Circulating Tumor DNA-Guided Cetuximab Rechallenge Shows Improved Outcomes for Select Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer
Key Clinical Summary
- Population and Design: Phase 2 randomized, open-label CAVE-2 GOIM trial enrolled 156 patients with refractory RAS/BRAF wild-type metastatic colorectal cancer (mCRC) who had previously responded to anti-EGFR therapy, using ctDNA profiling (FoundationOne Liquid CDx) to identify eligible patients; randomized 2:1 to cetuximab plus avelumab (n = 104) or cetuximab alone (n = 52).
- Efficacy: After a 20.4-month median follow-up, combination therapy did not significantly improve survival versus monotherapy—median OS 14.8 vs 12.9 mo (HR 1.00; P = 0.983) and PFS 5.3 vs 4.3 mo (HR NR). ORR 12% vs 8% (P = 0.581). However, ctDNA “negative hyper-selected” patients (no EGFR-pathway mutations) had superior PFS (5.35 vs 3.65 months; HR 0.62; P = 0.017) and OS (15.0 vs 11.1 mo; HR 0.61; P = 0.037) regardless of treatment arm.
- Safety: Grade 3 skin rash occurred in 8% (combo) vs 4% (mono); no new safety signals.
- Clinical Relevance: Adding avelumab to cetuximab did not improve efficacy, but ctDNA hyper-selection identified a molecularly defined subgroup deriving significant benefit from EGFR rechallenge, supporting precision-guided reuse of targeted therapy in refractory mCRC.
Comprehensive genomic profiling via circulating tumor DNA (ctDNA) identified patients most likely to benefit from cetuximab rechallenge for refractory RAS/BRAF wild-type metastatic colorectal cancer (mCRC), according to results from the phase 2 CAVE-2 GOIM trial published in Annals of Oncology.
Previous research had found cetuximab in combination with avelumab could have potential therapeutic benefit, however the value of additional immunotherapy to cetuximab remained unknown. To address this, researchers conducted a randomized, open-label study which compared cetuximab monotherapy or cetuximab plus avelumab among patients with RAS/BRAF wild-type mCRC who had previously responded to anti-EGFR therapy.
Patients were selected based on baseline ctDNA profiling using FoundationOne Liquid CDx and were randomized 2:1 to receive cetuximab plus avelumab or cetuximab alone. The primary end point was overall survival (OS) and secondary end points included progression-free survival (PFS) and objective response rate (ORR). A total of 156 patients were treated, of which 104 received cetuximab plus avelumab in Arm A and 52 patients received cetuximab alone in Arm B.
The median follow up was 20.4 months (interquartile range [IQR]1, IQR3 15.1 to 27.3). Approximately 92% of patients who received cetuximab plus avelumab and 96% of patients who received cetuximab monotherapy experienced disease progression, and 60.5% and 61.5% of patients experienced death, respectively.
The ORR was higher among patients treated with cetuximab plus avelumab (12%) compared with cetuximab monotherapy (8%, odds ratio [OR] 1.57; 95% confidence interval [CI], 0.479 to 5.12; P = 0.581). The median PFS was also slightly higher among patients treated with combination therapy than cetuximab monotherapy (5.3 months; 95% CI, 4.3 to 6 vs 4.3 months; 95% CI, 3.5 to 5.5). Additionally, the median OS was 14.8 months (95% CI, 12.1 to 18.3) in the combination arm compared with 12.9 months (95% CI, 11 to NE) in the monotherapy arm (hazard ratio [HR], 1.00; 95% CI, 0.65 to 1.52; P=0.983).
A pre-specified exploratory analysis stratified patients by the presence or absence of pathogenic variants in the EGFR pathway. Among 124 patients with no detectable alterations in KRAS, NRAS, BRAF, EGFR extracellular domain, PIK3CA exon 20, MAP2K1, AKT1, MET, PTEN, or ERBB2 (“negative hyper-selection”), outcomes were significantly improved compared to the 32 patients with at least one pathogenic alteration, (“positive hyper-selection”). The median PFS was 5.35 months (95% CI, 4.4 to 5.9) in the negative hyper-selection group versus 3.65 months (95% CI, 2.8 to 4.8) in the positive group (HR, 0.62; 95% CI, 0.42 to 0.92; P=0.017). additionally, the median OS was 15.0 months (95% CI, 12.6 to 19.9) in the negative hyper-selection group versus 11.1 months (95% CI, 8.6 to 15.6) in the positive hyper-selection group (HR, 0.61; 95% CI, 0.39 to 0.97; P=0.037). Improved outcomes were observed in both treatment arms for patients in the negative hyper-selection group.
In terms of safety, the most frequent grade 3 adverse events were skin rash among 8% of patients who received cetuximab plus avelumab and 4% of patients who received cetuximab monotherapy.
The researchers concluded, “the CAVE-2 GOIM study did not demonstrate that the addition of avelumab to cetuximab rechallenge is associated with improved survival.”
They added, “Collectively, these findings suggest that a subset of mCRC remains dependent on EGFR signaling and that this tumor dependency could allow the use of molecular targeted therapies also in refractory disease for appropriately selected patients.”
Source:
Ciardiello D, Martini G, Bielo LBoscolo, et al. Cetuximab rechallenge in molecularly selected metastatic colorectal cancer: the randomized CAVE-2 GOIM trial. Annals of Oncology. Published online December 22, 2025. doi:10.1016/j.annonc.2025.12.014
