Cetuximab Plus Avelumab as Rechallenge Therapy for RAS Wild-Type Metastatic Colorectal Cancer

Get Permission

In an Italian phase II trial reported in JAMA Oncology, Martinelli et al found that cetuximab rechallenge plus avelumab showed activity and was well tolerated in patients with RAS wild-type metastatic colorectal cancer who had responded to first-line chemotherapy plus an anti-EGFR agent and then failed to respond to second-line therapy.

Study Details

In the multicenter trial, 77 patients enrolled between August 2018 and February 2020 received avelumab at 10 mg/kg every 2 weeks and cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. Anti-EGFR agents in first-line treatment were panitumumab or cetuximab. A total of 92% of patients had microsatellite stable (MSS) tumors.

The primary endpoint was overall survival. The objective of the study was to show a median overall survival of 11.0 months, representing a 37.5% improvement vs a median of 8.0 months observed with standard third-line treatments.    

Overall Survival

Median follow-up was 19.5 months (interquartile range = 12.8–22.8 months). Median overall survival was 11.6 months (95% confidence interval [CI] = 8.4–14.8 months) and median progression-free survival was 3.6 months (95% CI = 3.2–4.1 months). Objective response was observed in 6 patients (8%), with complete response seen in 1; stable disease was observed in an additional 44 patients (57%), yielding a disease control rate of 65%. Among patients with MSS tumors, median overall and progression-free survival were 11.6 and 3.6 months, respectively. Overall, 67% of patients received an additional line of treatment after disease progression.


  • Median overall survival was 11.6 months.
  • Among patients with KRAS/NRAS/BRAF wild-type ctDNA, median overall survival was 17.3 months.

Analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-extracellular domain S492R mutations in 67 patients showed that 48 had KRAS/NRAS/BRAF wild-type DNA and 19 had RAS or BRAF mutations. Median overall survival was 17.3 months (95% CI = 12.5–22.0 months) among those with RAS/BRAF wild-type ctDNA vs 10.4 months (95% CI = 7.2–13.6 months) in those with mutated ctDNA (hazard ratio [HR] = 0.49, 95% CI = 0.27–0.90, P = .02).

Median progression-free survival was 4.1 months vs 3.0 months (HR = 0.42, 95% CI = 0.23–0.75, P = .004). Progression-free survival ranged from 6 to 15 months in 20 (41%) of 48 patients with RAS/BRAF wild-type ctDNA vs less than 6 months in all 19 patients with mutated ctDNA.

Adverse Events

No treatment-related grade 4 or 5 adverse events were observed. The most common treatment-related grade 3 adverse events were cutaneous eruption (14%) and diarrhea (4%).

Adverse events led to treatment delay in 36% of patients, due to cetuximab in 30%. The cetuximab dose was reduced in seven patients (9%) due to skin rash or diarrhea. No discontinuations of treatment due to adverse events were observed.

The investigators concluded, “The findings of this single-arm phase II trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in RAS wild-type  metastatic colorectal cancer. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit.”

Erika Martinelli, MD, PhD, of the Università degli Studi della Campania “Luigi Vanvitelli,” Naples, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by grants from Regione Campania (I-Cure Research Project) and Merck. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.