Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer (mCRC): AIO KRK-0104 trial

Background: The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of two capecitabine-based regimens: CAPIRI plus cetuximab (CAPIRI-C) and CAPOX plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment related skin toxicity was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed skin toxicity (Cape-ST) and parameters of treatment efficacy. Methods: mCRC patients were randomized to cetuximab (400mg/m2 day 1, followed by 250mg/m2 weekly) plus CAPIRI (irinotecan 200mg/m2, day 1; capecitabine 800mg/m2 twice daily, days 1-14, every 3 weeks) or cetuximab plus CAPOX (oxaliplatin 130mg/m2 day 1; capecitabine 1000mg/m2 twice daily, days 1-14, every 3 weeks). Results: Of 185 recruited patients, 149 patients (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumor assessment and were evaluable for efficacy. While cetuximab-specific skin toxicity such as acneiform rash, dry skin and others occurred in >90% of patients, Cape-ST, predominantly hand-foot syndrome, was observed in only 33.2% of patients. No Cape-ST grade 4 was documented. Cape-ST grade 1-3 was associated with a significantly higher CR rate (13.9% vs 2.1%, p=0.038) and disease control rate (DCR) (97.9% vs 86.1%, p=0.038) compared to grade 0 toxicity. Moreover, Cape-ST grade 1-3 related to a markedly longer PFS (9.9 vs 5.6 months, p<0.001) and OS (32.8 vs 22.4 months, p=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for the CAPIRI-C arm (8.5 vs 5.2 months, p=0.011) and the CAPOX-C arm (9.9 vs 6.5 months, p=0.004), while the effect on OS remained apparent as a strong trend for the CAPIRI-C arm (32.0 vs 19.7 months, p=0.125) and the CAPOX-C arm (37.5 vs 24.0 months, p=0.056). Conclusions: This analysis supports the hypothesis that for the evaluated regimens a correlation exists between capecitabine-specific skin toxicity and treatment efficacy regarding DCR, PFS and OS.