Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (RINDO study).

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 .