Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (RINDO study).
Authors: Masashi Hattori, Norifumi Hattori, Goro Nakayama, Shinichi Umeda, Takayoshi Kishida, Yoshihisa Kawase, Kazuhiro Ezaka, Masayuki Tsutsuyama, Mitsuru Sakai, Takeshi Ito, Yutaka Yanbe, Mitsuro Kanda, Chie Tanaka, Kenta Murotani, Masahiko Ando, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2025)

124 Background: Phase III trials (ML18147, VELOUR, and RAISE trials) of second-line combination therapy with molecular-targeted agents after first-line treatment with bevacizumab (BEV) for metastatic colorectal cancer (mCRC) demonstrated significant improvements in overall survival (OS). In the RAISE trial (irinotecan (IRI) dose: 180 mg/m²), the relative dose intensity (RDI) of IRI was lower (63.8%) and the incidence rates of adverse events leading to discontinuation of cytotoxic agents was higher (48.6%) in the Japanese population compared to all patients. Based on these results, we conducted a prospective trial to evaluate the efficacy and safety of fluorouracil, levofolinate, and IRI (150 mg/m², standard dose in Japan) (FOLFIRI) plus ramucirumab (RAM) as second-line treatment for mCRC in Japanese patients. Methods: On day 1 of each 2-week cycle, patients with unresectable mCRC who were refractory to oxaliplatin and fluoropyrimidine in combination with BEV or anti-epidermal growth factor receptor (EGFR) antibodies as first-line treatment received 8 mg/kg RAM, followed by the FOLFIRI regimen with low-dose IRI (150 mg/m²). The primary endpoint was progression-free survival (PFS), and secondary endpoints were OS, treatment compliance, and safety. We hypothesized an RFS threshold of 4.3 months and expected RFS of 5.7 months based on data from a Japanese subgroup of the RAISE trial. The protocol treatment was considered to be effective if the lower limit of the 95% confidence interval (CI) exceeded the 4.3-month threshold. Results: A total of 62 patients were enrolled from 15 institutions between January 2018 and August 2021. The intent-to-treat and safety populations included 61 and 58 patients, respectively. The cutoff date for the primary analysis was December 2023. Median PFS and OS were 5.9 months (95% CI, 4.8-6.9 months) and 17.0 months (95%CI, 12.0-21.0 months), respectively. Median PFS was 5.7 months (95% CI, 4.4-6.8 months) in patients treated with first-line chemotherapy with BEV and 7.4 months (95% CI, 4.6-11.0 months) in those treated with first-line chemotherapy with anti-EGFR antibodies (hazard ratio [HR], 1.17; 95% CI, 0.64-2.12; p = 0.60), and median OS was 19.8 months (95% CI, 10.4-22.4 months) and 17.5 months (95% CI, 11.5-26.1 months), respectively (HR, 0.96; 95% CI, 0.52-1.78; p = 0.91). The objective response rate and disease control rate were 8.2% and 74%, respectively. Median RDI of IRI, 5-fluorouracil, and RAM were 73.8% (range, 40.3-102.4%), 58.5% (range, 22.8-102.4%), and 80.8% (range, 36.1-102.4%), respectively. The observed Grade ≥3 adverse events included neutropenia (40%), anemia (1.7%), diarrhea (8.6%), fatigue (6.9%), decreased appetite (10%), hypertension (6.9%), and proteinuria (3.4%). Conclusions: FOLFIRI with low-dose IRI plus RAM is a feasible second-line treatment in Japanese patients with mCRC. Clinical trial information: jRCTs041180074 .