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Original Investigation
August 12, 2021

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

Author Affiliations
  • 1Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli,” Napoli, Italy
  • 2Oncologia Medica, Istituto Nazionale dei Tumori di Milano, Milan, Italy
  • 3Biologia Cellulare e Bioterapie, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, Napoli, Italy
  • 4Oncologia Medica, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, Napoli, Italy
  • 5Oncologia Medica, Ospedale Casa Sollievo della Sofferenza - San Giovanni Rotondo (FG), Italy
  • 6Oncologia Medica, Azienda Ospedaliera Universitaria, Università di Pisa, Pisa, Italy
  • 7Oncologia Medica, Azienda Ospedaliera di Rilievo Nazionale “S. G. Moscati”, Avellino, Italy
  • 8Oncologia Medica, IRCCS Santa Maria Nuova, Reggio Emilia, Italy
  • 9Oncologia Medica, Campus Biomedico, Roma, Italy
JAMA Oncol. 2021;7(10):1529-1535. doi:10.1001/jamaoncol.2021.2915
Key Points

Question  Is the combination of cetuximab plus avelumab effective as a rechallenge strategy in patients with RAS wild-type (WT) metastatic colorectal cancer?

Findings  This phase 2, single-arm clinical trial provides evidence of clinical activity of combining cetuximab plus avelumab in 77 patients with RAS WT metastatic colorectal cancer (mCRC) who benefited from first-line anti–epidermal growth factor receptor-containing therapy when retreated with cetuximab plus avelumab in third or further lines of therapy as a rechallenge strategy. Median overall survival (mOS) was 11.6 months and reached 17.3 months in patients with baseline RAS/BRAF WT circulating tumor DNA (ctDNA).

Meaning  The magnitude of overall survival benefit obtained with this treatment accompanied with a mild overall toxic effects profile provides a potential new therapeutic option for RAS WT mCRC in the rechallenge setting; the trial also identified that plasma RAS/BRAF WT ctDNA analysis might be used to select patients with mCRC who may benefit from the treatment.


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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