Combination cetuximab and avelumab seems feasible as rechallenge therapy in patients with chemotherapy-refractory, RAS wild-type (WT), metastatic colorectal cancer (mCRC), according to results published in JAMA Oncology.  

In the phase 2 CAVE trial ( Identifier: NCT04561336), researchers tested the combination in 77 patients with mCRC that was RAS WT at diagnosis. The patients had previously responded to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy.

At baseline, the patients’ median age was 63 years, 42 were men, and 35 were women.

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The cohort included 71 patients with microsatellite stable tumors (MSS), 3 with microsatellite instability-high tumors, and 3 with unknown microsatellite status.

The researchers analyzed circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR S492R mutations in 67 patients at baseline. The analysis revealed that 48 patients had WT KRAS/NRAS/BRAF, and 19 patients had RAS/BRAF mutations.

The patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (first at 400 mg/m2, then 250 mg/m2 weekly) until disease progression or unacceptable toxicity. The median follow-up was 19.5 months.

The overall response rate (ORR) was 7.8%, and the disease control rate was 65%. One patient achieved a complete response, 5 had a partial response, and 44 had stable disease.

There were 49 patients who received a subsequent line of therapy after disease progression.

For the entire cohort, the median progression-free survival (PFS) was 3.6 months, and the median overall survival (OS) was 11.6 months. The median PFS and OS were exactly the same among patients with MSS tumors.

There was a significant difference in PFS and OS between patients with WT RAS/BRAF and those with RAS/BRAF mutations according to ctDNA analysis at baseline.

The median OS was 17.3 months in patients with WT RAS/BRAF and 10.4 months in those with RAS/BRAF mutations (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90; P =.02). The median PFS was 4.1 months and 3.0 months, respectively (HR, 0.42; 95% CI, 0.23-0.75; P =.004).

Among patients with MSS tumors, the median OS was 17.3 months in patients with WT RAS/BRAF and 10.4 months in those with RAS/BRAF mutations (HR, 0.50; 95% CI, 0.27-0.93; P = .03). The median PFS was 3.9 months and 3.0 months, respectively (HR, 0.42; 95% CI, 0.23-0.77; P =.005).

The most common grade 3 adverse events (AEs) were cutaneous eruption (14%) and diarrhea (4%). None of the patients had treatment-related grade 4 or 5 AEs, and none of the patients discontinued treatment.

“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,” the study authors wrote. “Plasma ctDNA analysis before treatment may allow selection of patients who could benefit.”

Disclosures: This research was supported, in part, by Merck. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Martinelli E, Martini G, Famiglietti V, et al. Cetuximab rechallenge plus avelumab in pretreated patients with RAS wild-type metastatic colorectal cancer: The phase 2 single-arm clinical CAVE trial. JAMA Oncol. Published August 12, 2021. doi:10.1001/jamaoncol.2021.2915