A phase II, randomized, double-blind, placebo-controlled study of simtuzumab in combination with FOLFIRI for the Second-Line treatment of metastatic KRAS mutant colorectal adenocarcinoma

Background. Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro. Methods. Patients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed. Results. In total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n584), FOLFIRI/simtuzumab 200 mg (n585), and FOLFIRI/placebo (n580). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p5.10), 5.4 months (1.45 [1.01, 2.06]; p5.04), and 5.8 months.Median OS was 11.4 months (1.23 [0.80, 1.91]; p5.25), 10.5 months (1.50 [0.98, 2.30]; p5.06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients. Conclusion. The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC.