Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study.

Background: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer.
Methods: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m ² intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints.
Findings: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction).
Interpretation: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer.
Funding: Pfizer and Merck KGaA, Darmstadt, Germany.
Competing Interests: Declaration of interests EP-L reports personal fees from AstraZeneca, Clovis Oncology, Incyte, Pfizer, Roche, and Tesaro; non-financial support from AstraZeneca, Roche, and Tesaro; and is the chair of ARCAGY-Research. KF reports grants and personal fees from Pfizer during the conduct of the study; and grants and personal fees from AstraZeneca, Chugai Pharma, Eisai, Genmab, Merck & Co, Taiho Pharmaceutical, and Zeria Pharmaceutical; grants from GSK, Immunogen, Lilly, OncoTherapy, and Regeneron; and personal fees from Daiichi Sankyo, Janssen, Kyowa Hakko Kirin, Mochida, Nippon Kayaku, and Novartis outside the submitted work. JAL reports serving as a consultant or advisor for Artios Pharma, AstraZeneca, Clovis Oncology, Eisai, GSK, Merck & Co, and Pfizer; has received research funding from AstraZeneca and Merck & Co; has received honoraria from AstraZeneca, Clovis Oncology, Eisai, and GSK; and has participated in an independent monitoring committee for Regeneron. RK reports personal fees from Clovis Oncology, Eisai, GSK, Incyte, and Roche; has received non-financial support from GSK; and grants from Merck & Co. I-LR-C reports personal fees from AstraZeneca, Clovis Oncology, GSK, Merck KGaA, Mersana Therapeutics, and Roche; received grants from Bristol Myers Squibb and GSK; and has received reimbursement for travel and accommodation expenses from AstraZeneca and GSK. KY reports serving as a consultant or advisor for AstraZeneca, Chugai Pharma, Eisai, Novartis, and Takeda; and received honoraria from AstraZeneca, Eisai, Pfizer, Takeda, and Taiho Pharmaceutical. SB reports personal fees from AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck KGaA, Mersana Therapeutics, Pfizer, Roche, and Tesaro; and has received grants from AstraZeneca, GSK, Merck & Co, and Tesaro. AL reports grants from Pfizer during the conduct of the study; serving as a consultant or advisor for AstraZeneca, BIOCAD, Clovis Oncology, GSK/Tesaro, Merck KGaA, Merck & Co, and Zentalis Pharmaceuticals; and has received reimbursement for travel and accommodation expenses from AstraZeneca, Clovis Oncology, and GSK/Tesaro. AVT has received honoraria and grants from AstraZeneca. KHJ reports personal fees from AstraZeneca, Celgene, Novartis, Roche, and Takeda Pharmaceuticals. FZ reports employment at and holds stock in Pfizer. RAS reports employment at Pfizer at the time when the study was conducted. CW reports employment at and holds stock in Pfizer. SSD reports employment at Pfizer. BJM reports serving as a consultant or advisor for and has received honoraria from Agenus, Akeso Bio, Aravive, AstraZeneca, Clovis Oncology, Eisai, Elevar Therapeutics, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Merck & Co, Mersana Therapeutics, Myriad Pharma, Novocure, Pfizer, Puma Biotechnology, Roche/Genentech, Tesaro/GSK, and VBL Therapeutics; is a member of a speakers' bureau for AstraZeneca, Clovis Oncology, Eisai, Merck & Co, Roche/Genentech, and Tesaro/GSK; and reports employment at McKesson/US Oncology. All other authors declare no competing interests.
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