Cetuximab as third‐line rechallenge plus either irinotecan or avelumab is an effective treatment in metastatic colorectal cancer patients with baseline plasma RAS/BRAF wild‐type circulating tumor DNA: Individual patient data pooled analysis of CRICKET and CAVE trials

Abstract

The rechallenge strategy is based on the concept that a subset of patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti‐EGFR based‐therapy. We performed a pooled analysis of two‐phase II prospective trials to determine the role of rechallenge in third‐line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third‐line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression‐free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0–4.9) with median OS (mOS) of 16.9 months (95% CI 11.7–22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7–6.2); mOS was 13.1 months (95% CI 7.3–18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0–5.2); mOS was 18.6 months (95% CI 11.7–25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third‐line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

Exploring RAS mutation incidence and temporal heterogeneity in metastatic colorectal cancer patients – a single-institution experience utilising circulating tumour DNA

“…In prospective trials such as CHRONOS, CRICKET, and GEMCAD 17-01, patients with RAS/BRAF wild type were granted the opportunity for a therapeutic rechallenge if ctDNA testing revealed an absence of mutations in those genes. Those individuals who received personalised therapy based on their mutational status exhibited response rates ranging from 20 to 30% [39][40][41]. Therefore, monitoring guided by ctDNA facilitates the noninvasive molecular identification of patients within a subset of CRC who may exhibit a favourable response to anti-EGFR therapy.…”

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

“…Because the trial is still ongoing, results have not yet been reported. Martini et al [ 35 ] conducted a pooled analysis of two prospective phase II trials, CAVE and CRICKET. Individual data of 33 and 13 patients from CAVE and CRICKET trials that received cetuximab rechallenge as third-line therapy were collected.…”