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
Mené dans 24 pays sur 566 patientes atteintes d'un cancer de l'ovaire réfractaire ou résistant aux sels de platine, cet essai à 3 bras de phase III compare l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de la doxorubicine liposomale pégylée en monothérapie et de l'avélumab, dispensé seul ou en combinaison avec la doxorubicine liposomale pégylée
Background : Most patients with ovarian cancer will relapse after receiving frontline platinum-basedchemotherapy 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, phase3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligiblepatients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritonealcancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistantdisease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patientswere randomly assigned (1:1:1) via interactive response technology to avelumab (10mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, numberof 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 plusPLD is superior to PLD. Safety was assessed in all patients who received at leastone 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 bothprimary 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), medianduration of follow-up for overall survival was 18·4 months (IQR 15·6–21·9) for thecombination 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 centralreview 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-relatedadverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combinationgroup 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 inthe 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 PLDgroup (sepsis) and avelumab group (intestinal obstruction).
Interpretation : Neither avelumab plus PLD nor avelumab alone significantly improved progression-freesurvival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistantor platinum-refractory ovarian cancer.
The Lancet Oncology , résumé, 2020