{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:07:43Z","timestamp":1792634863499,"version":"4.5.0"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Microsatellite\u2010stable (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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This single\u2010arm, safety lead\u2010in study used a Simon's two\u2010stage design (enrolling 6 patients in the safety lead\u2010in, proceeding to stage 2 if \u22652 of the first 15 patients achieved a partial or complete response per immune\u2010related response criteria [irRC] within 6\u00a0months). Patients with histologically proven MSS mCRC, and disease progression after \u22652 prior chemotherapy regimens received FTD\/TPI (35\u00a0mg\/m<jats:sup>2<\/jats:sup> twice daily; days 1\u20135 and 8\u201312 every 28\u00a0days) plus nivolumab (3\u00a0mg\/kg every 2\u00a0weeks).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Between August 2016 and January 2017, 18 patients (50% men; median age 56.5\u00a0years) were enrolled; 72% had colon cancer and 56% had <jats:italic>KRAS<\/jats:italic> mutations. All patients received treatment (median, 2.5 cycles [range, 1\u20138]). No dose\u2010limiting 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 \u22653 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\u2010free survival was 2.2\u00a0months (95% CI, 1.8\u20136.0\u00a0months) per irRC and 2.8\u00a0months (95% CI, 1.8\u20135.1\u00a0months) per RECIST.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p>NCT02860546.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.3630","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T06:29:03Z","timestamp":1612765743000},"page":"1183-1190","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A phase 2 trial of trifluridine\/tipiracil plus nivolumab in patients with heavily pretreated microsatellite\u2010stable metastatic colorectal cancer"],"prefix":"10.1002","volume":"10","author":[{"given":"Manish R.","family":"Patel","sequence":"first","affiliation":[{"name":"Florida Cancer Specialists and Sarah Cannon Research Institute Sarasota Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9165-2191","authenticated-orcid":false,"given":"Gerald S.","family":"Falchook","sequence":"additional","affiliation":[{"name":"Sarah Cannon Research Institute at HealthONE Denver Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Hamada","sequence":"additional","affiliation":[{"name":"Taiho Oncology, Inc Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6963-0105","authenticated-orcid":false,"given":"Lukas","family":"Makris","sequence":"additional","affiliation":[{"name":"Stathmi, Inc New Hope Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9426-5891","authenticated-orcid":false,"given":"Johanna C.","family":"Bendell","sequence":"additional","affiliation":[{"name":"Sarah Cannon Research Institute and Tennessee Oncology Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.currproblcancer.2018.06.010"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2205"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604867"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200001133420201"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104193441603"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61900-X"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1414325"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500596"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30422-9"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0189848"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i29.3920"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm9010005"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01816"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.11.024"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clcc.2018.06.004"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30425-4"},{"issue":"10","key":"e_1_2_10_18_1","first-page":"2032","article-title":"Synergistic anticancer activity of a novel oral chemotherapeutic agent containing trifluridine and tipiracil in combination with anti\u2010PD\u20101 blockade in microsatellite stable\u2010type murine colorectal cancer cells","volume":"7","author":"Suzuki N","year":"2017","journal-title":"Am J Cancer Res"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0197-2456(89)90015-9"},{"key":"e_1_2_10_20_1","unstructured":"LONSURF (trifluridine and tipiracil) tablets for oral use. 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