Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability

Author(s): Julien Taïeb, MD, PhD1,2,3; Olivier Bouche, MD, PhD4; Thierry André, MD5; Karine Le Malicot, MS6; Pierre Laurent-Puig, MD, PhD1,2,3; Jérémie Bez, MS6; Clémence Toullec, MD7; Christophe Borg, MD8; Violaine Randrian, MD, PhD9; Ludovic Evesque, MD10; Stéphane Corbinais, MD11; Hervé Perrier, MD12; Bruno Buecher, MD13; Frederic Di Fiore, MD, PhD14; Claire Gallois, MD1,2; Jean Francois Emile, MD, PhD15; Côme Lepage, MD, PhD5,16; Farid Elhajbi, MD, PhD17; David Tougeron, MD, PhD9; for the SAMCO-PRODIGE 54 Investigators
Source: JAMA Oncol. Published online August 3, 2023. doi:10.1001/jamaoncol.2023.2761
Maem Hussein MD

Dr. Maen Hussein's Thoughts

If anti PD-L1 was not used as first line treatment, this study shows you can still use it as second line.

KEY POINTS

QUESTION

Are checkpoint inhibitors better than chemotherapy in the second-line setting for deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC)?

FINDINGS

In this phase 2 randomized clinical trial including 122 patients, avelumab, an anti–programmed cell death ligand 1 antibody, was associated with significantly better progression-free survival and disease control duration than standard second-line treatment. In addition, avelumab had a favorable safety profile in the second-line setting of dMMR/MSI mCRC.

MEANING

These findings suggest that for patients with dMMR/MSI mCRC not treated with pembrolizumab in the first-line setting, immune checkpoint inhibitors may be an option in the second-line setting, with better efficacy and tolerability than the current standard of care.

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

Author Affiliations

1Institut du Cancer Paris Cancer Research for Personalized Medicine, Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France; 2Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique, Sorbonne Université, Université Sorbonne Paris Cité, Université de Paris, Paris, France; 3Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, AP-HP Centre, Université Paris Cité, Paris, France; 4Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU) Reims, Reims, France; 5Sorbonne Université and Hôpital Saint Antoine, INSERM 938 and Site de Recherche Intégrée sur le Cancer CURAMUS, Paris, France; 6Fédération Francophone de Cancérologie Digestive, EPICAD INSERM Lipides Nutrition Cancer–Unité Mixte de Recherche 1231, University of Burgundy and Franche Comté, Dijon, France; 7Department of Medical Oncology, Institut du Cancer, Avignon-Provence, France; 8Department of Medical Oncology, University Hospital of Besançon, Besançon, France; 9Department of Gastroenterology and Hepatology, Poitiers University Hospital, Poitiers, France; 10Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France; 11Department of Medical Oncology, Centre François Baclesse, Caen, France; 12Department of Hepato-Gastroenterology, Hôpital Saint-Joseph, Marseille, France; 13Department of Oncology, Institut Curie, Paris, France; 14Hepatogastroenterology Department, CHU Rouen, University of Rouen Normandy, INSERM 1245, Institut de Recherche en Oncologie Group, Normandie University, Rouen, France; 15EA4340, Pathology Department and INSERM, Ambroise Paré Hospital, Boulogne, France; 16Department of Digestive Oncology, University Hospital Dijon, University of Burgundy and Franche Comté, Dijon, France; 17Medical Oncology Department, Oscar Lambret Center, Lille, France; JAMA Oncol. Published online August 3, 2023. doi:10.1001/jamaoncol.2023.2761

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