Biomarker-Guided Anti-EGFR Rechallenge Therapy in Metastatic Colorectal Cancer

Abstract

The prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.

Post-Induction Management in Patients With Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR-Based Doublet Regimens: A Multicentre Study

“…In the PaNama trial, reinduction therapy was more active and effective in patients who had received FU/LV compared to those who received FU/LV+anti-EGFR (ORR = 34.7% vs. 8.9%, PFS = 6.3 vs. 3.8 months, respectively). On the other hand, preclinical and clinical evidence suggests a potential role of anti-EGFR reintroduction beyond the second-line, particularly in patients selected with liquid biopsy (28)(29)(30)(31).…”

“…3.8 months, respectively). On the other hand, preclinical and clinical evidence suggests a potential role of anti-EGFR reintroduction beyond the second-line, particularly in patients selected with liquid biopsy ( 28 – 31 ).…”

“…Among these, 31 (34.4%) and 51 (65.6%) patients were treated with FOLFOX or FOLFIRI, respectively, in association with panitumumab (39, 43.3%) or cetuximab (51, 56.7%). Within the non-maintenance cohort, 70 (43.7%) patients were treated with a "stop-and-go" strategy with FOLFOX (39, 55.7%) or FOLFIRI (31,44.3%) in association with panitumumab (41, 58.6%) or cetuximab (29, 41.4%).…”

Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

“…Different studies have shown promising activity of reintroduction of anti-epidermal growth factor receptor (EGFR) drugs in patients with RAS wild-type ( RAS WT) metastatic colorectal cancer (mCRC), that obtained clinical benefit by first-line therapy with anti-EGFR drugs, then became resistant and progressed to second-line treatment [ 1 , 2 , 3 , 4 , 5 , 6 ]. This treatment strategy is called rechallenge.…”

“…So far, beside WT ctDNA at liquid biopsy analysis, several potential biomarkers have been investigated to predict the response to EGFRi rechallenge with discordant results [ 4 , 6 , 10 ].…”