Second-line raltitrexed plus irinotecan (SALIRI) with bevacizumab, cetuximab, or alone for metastatic colorectal cancer: a prospective multicenter cohort-based secondary analysis of the SALLY trial.

BACKGROUND: The prospective multicenter SALLY registry reported that raltitrexed plus irinotecan (SALIRI)-based regimens can be used as second-line treatment for metastatic colorectal cancer (mCRC). Outcomes according to the addition of bevacizumab (Bev), cetuximab (Cet), or no targeted agents are less clear in routine practice. We performed an exploratory secondary analysis of the SALLY registry. METHODS: We included patients who received second-line SALIRI + Bev, SALIRI + Cet, or SALIRI alone from the SALLY full analytical set. Treatment was selected by physicians in routine care; patients were not randomized. Tumor response, progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and treatment-related adverse events were compared descriptively and with unadjusted statistical tests. Baseline clinicopathologic and molecular characteristics were assessed across groups. RESULTS: The analysis included 1,049 patients: 678 received SALIRI + Bev, 103 received SALIRI + Cet, and 268 received SALIRI alone. Groups were broadly similar in sex, Eastern Cooperative Oncology Group (ECOG) performance status, pathological type, resection status, and metastatic burden, but differed in age, primary tumor location, and molecular profile among tested patients. The SALIRI + Cet group included more patients with left-sided or rectal tumors and RAS wild-type disease. BRAF-mutant tumors were found only in the SALIRI + Bev and SALIRI-alone groups. Compared with SALIRI alone, SALIRI + Cet was associated with a higher objective response rate (ORR) (27.2% vs. 15.7%; P=0.02) and longer OS (19.9 vs. 17.0 months; P=0.006). SALIRI + Bev showed numerically higher ORR, DCR, and PFS than SALIRI alone, but these differences were not statistically significant. SALIRI + Cet and SALIRI + Bev did not differ significantly in ORR, DCR, PFS, or OS. Grade 3-4 treatment-related adverse events were infrequent and generally similar across groups, although rash was more common with SALIRI + Cet. CONCLUSIONS: In this exploratory, nonrandomized secondary analysis of a prospective multicenter registry, SALIRI combined with Bev or Cet was feasible and tolerable as second-line therapy for mCRC. The observed favorable outcomes in the SALIRI + Cet subgroup should be interpreted cautiously because of nonrandom treatment allocation. Future prospective, biomarker-driven and randomized studies are warranted to define the optimal clinical positioning of SALIRI-based combinations.