| Contributors: |
Ciraci, P.; Germani, M. M.; Pietrantonio, F.; Manca, P.; Lonardi, S.; Busico, A.; Bergamo, F.; Burgio, V.; Mannavola, F.; Di Donato, S.; Fenocchio, E.; Palermo, F.; Capone, I.; De Grandis, M. C.; Pella, N.; Scartozzi, M.; Antonuzzo, L.; Passardi, A.; Claravezza, M.; Salvatore, L.; Tamberi, S.; Randon, G.; Conca, E.; Conca, V.; Antoniotti, C.; Moretto, R.; Masi, G.; Boni, L.; Rossini, D.; Cremolini, C.; Formica, V.; Martignetti, A.; Corsi, D. C.; Fea, E.; Parlagreco, E.; Gennari, A.; Berardi, R.; Simionato, F.; Sperti, E.; Pastorino, A.; Baldini, E.; Dell'Aquila, E.; Tamburini, E.; Zucchelli, G.; Buonadonna, A.; Chiari, R.; Cinieri, S.; Ballestrero, A.; Berenato, R.; Paris, M. K.; Cupini, S.; Ghidini, M.; Frisinghelli, M.; Sonaglio, C. |
| Description: |
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 ... |