Isabelle Ray-Coquard1, Philipp Harter2, Domenica Lorusso3, Cécile Dalban4, Ignace Vergote5, Keiichi Fujiwara6, Laurence Gladieff7, Hans-Joachim Lück8, Anne Floquet9, Annick Chevalier-Place10, Andreas Schnelzer11,12, Sandro Pignata13, Frédéric Selle14, Jalid Sehouli15, Fabien Brocard16, Giorgia Mangili17, Patricia Pautier18, Ugo De Giorgi19, Magali Provansal20, Pierre-Etienne Heudel21. 1. GINECO and Centre Léon Bérard, University Claude Bernard Lyon 1, Lyon, France. 2. AGO Study Group and Ev Kliniken Essen-Mitte, Essen, Germany. 3. MITO and Istituto Nazionale Tumori, Milan, Italy. 4. GINECO and Department of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France. 5. BGOG and University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium. 6. GOTIC and Saitama Medical University International Medical Center, Hidaka, Japan. 7. GINECO and Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France. 8. AGO Study Group and Gyneco-Oncological Practice, Hannover, Germany. 9. GINECO and Institut Bergonié, Bordeaux, France. 10. GINECO and Centre Oscar Lambret, Lille, France. 11. AGO Study Group and Frauenklinik Technical University Munich, Munich, Germany. 12. Current, RoMed Klinikum Rosenheim, Rosenheim, Germany. 13. MITO and Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. 14. GINECO and Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France. 15. AGO Study Group and Medical University of Berlin, Charité-CVK, Berlin, Germany. 16. GINECO and Centre Oncologie de Gentilly, Nancy, France. 17. MITO and Ospedale San Raffaele, Milan, Italy. 18. GINECO and Gustave Roussy, Villejuif, France. 19. MITO and Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS, Meldola, Italy. 20. GINECO and Institut Paoli Calmettes, Marseille, France. 21. GINECO and Centre Léon Bérard, Lyon, France.
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.
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.
Authors: Ignace Vergote; Antonio Gonzalez-Martin; Domenica Lorusso; Charlie Gourley; Mansoor Raza Mirza; Jean-Emmanuel Kurtz; Aikou Okamoto; Kathleen Moore; Frédéric Kridelka; Iain McNeish; Alexander Reuss; Bénédicte Votan; Andreas du Bois; Sven Mahner; Isabelle Ray-Coquard; Elise C Kohn; Jonathan S Berek; David S P Tan; Nicoletta Colombo; Rongyu Zang; Nicole Concin; Dearbhaile O'Donnell; Alejandro Rauh-Hain; C Simon Herrington; Christian Marth; Andres Poveda; Keiichi Fujiwara; Gavin C E Stuart; Amit M Oza; Michael A Bookman Journal: Lancet Oncol Date: 2022-08 Impact factor: 54.433