Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial
Mené dans 25 pays sur 998 patientes atteintes d'un cancer épithélial de l'ovaire, cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité d'une chimiothérapie dispensée seule et d'une chimiothérapie combinée avec l'avélumab puis suivie d'un traitement d'entretien par avélumab
Background : Although most patients with epithelial ovarian cancer respond to frontline platinum-basedchemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance,versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer. Methods : JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligiblewomen were aged 18 years and older with stage III–IV epithelial ovarian, fallopiantube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvantchemotherapy), and had an Eastern Cooperative Oncology Group performance status of0 or 1. Patients were randomly assigned (1:1:1) via interactive response technologyto receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-timecurve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenouslyevery 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenouslyevery 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapyfollowed by observation (control group). Randomisation was in permuted blocks of sizesix and stratified by paclitaxel regimen and resection status. Patients and investigatorswere masked to assignment to the two chemotherapy groups without avelumab at the timeof randomisation until completion of the chemotherapy phase. The primary endpointwas progression-free survival assessed by blinded independent central review in allrandomly assigned patients (analysed by intention to treat). Safety was analysed inall patients who received at least one dose of study treatment. This trial is registeredwith ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility,and efficacy is no longer being assessed. Findings : Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumabmaintenance n=332, avelumab combination n=331, and control n=335). At the plannedinterim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries werecrossed for the progression-free survival analysis, and the trial was stopped as recommendedby the independent data monitoring committee and endorsed by the protocol steeringcommittee. Median follow-up for progression-free survival for all patients was 10·8months (IQR 7·1–14·9); 11·1 months (7·0–15·3) for the avelumab maintenance group,11·0 months (7·4–14·5) for the avelumab combination group, and 10·2 months (6·7–14·0)for the control group. Median progression-free survival was 16·8 months (95% CI 13·5–notestimable [NE]) with avelumab maintenance, 18·1 months (14·8–NE) with avelumab combinationtreatment, and NE (18·2 months–NE) with control treatment. The stratified hazard ratiofor progression-free survival was 1·43 (95% CI 1·05–1·95; one-sided p=0·99) with theavelumab maintenance regimen and 1·14 (0·83–1·56; one-sided p=0·79) with the avelumabcombination regimen, versus control treatment. The most common grade 3–4 adverse eventswere anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in theavelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%],99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59[18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumabmaintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in thecontrol group. Treatment-related deaths occurred in one (<1%) patient in the avelumabmaintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumabcombination group (due to disease progression). Interpretation : Although no new safety signals were observed, results do not support the use of avelumabin the frontline treatment setting. Alternative treatment regimens are needed to improveoutcomes in patients with advanced epithelial ovarian cancer.