A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable metastatic colorectal cancer

Background Microsatellite-stable (MSS) colorectal cancer (CRC) tends to be poorly immunogenic, with limited treatment options. In MSS CRC xenograft models, trifluridine/tipiracil (FTD/TPI) plus programed death 1 inhibitors resulted in synergistic antitumor activity and increased tumor immunogenicity. This phase 2 study evaluated FTD/TPI plus nivolumab in patients with MSS metastatic CRC. Methods This single-arm, safety lead-in study used a Simon's two-stage design (enrolling 6 patients in the safety lead-in, proceeding to stage 2 if >= 2 of the first 15 patients achieved a partial or complete response per immune-related response criteria [irRC] within 6 months). Patients with histologically proven MSS mCRC, and disease progression after >= 2 prior chemotherapy regimens received FTD/TPI (35 mg/m(2) twice daily; days 1-5 and 8-12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks). Results Between August 2016 and January 2017, 18 patients (50% men; median age 56.5 years) were enrolled; 72% had colon cancer and 56% had KRAS mutations. All patients received treatment (median, 2.5 cycles [range, 1-8]). No dose-limiting toxicities were observed in the study. The most frequent adverse events (AEs) of any cause and grade were nausea (67%), diarrhea (61%), and neutropenia (50%); 13 patients (72%) experienced grade >= 3 AEs. No patients discontinued treatment because of AEs. No patient achieved a tumor response (either per Response Evaluation Criteria in Solid Tumors [RECIST] or irRC), and the study did not progress to the second stage. Stable disease was achieved in 8 patients per irRC and in 10 patients per RECIST. Median progression-free survival was 2.2 months (95% CI, 1.8-6.0 months) per irRC and 2.8 months (95% CI, 1.8-5.1 months) per RECIST. Conclusion Patients with refractory MSS metastatic CRC failed to experience clinical benefit with FTD/TPI plus nivolumab, although safety data in this population indicated tolerability and feasibility of this combination. Trial registration number NCT02860546.

Automated summary

In this study, MSS metastatic CRC patients were treated with FTD/TPI plus nivolumab, but no tumor response was achieved, and the study did not progress to the second stage. The most frequent adverse events during treatment were nausea, diarrhea, and neutropenia.