A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable metastatic colorectal cancer.
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Colorectal Neoplasms
/ drug therapy
Drug Combinations
Drug Resistance, Neoplasm
Female
Humans
Male
Microsatellite Repeats
Middle Aged
Neoplasm Metastasis
Nivolumab
/ administration & dosage
Pyrrolidines
/ administration & dosage
Survival Rate
Thymine
/ administration & dosage
Trifluridine
/ administration & dosage
chemotherapy
clinical trials
colorectal cancer
immunotherapy
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
31
07
2020
revised:
11
11
2020
accepted:
12
11
2020
pubmed:
6
2
2021
medline:
6
8
2021
entrez:
5
2
2021
Statut:
ppublish
Résumé
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. 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 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. 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. NCT02860546.
Sections du résumé
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
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.
Identifiants
pubmed: 33544407
doi: 10.1002/cam4.3630
pmc: PMC7926002
doi:
Substances chimiques
Drug Combinations
0
Pyrrolidines
0
trifluridine tipiracil drug combination
0
Nivolumab
31YO63LBSN
Thymine
QR26YLT7LT
Trifluridine
RMW9V5RW38
Banques de données
ClinicalTrials.gov
['NCT02860546']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1183-1190Informations de copyright
© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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