Choice of the 3rd and the 4th line therapy sequence in patients with metastatic colorectal cancer

<jats:p> <jats:bold>Introduction</jats:bold> : Treatment options in the third line for patients with metastatic colorectal cancer are limited in the Russian Federation to the multikinase inhibitor regorafenib and the strategy of re-administering previously effective chemo-targeted therapy (hereinafter referred to as chemotherapy re-challenge). </jats:p> <jats:p> <jats:bold>Aim</jats:bold> : To evaluate the efficacy and safety of regorafenib and chemotherapy re-challenge in later lines of therapy for metastatic colorectal cancer, and to identify patient subgroups deriving the greatest clinical benefit from the upfront choice of each approach. </jats:p> <jats:p> <jats:bold>Materials and methods:</jats:bold> A multicenter retrospective study was conducted (four oncology institutions in the Russian Federation, 2010–2021). A total of 218 patients with metastatic colorectal cancer after progression on fluoropyrimidines, oxaliplatin, and irinotecan were included; they received regorafenib or chemotherapy re-challenge in the 3rd and / or 4th line. All patients had 4‑th line of treatment. The primary endpoint was median progression-free survival in the 3rd line; secondary endpoints included median progression-free survival in the 4th line, median overall survival, and toxicity (CTCAE v5.0). Survival was analyzed using the Kaplan — Meier method with the logrank test; subgroup analyses were performed according to clinical and prognostic factors. </jats:p> <jats:p> <jats:bold>Results</jats:bold> : Chemotherapy re-challenge was administered to 121 patients (55.5 %) and regorafenib to 97 (44.5 %); median age was 63 and 62 years, respectively (p = 0.41). Median overall survival was higher with chemotherapy re-challenge: 19.05 months versus 13.6 months (HR = 0.60; 95 % CI 0.43–0.83; p &lt; 0.01). Median progression-free survival in the 3rd line was also higher in the chemotherapy re-challenge group: 6.06 versus 3.02 months (HR = 0.58; 95 % CI 0.44–0.76; p &lt; 0.01). In the 4th line, no statistically significant differences in median progression-free survival were observed: 3.7 vs 2.87 months (HR = 0.78; 95 % CI 0.59–1.04; p = 0.09). Subgroup analyses showed an overall survival and / or progression-free survival advantage for chemotherapy re-challenge across all prognostic groups. Chemotherapy re-challenge was associated with a more favorable toxicity profile. Dose reduction of regorafenib was required in approximately 40 % of patients, and treatment discontinuation due to toxicity occurred in 8–10 %. </jats:p> <jats:p> <jats:bold>Conclusion</jats:bold> : In a selected cohort of patients able to receive subsequent lines of therapy, third-line chemotherapy re-challenge was associated with longer overall survival and progression-free survival compared with regorafenib. </jats:p>