A single-arm, multicenter, phase II clinical trial, CAVE, found that patients with chemotherapy-refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC) who responded to first-line anti-EGFR therapy could be re-treated with cetuximab in combination with the immunotherapy drug avelumab as third- or fourth-line therapy. The results were published in JAMA Oncology.
CAVE Phase II clinical trial
The CAVE trial was a single-arm, multicenter, phase II, open-label clinical trial primarily evaluating the efficacy of cetuximab in combination with avelumab as reactivation therapy in patients with RAS wild-type mCRC. Enrolled patients received avelumab (10 mg/kg Q2W) plus cetuximab (400 mg/m2 [first dose], followed by cetuximab 250 mg/m2 Q1W) until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) as assessed according to RECIST 1.1, progression-free survival (PFS), and safety.
Test results
The median overall survival (OS) was 11.6 months, and the progression-free survival (PFS) was 3.6 months. One patient achieved complete remission (CR), five achieved partial remission (PR), and 44 patients had stable disease, with 36% of these patients remaining stable for ≥4 months. The disease control rate was 65%. At a median follow-up of 19.5 months, 95% of patients experienced disease progression, 73% died, and 5% continued treatment with cetuximab in combination with avelumab.
The enrolled patients included 71 patients with microsatellite stable (MSS) tumors, 3 patients with tumors of high microsatellite instability, and 3 patients with unknown microsatellite status. Circulating tumor DNA (ctDNA) analysis was performed on the baseline KRAS, NRAS, BRAF, and EGFR S492R mutation levels in 67 patients. The analysis revealed that 48 patients had WT KRAS/NRAS/BRAF mutations, and 19 patients had RAS/BRAF mutations.
A retrospective analysis showed that the median overall survival (OS) was 17.3 months for patients with WT RAS/BRAF and 10.4 months for patients with RAS/BRAF mutations (hazard ratio [HR] = 0.49; 95% CI, 0.27–0.90; P = 0.02). The median progression-free survival (PFS) was 4.1 months and 3.0 months, respectively (HR = 0.42; 95% CI, 0.23–0.75; 0.004).
In MSS cancer patients, the median overall survival (OS) was 17.3 months for WT RAS/BRAF patients and 10.4 months for RAS/BRAF mutant patients (HR=0.50; 95% CI, 0.27–0.93; P=.03). The median progression-free survival (PFS) was 3.9 months and 3.0 months, respectively (HR=0.42; 95% CI, 0.23–0.77; P=.005).
security
Regarding safety, the most common Grade 3 adverse events (AEs) included rash (14%) and diarrhea (4%). Notably, no Grade 4/5 treatment-related AEs were reported. A total of 28 patients experienced treatment delays, 23 of whom experienced delays due to cetuximab. Seven patients had their cetuximab dose reduced due to rash or diarrhea. No patients discontinued treatment, and 67% of patients continued further treatment after disease progression.
Research conclusion
The results of this study confirm that cetuximab combined with the immunotherapy drug avelumab is feasible in the treatment of RAS wild-type colorectal cancer.
References: 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
