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Clinical Trial
. 2021 Oct 1;7(10):1529-1535.
doi: 10.1001/jamaoncol.2021.2915.

Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With RAS Wild-type Metastatic Colorectal Cancer: The Phase 2 Single-Arm Clinical CAVE Trial

Erika Martinelli  1 , Giulia Martini  1 , Vincenzo Famiglietti  1 , Teresa Troiani  1 , Stefania Napolitano  1 , Filippo Pietrantonio  2 , Davide Ciardiello  1 , Marinella Terminiello  1 , Carola Borrelli  1 , Pietro Paolo Vitiello  1 , Filippo De Braud  2 , Federica Morano  2 , Antonio Avallone  3 , Nicola Normanno  4 , Anna Nappi  3 , Evaristo Maiello  5 , Tiziana Latiano  5 , Alfredo Falcone  6 , Chiara Cremolini  6 , Daniele Rossini  6 , Giuseppe Santabarbara  7 , Carmine Pinto  8 , Daniele Santini  9 , Claudia Cardone  1   3 , Nicoletta Zanaletti  1   3 , Alessandra Di Liello  1 , Daniela Renato  1 , Lucia Esposito  1 , Francesca Marrone  1 , Fortunato Ciardiello  1   5
Affiliations
Clinical Trial

Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With RAS Wild-type Metastatic Colorectal Cancer: The Phase 2 Single-Arm Clinical CAVE Trial

Erika Martinelli et al. JAMA Oncol. .

Abstract

Importance: Rechallenge therapy with anti-epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC) after initial response to anti-EGFR-based first-line treatment. The association of treatment with cetuximab plus avelumab with overall survival (OS) may be worthy of investigation in this setting.

Objective: To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab.

Design, setting, and participants: This single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients with RAS WT mCRC had a complete or partial response to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy. Baseline circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R mutation analysis was done.

Interventions: Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m2 and, subsequently, 250 mg/m2 weekly) until disease progression or unacceptable toxic effects.

Main outcomes and measures: The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety.

Results: Seventy-seven patients were enrolled (42 men, 35 women; median age, 63 years); 71 had microsatellite stable tumors (MSS), 3 microsatellite instability-high tumors (MSI-H), 3 unknown. The study met the primary end point, with median OS (mOS) of 11.6 months (95% CI, 8.4-14.8 months). Median PFS (mPFS) was 3.6 months (95% CI, 3.2-4.1 months). Common grade-3 adverse events were cutaneous eruption, 11 (14%), and diarrhea, 3 (4%). For 67 of 77 (87%) patients, baseline analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R variations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients with RAS/BRAF WT ctDNA had mOS of 17.3 months (95% CI, 12.5-22.0 months) compared with 10.4 months (95% CI, 7.2-13.6 months) in patients with mutated ctDNA (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90; P = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) in RAS/BRAF WT patients compared with 3.0 months (95% CI, 2.6-3.5 months) in patients with mutated ctDNA (HR, 0.42; 95% CI, 0.23-0.75; P = .004).

Conclusions and relevance: The findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in RAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit.

Trial registration: ClinicalTrials.gov Identifier: NCT04561336.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Martinelli has served as adviser and speaker for AstraZeneca, Amgen, Bayer, Merck-Serono, Roche, Sanofi, Servier, Pierre Fabre. Prof Troiani has served as a adviser and speaker for Roche, Merck-Serono, Sanofi, Servier, Novartis, Bayer. Dr Pietrantonio has served as adviser/speaker for Amgen, Roche, Lilly, Sanofi, Merck-Serono, Bayer, Servier. Received a research Grants from BMS. Prof De Braud has served as a consultant for Ignyta, BMS, Daiichi Sankyo, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, EMD Serono, Sanofi, NMS Nerviano Medical Science, Pharm Research Associated (UK) Ltd; has served as speaker for BMS, Roche, MSD, Ignyta, Bayer, ACCMED, Dephaforum S.r.l., Nadirex, Merck, Biotechspert Ltd, PriME Oncology, Pfizer, Servier, Celgene, Tesaro, Loxo Oncology Inc, Sanofi, Healthcare Research & Pharmacoepidemiology; has served as Principal Investigator for Novartis, Roche, BMS, Celgene, Incyte, NMS, Merck KGAA, Kymab, Pfizer, Tesaro, MSD. Dr Morano has served as speaker for Servier. Dr Avallone has served as advisory and speaker for Amgen and Servier. Dr Normanno has served as adviser and speaker for MSD, Qiagen, Biocartis, Incyte, Roche, BMS, MERCK, Thermofisher, Boehringer Ingelheim, AstraZeneca, Sanofi, Eli Lilly, Bayer. Dr Maiello has served as adviser and speaker for AstraZeneca, Eli Lilly, Servier, Sanofi Genzyme, Roche, Merck, Eisai, Pfizer. Dr Latiano has served as speaker for Servier. Dr Falcone has served as adviser and speaker for Bayer, Bristol, Eli Lilly, Merck, Pierre-Fabre, Roche, Servier, and received institutional support for clinical trials from AstraZeneca, Bayer, Bristol, Eli Lilly, Merck, MSD, Novartis, Roche, Sanofi, and Servier. Dr Cremolini has served as adviser for Roche, Bayer, Agmen, and speaker for Roche, Bayer, Agmen, Serveir; received research founding form Merck-Serono. Dr Rossini has served as speaker for Takeda. Dr Santabarbara has served as adviser for Amgen and Servier. Dr Pinto has served as adviser and speaker for MSD, Bayer, AstraZeneca, Roche, Merck-Serono, Lilly, Servier, Sanofi, Astellas. Prof Ciardiello has served as adviser and speaker for Roche, Amgen, Merck-Serono, Pfizer, Sanofi, Bayer, Servier, BMS, Cellgene, Lilly. Received institutional Research Grants form Bayer, Roche, Merck-Serono, Amgen, AstraZeneca, Takeda. Drs Martini, Famiglietti, Nappi, Santabarbara, Ciardiello, Terminiello, Borrelli, Vitiello, Napolitano, CC, Zanaletti, Di Liello, Ms Renato, Drs Esposito, and Marrone declare no competing interests.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Estimates
ITT indicates intention-to-treat; MSS, microsatellite stable tumors; OS, overall survival; PFS, progression-free survival. A, Overall survival in the ITT population. B, Progression-free survival in the ITT population. C, Overall survival in patients with microsatellite stable tumors. D, Progression-free survival in patients with microsatellite stable tumors.
Figure 2.
Figure 2.. Kaplan-Meier Estimates
A, Overall survival in patients with plasma circulating tumor DNA RAS/BRAF mutational status. B, Progression-free survival in patients with plasma circulating tumor DNA RAS/BRAF mutational status. C, Overall survival in patients with microsatellite stable tumors and plasma ctDNA RAS/BRAF mutational status. D, Progression-free survival in patients with microsatellite stable tumors and plasma ctDNA RAS/BRAF mutational status.
See this image and copyright information in PMC

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