crowley method. Differences in PFS between the Apa\u0026thinsp;+\u0026thinsp;IE group and the IE group were evaluated using an unstratified log-rank test. Additionally, an unstratified Cox proportional hazards regression model estimated the HR and its associated 95% CI. Subgroup analyses were performed according to baseline factors. The median values for OS, DoR, TTP, and TTR for each group were also estimated using the Kaplan-Meier method, with 95% CIs calculated by the Brookmeyer and Crowley method. The 95% CIs for the 4- and 6-month PFS rate, ORR and DCR were estimated using the Clopper-Pearson method. QoL assessments, as measured by the subscales of the EORTC QLQ-C30, were scored according to the EORTC scoring manual. Each scale was transformed so that scores ranged from 0 to 100, with higher scores indicating better functioning and lower scores indicating worse symptoms. Scale scores were summarized as continuous variables for baseline and each scheduled post-baseline visit by treatment group, with mean values and standard deviations reported for each time point. The Friedman test was used to assess significant changes in QoL scores over time. All statistical analyses were performed using SAS version 9.3 or higher. A P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eBaseline characteristics of patients\u003c/h2\u003e\n \u003cp\u003eBetween April 2022 and August 2023, 89 patients were assessed for eligibility, with 81 patients subsequently enrolled. Of these, 53 were randomized to the Apa\u0026thinsp;+\u0026thinsp;IE group and 28 to the IE group. All enrolled patients received treatment and were included in both the FAS and the SS (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, baseline characteristics were generally balanced between the two groups. The proportion of participants younger than 18 was comparable, accounting for 54.7% in the Apa\u0026thinsp;+\u0026thinsp;IE group and 53.6% in the IE group. The median time since initial diagnosis was slightly shorter in the Apa\u0026thinsp;+\u0026thinsp;IE group at 12.1 months (interquartile range [IQR] 5.4\u0026ndash;18.8) compared to 15.1 months (IQR 8.6\u0026ndash;22.7) in the IE group. Approximately 30% of patients had an ECOG PS of 0. Lung-only metastasis was observed in 66.0% of patients in the Apa\u0026thinsp;+\u0026thinsp;IE group and 71.4% in the IE group. All patients had received prior anthracyclines while 88.7% of the Apa\u0026thinsp;+\u0026thinsp;IE group and 92.9% of the IE group had received prior ifosfamide treatment in combination with other chemo-agents. 71.7% of patients in the Apa\u0026thinsp;+\u0026thinsp;IE group had undergone prior one surgery, compared to 64.3% in the IE group, while 22.6% and 32.1% respectively had two or more surgeries. With final analysis, we had 13.6% (11/81) patients censored due to local therapy of selected lesions, of which usually the biggest lesion that had been radiated to avoid secondary drug resistance.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics of patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eApa\u0026thinsp;+\u0026thinsp;IE group (n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIE group (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29 (54.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24 (45.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34 (64.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTime since initial diagnosis, months, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.1 (5.4, 18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.1 (8.6, 22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG PS*, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32 (60.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocation of primary tumor, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLimbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37 (69.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (30.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetastatic sites, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25 (47.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSites of metastasis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnly lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTargeted tumor burden, mm, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33.2 (10.0, 225.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.5 (10.0, 138.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious lines of therapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40 (75.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious chemotherapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnthracyclines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e53 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIfosfamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47 (88.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (92.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBest overall response to previous ifosfamide, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePartital response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23 (43.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20 (37.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious surgery, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38 (71.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious radiotherapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e*Only patients with an ECOG PS of 2\u0026ndash;3 for amputation surgery were included.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eIQR, interquartile range; ECOG PS, Eastern Cooperative Oncology Group performance status.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eBy the cut-off date of October 8, 2024, median follow-up was 19.9 months (95% CI: 19.1, 21.8). Treatment was ongoing for three patients in the Apa\u0026thinsp;+\u0026thinsp;IE group and one patient in the IE group with last follow-up.\u003c/p\u003e\n\u003cp\u003eThe Apa\u0026thinsp;+\u0026thinsp;IE group exhibited a median PFS of 5.5 months (95% CI: 3.9, 6.4), compared to 3.4 months (95% CI: 1.4, 4.6) in the IE group, with a HR of 0.60 (95% CI: 0.37, 0.98; P\u0026thinsp;=\u0026thinsp;0.0402) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The 4-month and 6-month PFS rates were 65.8% (95% CI: 50.3, 77.5) and 36.7% (95% CI: 22.5, 50.9) in the Apa\u0026thinsp;+\u0026thinsp;IE group, versus 41.6% (95% CI: 22.4, 59.8) and 15.9% (95% CI: 4.2, 34.3) in the IE group, respectively. If we calucated all those censoring data which were due to local therapy, the median EFS was 5.5 months (95% CI: 3.9, 5.9) for the Apa\u0026thinsp;+\u0026thinsp;IE group, compared to 3.4 months (95% CI: 1.4, 4.6) for the IE group (HR, 0.64; 95% CI: 0.40, 1.02, P\u0026thinsp;=\u0026thinsp;0.0598) (Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e). The median OS was 18.1 months (95% CI: 13.7, 25.2) for the Apa\u0026thinsp;+\u0026thinsp;IE group, compared to 22.9 months (95% CI: 19.3, not estimated [NE]) for the IE group (HR, 1.48; 95% CI: 0.76, 2.89) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\n\u003cp\u003eThe ORR was 32.1% in the Apa\u0026thinsp;+\u0026thinsp;IE group and 25.0% in the IE group. The DCR was observed at 90.6% in the Apa\u0026thinsp;+\u0026thinsp;IE group, while the IE group had a DCR of 60.7%. The median TTP was 5.1 months (95% CI: 3.7, 5.7) in the Apa\u0026thinsp;+\u0026thinsp;IE group and 2.5 months (95% CI: 1.4, 4.1) in the IE group (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). However, the median TTR was almost the same, with 1.4 months (95% CI: 1.2, 3.1) in the Apa\u0026thinsp;+\u0026thinsp;IE group while 1.5 months (95% CI: 1.3, 2.0) in the IE group. The DoR was also nearly the same between these two groups, with 3.9 months (95% CI: 1.9, 7.8) for the Apa\u0026thinsp;+\u0026thinsp;IE group and 4.1 months (95% CI: 1.7, NE) for the IE group. The percentage changes from baseline in target lesions for all patients are shown in Figure \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003eA, and treatment exposure along with DoR is presented in Figure \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003eB.\u0026nbsp;\u003c/p\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eEfficacy endpoints\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eApa\u0026thinsp;+\u0026thinsp;IE group (n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIE group (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBest overall response, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (30.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (58.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot evaluable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObjective response rate, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(19.9, 46.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(10.7, 44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease control rate, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (90.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(79.3, 96.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(40.6, 78.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTime to response, months, median (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.4 (1.2, 3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5 (1.3, 2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of response, months, median (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9 (1.9, 7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.1 (1.7, NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTime to progress, months, median (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.1 (3.7, 5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.5 (1.4, 4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProgression-free survival, median (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4 (4.9, 6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4 (1.4, 4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 months, % (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.8 (50.3, 77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.6 (22.4, 59.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months, % (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.7 (22.5, 50.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.9 (4.2, 34.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOverall survival, median (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR (12.3, NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR (12.0, NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months, % (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.2 (85.6, 99.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92.7 (73.9, 98.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 months, % (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.3 (54.1, 81.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.2 (58.3, 93.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 months, % (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57.9 (35.6, 74.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58.1 (28.8, 78.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eCI, confidence interval; NE, not estimable.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eFollowing disease progression, patients\u0026rsquo; general condition seemed to be better and later treatment options seemed to be more in the IE group. In the Apa\u0026thinsp;+\u0026thinsp;IE group, 30.2% had no further treatment (OS events) compared to 18.9% in the IE group. The most common subsequent therapies in the Apa\u0026thinsp;+\u0026thinsp;IE group were multiple other chemotherapy plus TKIs (18.9%), chemotherapy alone (17.0%), and other TKI monotherapy (9.4%). In the IE group, chemotherapy alone (21.4%), chemotherapy plus TKI (14.3%) and antibody-drug conjugates (14.3%) were primarily used (Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety profiles\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment-related adverse events (TRAEs) were reported in 98.1% of patients in the Apa+IE group and 89.3% of patients in the IE group. Grade 3 or higher TRAEs occurred in 69.8% of the Apa+IE group compared to 64.3% in the IE group. Serious adverse events (SAEs) were observed in 11.3% of patients receiving Apa+IE and 10.7% of those in the IE group. For combination group, indeed more toxicities occurred, like hand and foot syndrome, pneumothorax and so on. However neutropenia and thrombocytopenia did not seem to be more severe in the apa+IE group because the dose of the chemotherapy had been reduced in the combination group (Table 3). In the Apa+IE group, there were no dose interruptions or reductions with chemotherapy, whereas in the IE group, one patient (3.6%) discontinued treatment because of severe myelosuppression. For apatinib, dose interruptions occurred in seven patients (13.2%), dose reductions in 16 patients (30.2%), and discontinuation in one patient (1.9%) within the Apa+IE group.\u003c/p\u003e\n\u003cp\u003eTable 3. Treatment related adverse events (TRAEs) in at least 10% of patients in either group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eEvents, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eApa+IE group (n=53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eIE group (n=28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eGrade \u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eGrade \u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 40px;\"\u003e\n \u003cp\u003eAny TRAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e52 (98.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e37 (69.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e25 (89.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e18 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003ePlatelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e39 (73.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e21 (39.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e15 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eWhite blood cell decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e37 (69.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e27 (50.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e19 (67.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e17 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e35 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e17 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e21 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e15 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eNeutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e32 (60.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e26 (49.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e19 (67.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e15 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e32 (60.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eProteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e18 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eHypoproteinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e10 (18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e9 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e8 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eHypocalcemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e8 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eThyrotropin increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e7 (13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003ePneumothorax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e6 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eHypokalemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e5 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003eLymphocyte count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e3 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eQuality of life\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThroughout the treatment course, patients in the Apa+IE group reported a statistically significant improvement in global health status, with the mean score increasing from 47.12 at baseline to 56.67 by cycle 9 (P=0.042). Conversely, the IE group did not exhibit a statistically significant change in QoL over the course of treatment (Table S2).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis randomized, multicenter, phase II trial successfully met its primary endpoint, demonstrating a significantly longer median PFS for Apa\u0026thinsp;+\u0026thinsp;IE compared to IE alone. However, unlike our retrospective study where local therapy was permitted (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), current study failed to achieve a median PFS for 11 months or longer, but with only 5.5 months in the Apa\u0026thinsp;+\u0026thinsp;IE while 3.4 months in the IE group. For patients with unresectable and refractory osteosarcoma following first-line chemotherapy, the prognosis has remained dismal over the past 30 years, with a 5-year post-relapse survival rate of less than 20% (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Although multi-targeted TKIs can induce responses (as evidenced by similar ORR in the present study), long-term disease control remains to be a critical challenge (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In this study, the combination of apatinib and IE demonstrated superior PFS compared to IE alone in osteosarcoma progressed upon MAP\u0026thinsp;+\u0026thinsp;I first-line chemotherapy (Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e), particularly those with multiple metastatic sites and substantial tumor burden. However, as for lesions outside the lungs, it still seems to be challenging to be controlled by this combination, which partly might be due to the lower daily dose of IE. However in real world practice, we had ever tried higher daily dose in combination like OLIE/ITCC-082 did, there were rarely anyone could tolerate more than 5 cycles of chemotherapy since these patients had been heavily pretreated by first-line chemotherapy for a year or even more. In this study, the addition of metronomic chemotherapy did not effectively overcome rapid secondary resistance, prolonging PFS as we previously expected. But it did successfully prolong the mPFS compared to IE alone.\u003c/p\u003e \u003cp\u003eThe rationale for combining apatinib with IE in this study is grounded by the hypothesis that integrating traditional, effective second-line chemotherapy can enhance the overall disease control for both pulmonary and extrapulmonary lesions, which, especially the later, are often poorly controlled by apatinib alone (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Nathalie Gaspar et al. previously explored the combination of lenvatinib with IE in patients with refractory or relapsed osteosarcoma, achieving a median PFS of 8.7 months (95% CI 4.5\u0026ndash;12.0) in the phase 1/2 study of ITCC-050 (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Their approach was predicated on the synergistic mechanism of cytotoxic agents and VEGF pathway inhibition, which can slow tumor growth through angiogenesis suppression and indue more cytoxic reactions (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, results from the phase II randomized controlled study of OLIE/ITCC-082 did not demonstrate statistical superior survival benefit, even for PFS only (6.5 months vs. 5.5 months, respectively) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Our study, by contrast, has shown that the combination of apatinib with IE prolongs PFS in patients progressed upon MAP\u0026thinsp;+\u0026thinsp;I chemotherapy, which might mostly be due to a higher percentage of participants in our study had progressed following ifosfamide-containing combination chemo-protocol (Figure \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e) (90.1% compared to 46.9% in the OLIE/ITCC-082 study) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), which likely weakened the efficacy of the control group. Although single IE intensified the intensity and density of ifosphamide than first-line MAP\u0026thinsp;+\u0026thinsp;I, which could induce some responses or control disease for some time in our study, it was less effective in the ifosfamide-pretreated population other than in the ifosfamide-na\u0026iuml;ve population. Thus we did not have such powerful control as OLIE/ITCC-082 did, our study group won the control. This factor may account for the numerically shorter median PFS observed in both groups of our study compared to OLIE/ITCC-082.\u003c/p\u003e \u003cp\u003eIn the meanwhile, there are some other differences between the OLIE/ITCC-082 and present study (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Most notably, local therapy, which could be performed after 18 weeks of treatment in the lenvatinib plus IE, was not permitted in this study, which might partly explain why the mPFS seems to be longer in the OLIE/ITCC-082 than in our trial. For patients with advanced osteosarcoma, even when lesions are not fully resectable at baseline, local therapies such as radiotherapy for large tumor burdens can significantly delay secondary drug resistance and prolong EFS. This is exemplified in our retrospective study (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), where despite patients being in more advanced stages of their disease, the median EFS could reach 11 months. The restriction on localized treatment in the current study created a complex scenario. Although the trial targeted inoperable osteosarcomas, treatment led to downstaging in many cases after 3\u0026ndash;4 cycles of treatment, potentially converting inoperable tumors to operable ones. Consequently, some patients opted for local therapies, primarily radiotherapy, to reduce tumor burden and maintain longer disease stability, thus leading to data censoring (13.6%) in the present trial. Thus when we calculated all those censoring data to compare the mEFS between the two groups, it was interesting to notice that the P value seemed not to be so significant by 0.0598, which might also be deemed as a confounding factor in OLIE/ITCC-082. While not recommended within the study protocol, this real-world adjustment highlights the ethical dilemmas faced in balancing trial guidelines with patient best interests. As a result, the tumor burden in this study was expectedly higher compared to other trials where local therapies allowed, as we included a larger proportion of patients with late-stage disease, further complicating analysis and comparability of these trials\u003c/p\u003e \u003cp\u003eFurthermore, the two trials employed different TKIs, making it challenging to directly compare the efficacy of lenvatinib and apatinib given the varied patient populations. Additionally, there were discrepancies in the daily dose and duration of the IE chemotherapy between the trials. Our study utilized a lower daily dose of ifosfamide (1.8 g/m\u0026sup2;/day compared to 3 g/m\u0026sup2;/day in ITCC-050 and OLIE/ITCC-082) but extended the chemotherapy regimen to 10 cycles, compared to five cycles in the ITCC-050 and OLIE/ITCC-082 studies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This approach was informed by our retrospective findings indicating that Asian patients experienced significant myelosuppression after 3\u0026ndash;4 cycles of the higher ifosfamide dose (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), and almost all progressions in the ITCC-050 study occurred after the cessation of IE chemotherapy (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Therefore, to balance toxicity and efficacy, we reduced the daily dose and prolonged the duration of chemotherapy. Further investigations should be tried and conducted by managing the toxicities without compromsig the effectiveness of the chemotherapy in these kinds of combinations.\u003c/p\u003e \u003cp\u003eIn our previous retrospective study, the most prominent AEs associated with combination therapy were ifosfamide-induced encephalitis, which occurred more frequently and with greater severity than typically reported (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). This complication was partly attributed to hypoalbuminemia and hypertension induced by apatinib (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, in this trial, careful patient selection and preconditioning measures effectively mitigated the incidence of grade 3 or higher encephalitis. Another significant AE impacting patients' QoL was pneumothorax, likely due to necrosis within pulmonary lesions. All patients with pneumothorax were managed by chemical or mechanical pleurodesis in this trial. This procedure, though typically arduous and accompanied by chest pain and fevers, allowed for the continuation of treatment without interruption(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study has several limitations. Firstly, we did not include any biomarker analysis, which could have provided insights into the mechanisms underlying the efficacy of the combination. Secondly while our combination cohort demonstrated superior efficacy compared to IE alone, we did not evaluate the benefits of apa\u0026thinsp;+\u0026thinsp;IE against apatinib monotherapy or apatinib combined with anti-PD-1 therapy. This omission leaves an open question regarding which strategy might provide the most benefit for heavily pretreated populations.\u003c/p\u003e \u003cp\u003eIn summary, for patients with unresectable or refractory osteosarcomas that have progressed following ifosfamide-included chemotherapy, the combination of apatinib and IE demonstrated superior PFS compared to IE alone, with an acceptable toxicity profile. Prophylactic measures should be prioritized to mitigate serious AEs and improve patients' QoL.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Wei Guo, Xiaodong Tang and Lu Xie;\u003c/p\u003e\n\u003cp\u003eFinancial support: Lu Xie and Xiaodong Tang;\u003c/p\u003e\n\u003cp\u003eAdministrative support: Lu Xie;\u003c/p\u003e\n\u003cp\u003eProvision of study materials or patients: Lu Xie, Xin Sun, Jie Xu, Guangxin Zhou, Sujia Wu, Yingqi Hua, Haiyan Hu, Yi Yang, Tao Ji;\u003c/p\u003e\n\u003cp\u003eCollection and assembly of data: All authors;\u003c/p\u003e\n\u003cp\u003eData analysis and interpretation: All authors;\u003c/p\u003e\n\u003cp\u003eManuscript writing: All authors;\u003c/p\u003e\n\u003cp\u003eFinal approval of manuscript: All authors;\u003c/p\u003e\n\u003cp\u003eAccountable for all aspects of the work: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDu Wang, Shurong Shao, Zhongjiang Chen and Zheng Pang are employees of Jiangsu Hengrui Pharmaceuticals. The other authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOAIE/PKUPH-sarcoma 11 was funded by Jiangsu Hengrui Pharmaceuticals Co, Ltd. Apatinib as well as ifosfamide and etoposide in this trial were all provided free of charge by Jiangsu Hengrui Pharmaceuticals Co, Ltd. The first author LX also received Research and Development Fund of Peking University People’s Hospital (Clinical research incubation program, No. RDL2022-37) and Beijing Natural Science Foundation-Changping Innovation Collaborative Fund (No. L234041) to support this trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of the Funding Source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funder of the study was involved in the study design, data collection, data analysis, data interpretation, and writing of the report. All authors had full access to all the data in this study and take final responsibility for the decision to submit the manuscript for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeeting Presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreliminary findings from this study were presented at the 2024 ASCO Annual Meeting and the 2024 CTOS Annual Meeting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Sharing Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeidentified participant data from this study will be made available to qualified researchers upon reasonable request. Requests should be directed to the corresponding author via email and will require approval from the study sponsor. Data access will be provided starting two years after the study's completion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extend our deepest gratitude to the patients and their families for their invaluable participation. We also acknowledge the dedicated efforts of all investigators and study staff who contributed to the execution of this trial.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eGrignani G, Palmerini E, Dileo P, Asaftei SD, D\u0026apos;Ambrosio L, Pignochino Y, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23(2):508-16.\u003c/li\u003e\n \u003cli\u003eDavis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, et al. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019;37(16):1424-31.\u003c/li\u003e\n \u003cli\u003eDuffaud F, Mir O, Boudou-Rouquette P, Piperno-Neumann S, Penel N, Bompas E, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2019;20(1):120-33.\u003c/li\u003e\n \u003cli\u003eXie L, Xu J, Sun X, Tang X, Yan T, Yang R, et al. Apatinib for Advanced Osteosarcoma after Failure of Standard Multimodal Therapy: An Open Label Phase II Clinical Trial. Oncologist. 2019;24(7):e542-e50.\u003c/li\u003e\n \u003cli\u003eGaspar N, Campbell-Hewson Q, Gallego Melcon S, Locatelli F, Venkatramani R, Hecker-Nolting S, et al. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)(☆). ESMO Open. 2021;6(5):100250.\u003c/li\u003e\n \u003cli\u003eXie L, Xu J, Sun X, Guo W, Gu J, Liu K, et al. Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial. J Immunother Cancer. 2020;8(1).\u003c/li\u003e\n \u003cli\u003eSchott C, Shah AT, Sweet-Cordero EA. Genomic Complexity of Osteosarcoma and Its Implication for Preclinical and Clinical Targeted Therapies. Adv Exp Med Biol. 2020;1258:1-19.\u003c/li\u003e\n \u003cli\u003eScott LJ. Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers. Drugs. 2018;78(7):747-58.\u003c/li\u003e\n \u003cli\u003eBlackledge G, Steward WP, Verweij J, Mouridsen H, Bramwell V, Schutte J, et al. Experience with ifosfamide in the EORTC Soft Tissue and Bone Sarcoma Group. Semin Oncol. 1992;19(1 Suppl 1):14-8.\u003c/li\u003e\n \u003cli\u003eGentet JC, Brunat-Mentigny M, Demaille MC, Pein F, Avet-Loiseau H, Berger C, et al. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. Eur J Cancer. 1997;33(2):232-7.\u003c/li\u003e\n \u003cli\u003eGaspar N, Campbell-Hewson Q, Huang J, Okpara CE, Bautista F. OLIE, ITCC-082: a Phase II trial of lenvatinib plus ifosfamide and etoposide in relapsed/refractory osteosarcoma. Future Oncol. 2021;17(32):4249-61.\u003c/li\u003e\n \u003cli\u003eGaspar N, Venkatramani R, Hecker-Nolting S, Melcon SG, Locatelli F, Bautista F, et al. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. 2021;22(9):1312-21.\u003c/li\u003e\n \u003cli\u003eGaspar N, Hung G-Y, Strauss S, Campbell-Hewson Q, Dela Cruz F, Glade Bender J, et al. A multicenter, open-label, randomized, phase 2 study of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. 2022 Connective Tissue Oncology Society (CTOS) Annual Meeting. 2022.\u003c/li\u003e\n \u003cli\u003eXie L, Xu J, Sun X, Li X, Liu K, Liang X, et al. Apatinib plus ifosfamide and etoposide for relapsed or refractory osteosarcoma: A retrospective study in two centres. Oncol Lett. 2021;22(1):552.\u003c/li\u003e\n \u003cli\u003eXie L, Xu J, Guo W, Wang Z, Yao Y, Li J, et al. Management of Apatinib-Related Adverse Events in Patients With Advanced Osteosarcoma From Four Prospective Trials: Chinese Sarcoma Study Group Experience. Front Oncol. 2021;11:696865.\u003c/li\u003e\n \u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47.\u003c/li\u003e\n \u003cli\u003eAaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76.\u003c/li\u003e\n \u003cli\u003eLagmay JP, Krailo MD, Dang H, Kim A, Hawkins DS, Beaty O, 3rd, et al. Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children\u0026apos;s Cancer Group, Pediatric Oncology Group, and Children\u0026apos;s Oncology Group: Learning From the Past to Move Forward. J Clin Oncol. 2016;34(25):3031-8.\u003c/li\u003e\n \u003cli\u003evan Ewijk R, Cleirec M, Herold N, le Deley MC, van Eijkelenburg N, Boudou-Rouquette P, et al. A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design? Cancer Treat Rev. 2023;120:102625.\u003c/li\u003e\n \u003cli\u003eSchulte B, Mohindra N, Milhem M, Attia S, Robinson S, Monga V, et al. Phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas. Br J Cancer. 2021;125(4):528-33.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5641573/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5641573/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eRetrospective analysis have indicated potential benefits of combining apatinib, a multi-targeted tyrosine kinase inhibitor, with ifosfamide and etoposide (IE) for advanced osteosarcoma. This study aims to compare the efficacy of apatinib plus IE versus IE alone in patients with relapsed or refractory osteosarcoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis multicenter, randomized controlled trial (NCT05277480) involved patients with relapsed or refractory osteosarcoma, who had progressed on first-line chemotherapy, typically comprising high-dose methotrexate, doxorubicin, cisplatin with or without ifosfamide (MAP/I). Participants were randomized in a 2:1 ratio to receive either apatinib plus IE or IE alone. The apatinib plus IE group received 500 mg of oral apatinib daily, along with ifosfamide (1.8 g/m²/day) and etoposide (100 mg/m²/day) d\u003csub\u003e1-3\u003c/sub\u003e q3w. The IE group received the same daily regimen d\u003csub\u003e1-5\u003c/sub\u003e q3w. The primary endpoint was median progression-free survival (mPFS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eFrom April 2022 to August 2023, 81 patients were enrolled, with 53 receiving apatinib plus IE and 28 receiving IE alone. With median follow-up of 19.9 months, the mPFS was 5.5 months (95% confidence interval [CI], 3.9 to 6.4) for the apatinib+IE, compared to 3.4 months (95% CI, 1.4 to 4.6) for single IE (hazard ratio, 0.60; 95% CI, 0.37 to 0.98; P=0.0402). The median OS was 18.2 months (95% confidence interval [CI], 13.7 to 25.2) for apatinib+IE, compared to 22.9 months (95% CI, 19.3 to NE) for single IE (hazard ratio, 1.48; 95% CI, 0.76 to 2.89; P=0.2493). The incidence of neutropenia and thrombocytopenia was similar between two groups. Quality of life assessments revealed significant improvements in global health status in apatinib+IE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eCombining apatinib with IE significantly enhances PFS in patients with relapsed or refractory osteosarcoma post MAP/I chemotherapy, maintaining an acceptable safety profile.\u003c/p\u003e","manuscriptTitle":"Randomized Study of Apatinib plus Ifosfamide and Etoposide versus Ifosfamide and Etoposide in Patients With Advanced Osteosarcomas (OAIE/PKUPH-sarcoma 11)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-16 08:13:58","doi":"10.21203/rs.3.rs-5641573/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"40b5ff8c-ec13-4c1d-bf97-d647cf5b425d","owner":[],"postedDate":"January 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":42901134,"name":"Health sciences/Oncology/Cancer/Sarcoma"},{"id":42901135,"name":"Health sciences/Oncology/Cancer/Paediatric cancer"}],"tags":[],"updatedAt":"2025-11-26T08:13:07+00:00","versionOfRecord":{"articleIdentity":"rs-5641573","link":"https://doi.org/10.1038/s41467-025-65467-8","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-11-25 05:00:00","publishedOnDateReadable":"November 25th, 2025"},"versionCreatedAt":"2025-01-16 08:13:58","video":"","vorDoi":"10.1038/s41467-025-65467-8","vorDoiUrl":"https://doi.org/10.1038/s41467-025-65467-8","workflowStages":[]},"version":"v1","identity":"rs-5641573","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5641573","identity":"rs-5641573","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}