Anti-EGFR Rechallenge in RAS/BRAF Wild-Type Metastatic Colorectal Cancer

Key Clinical Takeaways: 

• Anti-EGFR rechallenge is a viable later-line option in patients with RAS/BRAF wild-type metastatic colorectal cancer, but optimal molecular selection criteria and treatment sequencing remain under investigation.
• Combining anti-EGFR therapy with immunotherapy has strong biologic rationale in microsatellite-stable disease, leveraging antibody-dependent cellular cytotoxicity to potentially enhance immune responsiveness.
• The phase 2 CAVE-2 GOIM trial prospectively evaluates this approach, using ctDNA profiling to select RAS/BRAF wild-type patients and randomizing them to cetuximab plus avelumab versus cetuximab alone, with overall survival as the primary endpoint.

Stefania Napolitano, MD, PhD, University of Campania Luigi Vanvitelli, Naples, Italy, discusses background and methods from the phase 2 CAVE-2 GOIM trial evaluating anti-EGFR rechallenge strategies in patients with RAS/BRAF wild-type metastatic colorectal cancer selected using ctDNA profiling. 

For part 2, please click here. 

Transcript: 

My name is Stefania Napolitano, I work in medical oncology and precision medicine at the University of Campania Luigi Vanvitelli in Naples, Today I will present cetuximab rechallenge in molecularly selected metastatic colorectal cancer, the randomized CAVE-2 GOIM trial. 

Recently, rechallenge with anti-EGFR drugs has been proposed as a potential strategy in later lines of therapy for patients who previously responded to anti-EGFR treatment but subsequently experienced disease progression and received at least 1 subsequent anti-EGFR–free therapy interval, and of course are RAS wild type at liquid biopsy. 

In the past year, several clinical trials have been conducted in order to evaluate which is the best anti-EGFR rechallenge strategy. However, a lot of questions remain unsolved – We do not know which is the most important resistance panel to use to identify patients that benefit from anti-EGFR rechallenge strategy, which are the molecular alterations that we need to identify, if the anti-EGFR should be used alone, or which is the best partner drug for anti-EGFR rechallenge strategy. 

Also, we do not know if there is a role for metastatic sites to predict the benefit from anti-EGFR rechallenge strategy, and again, which is the best setting in which we need to use the anti-EGFR rechallenge strategy, earlier or subsequent lines. For this reason, a lot of clinical trials are still ongoing in anti-EGFR rechallenge strategy. 

In this scenario, there is the CAVE trial. The CAVE program is the first clinical trial in which we combine anti-EGFR rechallenge strategy with immunotherapy. We know that immunotherapy has dramatically changed the treatment of several cancers however, the application in metastatic colorectal cancer has been limited, since only a small subset of metastatic colorectal cancer patients, ones with hypermutated tumors with polymerase mutations or the presence of microsatellite instability, are the ones that are responsive to immune checkpoint inhibitors. Therefore, a major clinical challenge is to develop therapeutic approaches that can switch microsatellite-stable metastatic colorectal cancer to an immune-responsive phenotype.

In this context, we combine an anti-EGFR, cetuximab, with anti-PD-L1 avelumab. The combination of these 2 drugs is because both monoclonal antibodies are able to activate natural killer cells through antibody-dependent cell cytotoxicity, thus providing a biological rationale for their combination. We previously conducted a multicenter, single-arm, phase 2 CAVE study to evaluate the antitumor activity of cetuximab plus avelumab in refractory metastatic RAS/BRAF wild-type colorectal cancer. The trial demonstrated promising clinical activity in patients with RAS/BRAF wild-type status at baseline liquid biopsy, but this is a single-arm phase 2 trial. For this reason, we developed the phase 2 CAVE-2 GOIM trial. 

This is a randomized phase 2 trial in which pretreated patients with metastatic colorectal cancer are selected thanks to liquid biopsy by FoundationOne to identify RAS/BRAF wild-type patients to be enrolled in the combination arm, avelumab plus cetuximab, or cetuximab alone. The primary end point of the study is overall survival. Secondary end points include progression-free survival, response rate, and safety.

From July 2022 to December 2024, 328 patients were screened. While 172 patients were not eligible for different reasons, like blood samples not available or the presence of RAS/BRAF clonal alterations at liquid biopsy. So, 156 patients were included in the trial and randomly assigned in a 2:1 randomization to cetuximab plus avelumab or cetuximab alone.

Source: 

Ciardiello D, Martini G, Bielo LB, et al. Cetuximab rechallenge in molecularly selected metastatic colorectal cancer: the randomized CAVE-2 GOIM trial. Ann Oncol. Published online: December 22, 2025. doi: 10.1016/j.annonc.2025.12.014