A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite‐stable metastatic colorectal cancer. (5th February 2021)

• Record Type: Journal Article
• Authors: Patel, Manish R.; Falchook, Gerald S.; Hamada, Kensuke; Makris, Lukas; Bendell, Johanna C.
• Is Part Of: Cancer medicine. Volume 10:Number 4(2021)
• Page Start: 1183
• Page End: 1190
• Publication Date: 2021-02-05
• Subjects: chemotherapy -- clinical trials -- colorectal cancer -- immunotherapy; 616.994005
• DOI: 10.1002/cam4.3630
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: 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. Abstract : This phase 2 study utilized a Simon's 2‐stage design to evaluate the combination of trifluridine/tipiracil (FTD/TPI) and nivolumab in patients with microsatellite‐stable (MSS) metastatic colorectal cancer (mCRC). Among 18 patients enrolled in the first stage, no clinical responses were observed with FTD/TPI plus nivolumab, and therefore, the study did not progress to the second stage. Patients with refractory MSS mCRC failed to experience clinical benefit with the FTD/TPI plus nivolumab combination, although safety data indicated that this combination was tolerable in these patients.