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Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer

BACKGROUND: Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatelli...

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Autores principales: Akce, Mehmet, Farran, Batoul, Switchenko, Jeffrey M, Rupji, Manali, Kang, Sandra, Khalil, Lana, Ruggieri-Joyce, Amanda, Olson, Brian, Shaib, Walid L, Wu, Christina, Alese, Olatunji B, Diab, Maria, Lesinski, Gregory B, El-Rayes, Bassel F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603338/
https://www.ncbi.nlm.nih.gov/pubmed/37852737
http://dx.doi.org/10.1136/jitc-2023-007235
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author Akce, Mehmet
Farran, Batoul
Switchenko, Jeffrey M
Rupji, Manali
Kang, Sandra
Khalil, Lana
Ruggieri-Joyce, Amanda
Olson, Brian
Shaib, Walid L
Wu, Christina
Alese, Olatunji B
Diab, Maria
Lesinski, Gregory B
El-Rayes, Bassel F
author_facet Akce, Mehmet
Farran, Batoul
Switchenko, Jeffrey M
Rupji, Manali
Kang, Sandra
Khalil, Lana
Ruggieri-Joyce, Amanda
Olson, Brian
Shaib, Walid L
Wu, Christina
Alese, Olatunji B
Diab, Maria
Lesinski, Gregory B
El-Rayes, Bassel F
author_sort Akce, Mehmet
collection PubMed
description BACKGROUND: Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study. METHODS: Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry. RESULTS: A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475). CONCLUSIONS: Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.
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spelling pubmed-106033382023-10-28 Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer Akce, Mehmet Farran, Batoul Switchenko, Jeffrey M Rupji, Manali Kang, Sandra Khalil, Lana Ruggieri-Joyce, Amanda Olson, Brian Shaib, Walid L Wu, Christina Alese, Olatunji B Diab, Maria Lesinski, Gregory B El-Rayes, Bassel F J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study. METHODS: Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry. RESULTS: A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475). CONCLUSIONS: Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients. BMJ Publishing Group 2023-10-18 /pmc/articles/PMC10603338/ /pubmed/37852737 http://dx.doi.org/10.1136/jitc-2023-007235 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Clinical/Translational Cancer Immunotherapy
Akce, Mehmet
Farran, Batoul
Switchenko, Jeffrey M
Rupji, Manali
Kang, Sandra
Khalil, Lana
Ruggieri-Joyce, Amanda
Olson, Brian
Shaib, Walid L
Wu, Christina
Alese, Olatunji B
Diab, Maria
Lesinski, Gregory B
El-Rayes, Bassel F
Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
title Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
title_full Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
title_fullStr Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
title_full_unstemmed Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
title_short Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
title_sort phase ii trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603338/
https://www.ncbi.nlm.nih.gov/pubmed/37852737
http://dx.doi.org/10.1136/jitc-2023-007235
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