Cetuximab/Avelumab Combo Yields Promising Results in Cohort of Patients With RAS Wild-Type mCRC

The phase 2 CAVE trial indicated that a combination of cetuximab and avelumab is a promising rechallenge treatment for patients with RAS wild-type metastatic colorectal cancer.

Cetuximab (Erbitux) and avelumab (Bavencio) appears to be an efficacious and well tolerated rechallenge therapy for patients with RAS wild-type metastatic colorectal cancer (mCRC), according to findings from the phase 2 CAVE trial (NCT04561336).

Data from the study indicated that patients treated with the combination experienced a median overall survival (OS) of 11.6 months (95% CI, 8.4-14.8). Additionally, investigators reported a median progression-free survival (PFS) of 3.6 months (95% CI, 3.2-4.1). In total, 1 patient achieved a complete response (CR), 5 achieved partial responses (PR), and 44 achieved stable disease, 36% of whom were stable for 4 months or more. The disease control rate was 65%.

The single arm, multicenter, open label CAVE trial enrolled adult patients with RAS wild-type disease, including NRAS, KRAS, and exon 2/3/4. A diagnosis of mCRC needed to be confirmed histologically and patients needed to have previously achieved a major response during first-line chemotherapy plus an EGFR inhibitor such as panitumumab or cetuximab. Patients who enrolled were given a 400 mg/m2 loading dose of cetuximab followed by a subsequent 250 mg/m2 dose weekly with 10 mg/kg of avelumab every 2 weeks.

The primary end points of the study were OS and key secondary endpoints included PFS, OS, overall response rate, and safety.

From August 2018 to February 2020, a total of 83 patients were screened and 77 were treated in the CAVE study. Investigators reported that 49% of patients had previously been treated with cetuximab and 51% had received panitumumab in addition to chemotherapy during their first line of treatment. Nearly all patients experienced a PR (95%) to their first line treatment and 5% achieved a CR. Sixty-eight percent of patients underwent treatment with 2 prior lines of therapy and 32% had received 3 or more. Most patients were microsatellite stable (92%).

The study had a median follow up of 19.5 months (interquartile range [IQR], 12.8-22.8). A total of 95% of patients progressed, 73% died, and 5% continued to receive treatment with cetuximab and avelumab.

Additional findings from a post-hoc analysis assessed the efficacy of the combination according to ctDNA detection of KRAS, NRAS, BRAF, and EGFR mutations. After collecting samples from 67 patients, 48 patients tested positive for KRAS, NRAS, and BRAF wild-type mutations and 19 tested positive for RAS and/or BRAF. Those with RAS or BRAF wild-type ctDNA had a median OS of 17.3 months (95% CI, 12.5-22.0) vs 10.4 months (95% CI, 7.2-13.6) in those with mutant ctDNA (HR, 0.49; 95% CI, 0.27-0.90; P = .02). The median PFS was 4.1 months (95% CI, 2.9-5.2) and 3.0 months (95% CI, 2.6-3.5) in the 2 arms, respectively (HR, 0.42; 95% CI, 0.23-0.75; P = .004).

In terms of safety, the most common grade 3 adverse effects (AEs) included cutaneous eruption (14%) and diarrhea (4%). Notably, no grade 4/5 treatment-related AEs were reported. In total, 28 patients had a treatment delay, with 23 experiencing delays due to cetuximab. The dose of cetuximab was reduced in 7 patients due to skin rash or diarrhea. No patients discontinued treatment and 67% of patients went on to receive a further line of therapy following disease progression.

Reference

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