Abstract
Simple SummaryAnti-EGFR-related skin toxicity has been described as a predictive biomarker of response in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). With the CAVE mCRC trial we previously provided the first evidence of the activity of cetuximab plus avelumab as rechallenge treatment in pretreated chemo-refractory RAS WT mCRC. Nowadays, skin toxicity remains the only confirmed clinical biomarker of response to anti-EGFR treatment in mCRC. The role of skin toxicity has not yet been explored in a rechallenge setting. In this paper we provide a post-hoc analysis of the CAVE mCRC trial that investigated the role of skin toxicity as a predictive biomarker of activity of cetuximab plus avelumab treatment and its correlation with different clinico-molecular variables on survival at the univariate and multivariate levels. High-grade skin toxicity, together to the circulating tumor DNA RAS/BRAF/EGFR wild-type status were the only variables with an impact on PFS and OS.The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2–3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9–20.6); whereas 44/77 (57.1%) patients with grade 0–1 ST exhibited mOS of 8.2 months (CI 95%, 5.5–10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29–0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4–5.7) in patients with grade 2–3 ST, compared to patients with grade 0–1 ST with mPFS of 3.4 months (CI 95%, 2.7–4.1; HR, 0.49; CI 95%, 0.3–0.8; p = 0.004). Grade 2–3 ST (HR, 0.51; CI 95%, 0.29–0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27–0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27–0.9; p = 0.023), whereas there was a trend towards ST grade 2–3 (HR, 0.54; CI 95%, 0.29–1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.
Highlights
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, that obtained clinical benefit by first-line therapy with anti-EGFR drugs, became resistant and progressed to second-line treatment [1,2,3,4,5,6]
At univariate analysis for progression-free survival (PFS), besides skin toxicity, another three variables were associated with an improvement in PFS: number of metastatic sites ≤2 (HR, 0.54; CI 95%, 0.33–0.87; p = 0.013); surgery of primary tumor (HR, 0.58; CI 95%, 0.36–0.94; p = 0.028); and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA)
We evaluated response rate (RR) and disease-control rate (DCR) in each defined subgroup (Table 3)
Summary
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, became resistant and progressed to second-line treatment [1,2,3,4,5,6]. The highest benefit was observed in patients with RAS, BRAF, and EGFR wild-type tumor assessed by basal plasma circulating tumor DNA (ctDNA) analysis [5]
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