Anti-EGFR rechallenge has emerged as a potential treatment strategy for selected patients with metastatic colorectal cancer (mCRC) who previously benefited from EGFR-targeted therapy. However, beyond molecular selection using circulating tumor DNA (ctDNA), it remains unclear whether clinical characteristics can help identify patients more likely to benefit from rechallenge.
A pooled analysis of the CAVE-GOIM and CAVE-2 GOIM studies, published in ESMO Gastrointestinal Oncology, evaluated potential clinical biomarkers associated with outcomes following cetuximab-based rechallenge in molecularly selected mCRC.
The study, titled “Predictive biomarkers for cetuximab-based rechallenge therapy in metastatic colorectal cancer: a pooled analysis of the CAVE and CAVE-2 GOIM studies,” included individual patient data from two phase II trials.
Authors: D. Ciardiello, G. Martini, F. Pietrantonio, A. Avallone, S. Pisconti, G. Santabarbara, T.P. Latiano, G. Tortora, A. Sartore-Bianchi, C. Cremolini, M. Messina, M.G. Zampino, L. Foltran, C. Pinto, A. Zaniboni, L. Antonuzzo, N. Normanno, R. Berardi, A. Cogoni, C. Lotesoriere, R. Bordonaro, L. Boscolo Bielo, G. Curigliano, P. Manca, A.G. Leone, A. De Stefano, C. Nisi, D. Rossini, L. Salvatore, E. Maiello, S. Siena, T. Troiani, F. De Vita, N. Fazio, E. Martinelli, F. Ciardiello, and S. Napolitano.
Why Rechallenge?
Resistance to anti-EGFR therapy can emerge through resistant tumor clones during treatment. When EGFR-targeted therapy is discontinued, these resistant clones may decline over time, potentially restoring sensitivity to EGFR inhibition. Previous phase II studies have reported objective response rates of approximately 10%–30%, progression-free survival of 4–6 months, and overall survival of 11–16 months with cetuximab- or panitumumab-based rechallenge.
At present, the absence of resistance-associated alterations detected by liquid biopsy remains the established biomarker used to select patients for this strategy. Whether clinical factors can further refine patient selection has remained uncertain.
A Pooled Analysis of CAVE and CAVE-2 GOIM
The investigators conducted an individual patient data pooled analysis of the phase II CAVE-GOIM and CAVE-2 GOIM studies. CAVE-GOIM was a single-arm, multicenter phase II study evaluating cetuximab plus avelumab rechallenge in patients with chemorefractory RAS/BRAF wild-type mCRC.
CAVE-2 GOIM was a randomized, multicenter phase II study comparing cetuximab plus avelumab with cetuximab monotherapy as rechallenge in patients with pretreated RAS/BRAF wild-type ctDNA, microsatellite-stable (MSS) mCRC. For the pooled analysis, patients with MSS mCRC and ctDNA RAS/BRAF/EGFR-extracellular domain wild-type status were included, while cases harboring pathogenic alterations associated with anti-EGFR resistance were excluded.
Overall, 180 patients met the eligibility criteria. Among them, 136 received cetuximab plus avelumab and 44 received cetuximab alone. The investigators examined the association between PFS and OS and several clinical variables, including age, sex, ECOG performance status, primary tumor sidedness, number and location of metastatic sites, and the anti-EGFR-free interval.
Because the median interval from the last anti-EGFR treatment was 16 months, patients were evaluated according to an anti-EGFR-free interval of ≤16 months versus >16 months.
Outcomes in the Overall Population
After a median follow-up of 23 months, 170 of 180 patients had experienced disease progression and 112 had died. Across the entire study population, median PFS was 4.85 months (95% CI 4.30–5.70), while median OS was 15.1 months (95% CI 12.9–18.8).
The objective response rate was 10.6%, and the disease control rate was 68.9%. Among patients receiving cetuximab plus avelumab, median PFS was 5.00 months (95% CI 4.30–5.90) and median OS was 15.7 months (95% CI 13.0–19.9). The ORR was 11%, and the DCR was 71.3%.
For patients treated with cetuximab monotherapy, median PFS was 4.80 months (95% CI 3.90–5.90), while median OS was 12.9 months (95% CI 11.1–not evaluable). The ORR and DCR were 9.1% and 61.4%, respectively.
Liver Metastases and PFS With Cetuximab–Avelumab
The exploratory analysis identified two variables associated with shorter PFS among patients treated with cetuximab plus avelumab. In univariable analysis, the presence of liver metastases was associated with shorter PFS (HR 2.19; 95% CI 1.51–3.20; P<0.001). Median PFS was 4.29 months in patients with liver metastases compared with 6.75 months in those without liver involvement. Liver metastases remained significantly associated with shorter PFS in multivariable analysis (HR 2.13; 95% CI 1.46–3.11; P<0.001).
Does the Anti-EGFR-Free Interval Matter?
The duration of the anti-EGFR-free interval was also associated with PFS in patients receiving cetuximab plus avelumab. Patients with an interval of ≤16 months had a median PFS of 4.3 months, compared with 6.0 months among those with an interval of >16 months (HR 1.62; 95% CI 1.13–2.31; P=0.008).
The association remained statistically significant in multivariable analysis. The authors noted, however, that the role of the anti-EGFR-free interval remains uncertain across studies, and further investigation is needed to confirm its predictive value and determine the optimal cutoff.
Metastatic Site and Overall Survival
For OS, univariable analysis in the cetuximab–avelumab group identified associations with metastatic burden, liver metastases, and peritoneal metastases. After multivariable adjustment, only liver and peritoneal involvement remained statistically significant.
Patients with liver metastases had a median OS of 14.8 months, compared with 20.5 months in those without liver metastases (HR 1.82; 95% CI 1.15–2.88; P<0.011). In multivariable analysis, the HR was 1.70 (95% CI 1.05–2.77; P=0.032).
Median OS was also 13.0 months among patients with peritoneal metastases compared with 19.9 months in those without peritoneal involvement (HR 1.90; 95% CI 1.23–2.93; P=0.004). Peritoneal metastases remained significant in multivariable analysis (HR 1.73; 95% CI 1.06–2.82; P=0.027).
A Different Pattern With Cetuximab Alone
Notably, the investigators did not observe a significant association between any of the evaluated clinical variables and PFS or OS among patients treated with cetuximab monotherapy.
According to the authors, cetuximab rechallenge therefore retained activity irrespective of the investigated clinical factors in this molecularly selected population. Because no differential efficacy according to liver involvement was observed with cetuximab monotherapy, the investigators proposed that the presence of liver metastases might represent a potential predictive biomarker for cetuximab–avelumab combination therapy.
The authors highlighted previous evidence suggesting that liver metastases may be associated with an immunosuppressive tumor microenvironment and reduced activity of immunotherapy in MSS mCRC. However, they emphasized that further translational studies are required to confirm this hypothesis.
Limitations
The authors acknowledged several limitations. The analysis was exploratory, and different liquid biopsy assays were used across the two studies. CAVE-GOIM retrospectively used an RT-PCR-based assay with lower sensitivity than the FoundationOne Liquid Companion Diagnostic used in CAVE-2, potentially introducing differences in the detection of resistance-associated alterations.
The cetuximab monotherapy cohort was also relatively small, with only 44 patients, which could have limited the ability to detect prognostic or predictive associations. The investigators additionally cautioned that the very small number of patients in the peritoneal-metastasis subgroup could have influenced these findings.
Expert Highlight: Davide Ciardiello on Anti-EGFR Rechallenge
Commenting on the clinical implications of the findings, Davide Ciardiello, MD, PhD, medical oncologist at the Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, IEO, IRCCS, Milan, Italy, told OncoDaily:
“ Within the limitations of an exploratory analysis, the data suggest that rechallenge with single-agent cetuximab is effective—regardless of the clinical factors examined—in molecularly selected patients. Liquid biopsy is therefore a crucial test for identifying patients who might benefit from rechallenge with anti-EGFR drugs. Current international guidelines recommend testing for RAS/BRAF and, if possible, EGFR before proposing this treatment. Future studies will evaluate whether improved molecular selection can enhance patient stratification.”
On the potential role of liver metastases in treatment selection, he added:
“The study confirms that, in patients with refractory MSS/pMMR mCRC, the absence of liver metastases may be a predictive factor for response. Additional potential biomarkers and therapeutic combinations are needed to improve the activity of immunotherapy in non-hypermutated mCRC.”
What Does This Mean?
This pooled analysis supports ctDNA-guided cetuximab-based rechallenge as an active treatment strategy in molecularly selected mCRC. For cetuximab monotherapy, activity was observed regardless of the clinical factors investigated. In contrast, among patients receiving cetuximab plus avelumab, the absence of liver metastases was associated with longer PFS and OS, while a longer anti-EGFR-free interval was associated with longer PFS.
The findings suggest that liver involvement and the duration of the anti-EGFR-free interval could potentially help refine patient selection for cetuximab–avelumab rechallenge, but further studies are needed before these factors can be established as predictive biomarkers.
The full article is available in ESMO Gastrointestinal Oncology.