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. 2023 Oct 1;9(10):1356-1363.
doi: 10.1001/jamaoncol.2023.2761.

Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability: A Randomized Clinical Trial

Julien Taïeb  1   2   3 , Olivier Bouche  4 , Thierry André  5 , Karine Le Malicot  6 , Pierre Laurent-Puig  1   2   3 , Jérémie Bez  6 , Clémence Toullec  7 , Christophe Borg  8 , Violaine Randrian  9 , Ludovic Evesque  10 , Stéphane Corbinais  11 , Hervé Perrier  12 , Bruno Buecher  13 , Frederic Di Fiore  14 , Claire Gallois  1   2 , Jean Francois Emile  15 , Côme Lepage  5   16 , Farid Elhajbi  17 , David Tougeron  9 ; SAMCO-PRODIGE 54 Investigators
Collaborators, Affiliations

Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability: A Randomized Clinical Trial

Julien Taïeb et al. JAMA Oncol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Prof Taïeb reported receiving personal fees a speaker or in an advisory role from Merck & Co Inc, Amgen Inc, Bristol Myers Squibb, MSD, AstraZeneca, Astellas Pharma Inc, Novartis AG, Pfizer Inc, Pierre Fabre, and Servier Laboratories outside the submitted work. Dr Bouché reported receiving personal fees as a speaker or in an advisory role from Merck KGaA, Apmonia Therapeutics, Bayer AG, Grünenthal, MSD, Amgen Inc, Servier Laboroatories, and Pierre Fabre outside the submitted work. Prof André reported receiving honoraria as a speaker or in an advisory role from Amgen Inc, Astellas Pharma Inc, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Gritstone Oncology, Merck & Co Inc, Merck Serono, Nordic Oncology, Pierre Fabre, F. Hoffmann–La Roche AG, Sanofi SA, and Servier Laboratories and support for meetings from Bristol Myers Squibb, Merck & Co Inc, and Servier Laboratories outside the submitted work. Professor Laurent-Puig reported serving as a consultant or advisory board member for Merck Serono, AstraZeneca, Amgen Inc, Boehringer Ingelheim, Biocartis NV, F. Hoffmann–La Roche AG, Bristo -Myers Squibb, Pierre Fabre, Servier Laboratories, and MSD outside the submitted work. Dr Toullec reported receiving honoraria as a speaker or in an advisory role from Amgen Inc, AstraZeneca, Bayer AG, Bristol Myers Squibb, Ipsen, Merck Serono, MSD, Pierre Fabre, Sanofi SA, and Servier Laboratories outside the submitted work. Professor Borg reported receiving honoraria as an advisory board member from Neogene Therapeutics Inc, Bayer AG, and AstraZeneca and research grants from Bayer AG, F. Hoffmann–La Roche AG, and Boehringer Ingelheim outside the submitted work. Dr Randrian reported receiving nonfinancial support for meetings from Merck & Co Inc, during the conduct of the study; nonfinancial support for meetings from MSD, Bayer AG, and Accord Healthcare outside the submitted work; and honoraria from Amgen Inc, Pierre Fabre, and Servier Laboratories outside the submitted work. Professor Di Fiore reported receiving honoraria as a speaker or in an advisory role from Amgen Inc, AstraZeneca, Bayer AG, Bristol Myers Squibb, Ipsen, Merck Serono, Pierre Fabre, F. Hoffmann–La Roche AG, Sanofi SA, and Servier Laboratories and support for meetings from Amgen Inc, Pierre Fabre, Servier Laboratories, Ipsen, F. Hoffmann–La Roche AG, and Sanofi SA during the conduct of the study. Dr Gallois reported receiving personal fees from Pierre Fabre, Servier Laboratories, and Merck & Co Inc, outside the submitted work. Professor Lepage reported receiving grant funding from Merck KGgA during the conduct of the study and personal fees from AAA Pharmaceutical Inc, Amgen Inc, and Pierre Fabre outside the submitted work. Professor Tougeron reported receiving honoraria as a speaker or in an advisory role from Merck Serono during the conduct of the study and honoraria as a speaker or in an advisory role from F. Hoffmann–La Roche AG, Amgen Inc, Servier Laboratories, MSD, Bristol Myers Squibb, AstraZeneca, Novartis AG, and Pierre Fabre outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
dMMR indicates deficient mismatch repair; FOLFIRI, leucovorin calcium (folinic acid), fluorouracil, and irinotecan hydrochloride; FOLFOX, leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin; mITT, modified intention to treat; MSI, microsatellite instability; MSS, microsatellite stability; pMMR, proficient MMR.
Figure 2.
Figure 2.. Progression-Free Survival and Duration of Disease Control in the Avelumab Group and the Chemotherapy Group
For duration of disease control, each bar represents 1 patient in the study. Rightward arrows indicate continuing treatment. dMMR indicates deficient mismatch repair; MSI, microsatellite instability; PFS, progression-free survival.
See this image and copyright information in PMC

Comment in

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