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. 2025 Jul 25:225:115560.
doi: 10.1016/j.ejca.2025.115560. Epub 2025 Jun 11.

Morphine and metformin impact immunotherapy benefit in patients with NSCLC: Results of the real-world study IFCT-1502 CLINIVO-SNDS

Elisa Gobbini  1 , Alexandra Langlais  2 , Pascale Missy  2 , Sébastien Chanoine  3 , Benjamin Besse  4 , Pierre-Jean Souquet  5 , Fabrice Barlesi  6 , Clarisse Audigier-Valette  7 , Anne-Cécile Métivier  8 , Isabelle Monnet  9 , José Hureaux  10 , Gaelle Jeannin  11 , Jacques Cadranel  12 , Aurélie Lagrange  13 , Quân Tran  2 , Franck Morin  2 , Olivier Molinier  14 , Virginie Westeel  15 , Nicolas Girard  16 , Denis Moro-Sibilot  17
Affiliations
Free article

Morphine and metformin impact immunotherapy benefit in patients with NSCLC: Results of the real-world study IFCT-1502 CLINIVO-SNDS

Elisa Gobbini et al. Eur J Cancer. .
Free article

Abstract

Background: Most patients with lung cancer have comorbidities at the time of diagnosis. Treatments prescribed for cancer-related symptoms are thus added to drugs for chronic diseases. The impact of comedication on immunotherapy efficacy has been studied in retrospective series, but the results are often biased by the lack of information on the independent prognostic impact of comedication weighted for comorbidities and disease aggressiveness.

Methods: The IFCT-1502 CLINIVO study is a nationwide retrospective cohort of patients with advanced non-small cell lung cancer who received nivolumab in second or later lines of treatment as part of the French Expanded Access Program. We retrieved comedication prescriptions from 90 days before to 30 days after the first nivolumab administration via the French national healthcare database. We report the results of a comprehensive post hoc analysis investigating the impact of comedication on treatment response considering well-known negative prognostic factors.

Results: We selected 753 patients whose medical and comedication records were available. According to the multivariate analysis, morphine and corticosteroids > 20 mg per day were associated with poor overall survival regardless of disease aggressiveness. Conversely, metformin was associated with better overall survival. Morphine and corticosteroids were also found to be associated with shorter real-world progression-free survival according to multivariate analysis, as were poor prognostic factors such as liver metastasis and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≥ 2.

Conclusion: Our study confirmed the negative impact of morphine and high-dose corticosteroids on immunotherapy efficacy regardless of poor prognostic factors related to disease aggressiveness. On the other hand, our findings suggested a positive impact of metformin on immunotherapy outcomes.

Keywords: Comedication; Drug interaction; Immunotherapy; NSCLC.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EG: speaker bureau for Merck Sharp & Dohme, Bristol-Myers Squibb, Regeneron, Sanofi, Janssen. Spouse of an AstraZeneca employee. FB: Institutional financial interests from Abbvie, ACEA, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Summit Therapeutics and Takeda; Principal Investigator for Astra-Zeneca, BMS, Innate Pharma, Merck, Mirati, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR). A-CM: Research grants/support from Abbvie, Astra Zeneca, Daiichi-Sankyo, MSD, Takeda. IM: honoraria from Regeneron, support for attending meetings from Takeda, Oxyvie, Pfizer, MSD. VW: Consulting fees from Amgen; Payment or honoraria for lectures, presentations, speakers bureau, manuscript writing or educational events for Amgen, Astra Zeneca, Bristol Myers Squibb, MSD, Roche, Sanofi; Support for attending meetings and/or travel from Astra Zeneca, Bristol Myers squibb, Janssen, MSD, Roche, Sanofi; Participation on a Data Safety Monitoring Board or Advisory Board for Amgen, Astra Zeneca, Ipsen. NG: Research grants/support from Abbvie, Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Gilead, Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merk Serono, Merck Sharp & Dohme, Novartis, Sanofi, Sivan; Consultative services for Abbvie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, Daiichi-Sankyo, Gilead, Ipsen Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Pierre Fabre, Sanofi, Sivan Takeda; Participation on a data safety monitoring board for Hoffmann-La Roche; Employment of a family member with AstraZeneca. DMS: Clinical Trial Principal investigator: AstraZeneca, Boehringer–Ingelheim, BMS, Novartis, Roche Daiichi, Sanofi; Consulting: AstraZeneca, Boehringer–Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche, Takeda, Daiichi. Speaker bureau: AstraZeneca, Boehringer–Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. Other authors declare no conflict of interest for the present paper.

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