Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability
Julien Taı̈eb, Olivier Bouché, Thierry André, Karine Le Malicot, Pierre Laurent‐Puig, Jérémie Bez, Clémence Toullec, Christophe Borg, Violaine Randrian, Ludovic Evesque, Stéphane Corbinais, Hervé Perrier, Bruno Buecher, Frédéric Di Fiore, Claire Gallois, Jean‐François Emile, Côme Lepage, Farid El-Hajbi, David Tougeron, SAMCO-PRODIGE 54 Investigators, Anne Thirot‐Bidault, Laurent Mineur, Franck Audemar, Fayçal HOCINE, Stéfano Kim, Francine Fein, Hamadi Almotlak, Mélanie Dos Santos, Johannes Hartwig, Adrien MELIS, Marion Bolliet, Kaïs Aldabbagh, S. Cheaib, Sophie Hans, François Ghiringhelli, Christine Rebischung, Gaël S. Roth, Victoire Granger, Benoist Chibaudel, Aurélien Carnot, Diane Pannier, Samira Makhloufi, Thomas Walter, Christelle de la Fouchardière, Christelle BASTHISTE-PELE, Muriel Duluc, Emmanuel Guardiola, B. Linot, H. Castanie, Jean-Paul Lagasse, Jean-Nicolas Vaillant, Romain Coriat, Romain Cohen, D. López-Valbuena, Pauline Vaflard, Thomas Aparicio, J. Thaury, F. Khemissa Akouz, Denis Smith, Marion Chauvenet, Aurélie Ferru, Armelle Pillet, Anaïs de Singly, Karine Bideau, Damien Botsen, Mathilde Brasseur, Astrid Lièvre, Marie-Claude Gouttebel, David Sefrioui, Pierre MICHEL, Alice Gangloff, J. Chamois, Laurent Gasnault, Catherine Poisson, Jean–Marc Phelip, Méher Ben Abdelghani, Pierre Guillet, Camille Sibertin-Blanc, Morgane Caulet, Anthony Lopez
Abstract
Importance: Only 1 randomized clinical trial has shown the superiority of immune checkpoint inhibitors in patients with deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC) in the first-line setting. Objectives: To determine whether avelumab (an anti-programmed cell death ligand 1 antibody) improves progression-free survival (PFS) compared with standard second-line chemotherapy in patients with dMMR/MSI mCRC. Design, Setting, and Participants: The SAMCO-PRODIGE 54 trial is a national open-label phase 2 randomized clinical trial that was conducted from April 24, 2018, to April 29, 2021, at 49 French sites. Patients with dMMR/MSI mCRC who experienced progression while receiving standard first-line therapy were included in the analysis. Interventions: Patients were randomized to receive standard second-line therapy or avelumab every 2 weeks until progression, unacceptable toxic effects, or patient refusal. Main Outcome and Measures: The primary end point was PFS according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1, evaluated by investigators in patients with mCRC and confirmed dMMR and MSI status who received at least 1 dose of treatment (modified intention-to-treat [mITT] population). Results: A total of 122 patients were enrolled in the mITT population. Median age was 66 (IQR, 56-76) years, 65 patients (53.3%) were women, 100 (82.0%) had a right-sided tumor, and 52 (42.6%) had BRAF V600E-mutated tumors. There was no difference in patients and tumor characteristics between treatment groups. No new safety concerns in either group were detected, with fewer treatment-related adverse events of at least grade 3 in the avelumab group than in the chemotherapy group (20 [31.7%] vs 34 [53.1%]; P = .02). After a median follow-up of 33.3 (95% CI, 28.3-34.8) months, avelumab was superior to chemotherapy with or without targeted agents with respect to PFS (15 [24.6%] vs 5 [8.2%] among patients without progression; P = .03). Rates of PFS rates at 12 months were 31.2% (95% CI, 20.1%-42.9%) and 19.4% (95% CI, 10.6%-30.2%) in the avelumab and control groups, respectively, and 27.4% (95% CI, 16.8%-39.0%) and 9.1% (95% CI, 3.2%-18.8%) at 18 months. Objective response rates were similar in both groups (18 [29.5%] vs 16 [26.2%]; P = .45). Among patients with disease control, 18 (75.7%) in the avelumab group compared with 9 (19.1%) in the control group had ongoing disease control at 18 months. Conclusions: The SAMCO-PRODIGE 54 phase 2 randomized clinical trial showed, in patients with dMMR/MSI mCRC, better PFS and disease control duration with avelumab over standard second-line treatment, with a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03186326.