Carlo Signorelli, Michele A. Basso, Maria Alessandra Calegari, Annunziato Anghelone, Alessandro Passardi, Chiara Gallio, Alessandro Bittoni, Jessica Lucchetti, Lorenzo Angotti, Emanuela Di Giacomo, Ina Valeria Zurlo, Maria Cristina Morelli, Emanuela Dell’Aquila, Adele Artemi, Donatello Gemma, Alessandra Emiliani, Marta Ribelli, Domenico Corsi, Giulia Arrivi, Federica Mazzuca, Federica Zoratto, Marta Schirripa, Francesco Schietroma, Maria Grazia Morandi, Fiorenza Santamaria, Manuela Dettori, Antonella Cosimati, Rosa Saltarelli, Alessandro Minelli, Emanuela Lucci‐Cordisco, Mario Giovanni Chilelli
Background: Regorafenib is a recognised treatment for refractory metastatic colorectal cancer (mCRC). The phase II ReDOS trial indicated that a stepwise dose escalation approach could enhance tolerability and persistence while maintaining efficacy. The ReTrITA study, a significant multicentre real-world cohort in Italy, served as the foundation for this sub-analysis concentrating solely on patients treated with regorafenib. Methods: This retrospective analysis encompassed 713 patients treated at 17 Italian centres from 2012 to 2023. Patients were categorised into two groups: ReDOS-like escalation (n = 313) and fixed dosing (no-ReDOS) (n = 400). The endpoints assessed were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and safety. Survival was assessed using Kaplan–Meier and Cox models, accompanied by exploratory subgroup analyses. Results: The median overall survival (OS) was comparable between the escalation and fixed dosing groups, recorded at 7.4 months and 6.7 months, respectively (HR 1.00, 95% CI 0.85–1.18, p = 0.93). Progression-free survival (PFS) demonstrated a significant improvement with escalation, recording 3.1 months compared to 3.9 months (HR 0.76, 95% CI 0.65–0.89, p = 0.0007). Subgroup analyses demonstrated a consistent progression-free survival (PFS) benefit in patients aged ≥70 years (HR 0.71, p = 0.015), with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 (HR 0.76, p = 0.022), RAS wild-type tumours (HR 0.69, p = 0.026), and rectal primaries (HR 0.72, p = 0.043). The disease control rate (DCR) and objective response rate (ORR) were comparable, at 23.2% versus 25.3% and 2.0% compared 2.6%, respectively. Although not statistically significant, the fixed dose group’s duration of response (DoR) was numerically longer (15.4 months) than that of the variable dosing group (8.9 months). A lower percentage of patients experienced grade 3/4 adverse events with escalation (35.4% compared to 39.5%, p = 0.0042). Conclusions: This sub-analysis of the ReTrITA cohort demonstrates that regorafenib dose escalation is achievable in real-world settings, resulting in notable improvements in progression-free survival and enhanced tolerability, while not adversely affecting overall survival. These results support and improve the findings of the ReDOS study, showing that dosage escalation is possible and helpful in a diverse, unselected group of people, which is what is performed in routine oncology treatment. The findings are consistent with both randomised and observational studies, endorsing individualised dosing as a practical strategy in refractory mCRC.