Effect of Weekly Paclitaxel With or Without Bevacizumab on Progression-Free Rate Among Patients With Relapsed Ovarian Sex Cord-Stromal Tumors: The ALIENOR/ENGOT-ov7 Randomized Clinical Trial

Abstract

Importance: To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting.

Objective: To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate.

Design, setting, and participants: This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months).

Interventions: Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone.

Main outcomes and measures: Six-month progression-free rate.

Results: Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity.

Conclusions and relevance: Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit.

Trial registration: ClinicalTrials.gov Identifier: NCT01770301.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Ray-Coquard reported personal fees from Roche, AstraZeneca, GSK, Clovis, Genmab, Advaxis, Amgen, and PharmaMar outside the submitted work. Dr Harter reported grants and personal fees from AstraZeneca, GSK/Tesaro, and Roche; personal fees from Immunogen, Clovis, Sotio, Stryker, ZaiLab, and MSD; and grants from Boehringer Ingelheim, Medac, and Genmab outside the submitted work. Dr Lorusso reported personal fees from AstraZeneca, Amgen, and PharmaMar and grants and personal fees from GSK, Clovis, and Merck outside the submitted work. Dr Vergote reported personal fees from Amgen Europe, AstraZeneca, Clovis Oncology Inc, Carrick Therapeutics, Debiopharm International, F. Hoffmann-La Roche Ltd, Genmab, GlaxoSmithKline Pharmaceuticals, Immunogen Inc, Medical University of Vienna, Millennium Pharmaceuticals, MSD Belgium, Octimet Oncology NV, Oncoinvent, PharmaMar-Doctaforum, Sotio a.s., Tesaro, Deciphera Pharmaceuticals, and Verastem Oncology outside the submitted work; grants from Amgen; grants and personal fees from Roche; and accommodations/travel expenses in the past from Amgen, MSD/Merck, Roche, AstraZeneca, and Tesaro. Dr Fujiwara reported grants and personal fees from Chugai-Roche during the conduct of the study. Dr Gladieff reported personal fees from Roche, Clovis, and GSK; personal fees and nonfinancial support from AstraZeneca; and grants from MSD outside the submitted work. Dr Lück reported fees for consulting, lectures, and speakers’ bureaus from Roche, GSK, Lilly, Novartis, Pfizer, AstraZeneca, Clovis, Amgen, and Pierre Fabre. Dr Floquet reported nonfinancial support from Roche during the conduct of the study. Dr Pignata reported grants and personal fees from Roche, AstraZeneca, MSD, and Clovis and personal fees from Tesaro/GSK during the conduct of the study. Dr Selle reported personal fees and nonfinancial support from Roche, AstraZeneca, Tesaro, PharmaMar, and MSD and personal fees from Clovis and GlaxoSmithKline outside the submitted work. Dr Sehouli reported study fees from ENGOT/GINECO during the conduct of the study; grants and service on the advisory board for Roche, Clovis, GSK/Tesaro, PharmaMar, and Lilly; service on the advisory boards for AstraZeneca, NovoCure, MSD, Pfizer, and EISAI; and grants from Riemser and Medac outside the submitted work. Dr De Giorgi reported personal fees and nonfinancial support from Pfizer, Ipsen, BMS, and Janssen-Cilag; personal fees from Astellas, Bayer, Novartis, MSD, and PharmaMar; grants and personal fees from Sanofi; grants and nonfinancial support from Roche; and grants from AstraZeneca. Dr Heudel reported grants and nonfinancial support from AstraZeneca and Roche during the conduct of the study; personal fees from Myland; grants and nonfinancial support from Novartis and Pfizer outside the submitted work; and personal fees and nonfinancial support from Eisai outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Trial Profile

aOne case each of hypertension (serious adverse event) and neuropathy/proteinuria. bOne case each of hypertension (intermittent grade 3) and proteinuria. cOne case each of hypertension (intermittent grade 3), liver hematoma, and proteinuria (grade 3 serious adverse event).

Figure 2.. Swimmer Plot of Treatment and Disease Course

A, Paclitaxel-alone group. B, Paclitaxel plus bevacizumab group. Each bar represents a patient.

Figure 3.. Efficacy

A, Progression-free survival. B, Overall survival. C, Progression-free survival after switching to bevacizumab for 16 patients who were initially randomized to paclitaxel alone who received bevacizumab after progression. D, Time to first subsequent therapy.