Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With RAS Wild-type Metastatic Colorectal Cancer

Importance

Rechallenge therapy with anti–epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractoryRASwild-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 withRASWT 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) forKRAS, NRAS, BRAF,andEGFR-S492Rmutation analysis was done.

Interventions

Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m²and, subsequently, 250 mg/m²weekly) 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,andEGFR-S492Rvariations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients withRAS/BRAFWT 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) inRAS/BRAFWT 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 inRAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit.

Trial Registration

ClinicalTrials.gov Identifier:NCT04561336