Re-treatment with panitumumab followed by regorafenib versus the reverse sequence in chemorefractory metastatic colorectal cancer patients with RAS and BRAF wild-type circulating tumor DNA: the PARERE study by GONO

Background: Re-treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies offers a promising approach to extend the continuum of care of patients with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) with no mutations of resistance in their circulating tumor DNA (ctDNA) at the time of treatment re-exposure. Patients and methods: PARERE (NCT04787341) is an open-label, multicenter, randomized phase II trial investigating the optimal sequencing of panitumumab and regorafenib in chemorefractory RAS and BRAF wt mCRC patients, who previously derived benefit from first-line anti-EGFR-containing regimens, then received at least one intervening anti-EGFR-free line of treatment, and were prospectively selected for the absence of RAS and BRAF mutations in their ctDNA. Eligible patients were randomly assigned 1 : 1 to receive anti-EGFR re-treatment with panitumumab followed by regorafenib after progression (arm A) versus the reverse sequence (arm B). The primary endpoint was overall survival (OS). Results: Between December 2020 and December 2024, 428 patients underwent molecular screening, and 213 with RAS/BRAF ctDNA wt were randomized (arm A/B = 106/107). At a median follow-up of 31.9 months, no difference in terms of OS was observed between treatment arms, with a median OS of 11.7 and 11.6 months in arms B and A, respectively (hazard ratio 1.13, 85% confidence interval 0.90-1.41, P = 0.441). However, re-treatment with panitumumab was associated with higher objective response rate (ORR; first ORR: 16% versus 2%, P = 0.003; second ORR: 18% versus 0%, P = 0.013) and disease control rate (DCR; first DCR: 61% versus 36%, P < 0.001; second DCR: 62% versus 38%, P = 0.003), and longer progression-free survival (PFS; first PFS: 4.2 versus 2.4 months, P = 0.103; second PFS: 3.9 versus 2.7 months, P = 0.019) than regorafenib, regardless of the sequence of the study treatments. Conclusions: Anti-EGFR re-treatment should be regarded as an option in the continuum of care of chemorefractory mCRC patients with RAS and BRAF wt tumors, with no alterations of acquired resistance in their ctDNA.