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Translational Therapeutics

Extending the dosing intervals of nivolumab: model-based simulations in unselected cancer patients

British Journal of Cancer (2024)Cite this article

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Abstract

Background

Reducing nivolumab dose intensity could increase patients’ life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC).

Methods

Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated.

Results

Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744€ to 26,248€ in France).

Conclusions

Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.

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Fig. 1: Simulations of extended-interval dosing regimens of nivolumab.
Fig. 2: Minimum sample size for a pharmacokinetic non-inferiority clinical trial of extended-interval dosing regimens with 240 mg or 480 mg dose according to minimal effective plasma concentration (MEPC) target of 1.5 mg/L or 2.5 mg/L.
Fig. 3: Individual adaptation of nivolumab dosing regimen using Bayesian estimation with the final PK model.
Fig. 4: Pharmacoeconomic comparison of standard, extended-interval and individually adjusted dosing regimens of nivolumab.

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Data availability

The Monolix code of the final popPK model and the dataset can be accessed on request.

Code availability

The Monolix code of the final popPK model and the dataset can be accessed on request.

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Author information

Author notes

  1. These authors contributed equally: Alicja Puszkiel, Guillaume Bianconi, Blaise Pasquiers.

Authors and Affiliations

  1. Université Paris Cité, Faculté de Pharmacie de Paris, INSERM UMR-S1144, Paris, France

    Alicja Puszkiel, Blaise Pasquiers & Xavier Declèves

  2. Biologie du Médicament – Toxicologie, Cochin University Hospital, AP-HP, Paris, France

    Alicja Puszkiel, Guillaume Bianconi, David Balakirouchenane, Xavier Declèves, Michel Vidal & Benoit Blanchet

  3. PhinC Development, Massy, France

    Blaise Pasquiers

  4. Department of Medical Oncology, Cochin University Hospital, Institut du Cancer Paris CARPEM, AP-HP, Paris, France

    Jennifer Arrondeau, Pascaline Boudou-Rouquette, Olivier Huillard, Jérôme Alexandre & François Goldwasser

  5. Department of Pharmacology, Pharmacovigilance Unit, Pitié-Salpêtrière Hospital, AP-HP, Paris, France

    Marie-Claire Bretagne & Joe-Elie Salem

  6. INSERM, CIC-1901, Sorbonne Université, Paris, France

    Joe-Elie Salem

  7. Université Paris Cité, Faculté de Pharmacie de Paris, UMR8038 CNRS CiTCoM, U1268 INSERM, CARPEM, Paris, France

    Michel Vidal & Benoit Blanchet

  8. Department of Dermatology, Cochin University Hospital, AP-HP, Paris, France

    Nora Kramkimel, Sarah Guegan & Selim Aractingi

  9. Université Paris Cité, INSERM, Centre de Recherche des Cordeliers, Équipe labélisée Ligue Contre le Cancer, CNRS SNC 5096, Sorbonne Université, Paris, France

    Jérôme Alexandre

  10. Department of Pneumology, Cochin University Hospital, AP-HP, Paris, France

    Marie Wislez

  11. Université Paris Cité, Faculté de Médecine, INSERM, U1016, Institut Cochin, Paris, France

    François Goldwasser

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Contributions

Wrote Manuscript: AP, BP, BB. Designed Research: AP, JAl, FG, BB. Performed Research: AP, GB, BP, DB, JAr, PB-R, M-CB, J-ES, XD, MV, NK, SG, SA, OH, JAl, MW, FG, BB. Analyzed Data: AP, GB, BP, BB.

Corresponding author

Correspondence to Alicja Puszkiel.

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Competing interests

AP received speaking fees from Bristol Myers Squibb, Eisai and Pierre Fabre Oncology. BP is employed by PhinC Development (Contract Research Organization). J-ES participated in advisory boards, consultancy or received grants from Bristol Myers Squibb, Novartis, AstraZeneca, CRC-Oncology, Servier, IPSEN, Eisai and BeiGene. SG participated in advisory board, consultancy or received grants from Janssen, Bristol Myers Squibb, Pierre Fabre and Sanofi. OH received honoraria from Sanofi, Bayer, MSD, Bristol Myers Squibb, Ipsen, Pfizer, Eisai, Janssen, AstraZeneca and Merck. JAl participated to advisory boards, consultancy or received grants from Astra Zeneca, GSK, MSD, Eisai, Novartis, Janssen. PB-R received travel fees from Pharmamar, Pfizer and grants from Ipsen. MW participated to advisory boards, consultancy or received grants from MSD, Bristol Myers Squibb, Novartis, AstraZeneca, Sanofi, Janssen and Pfizer. JAr participed in advisory board or speaking and received travel fees from Bristol Myers Squibb, Takeda, Pfizer and AstraZeneca. BB received consulting and speaking fees from Bristol Myers Squibb, Clovis Oncology, Janssen, Pierre Fabre, Pfizer and Promise. The remaining authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Institutional Review Board for retrospective analysis of the data collected as part of routine clinical practice and was conducted according to the declaration of Helsinki. Patients provided written informed consent (Cochin University Hospital: CERTIM cohort, Pitié-Salpétrière Hospital: MASC cohort, NCT04637672).

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Puszkiel, A., Bianconi, G., Pasquiers, B. et al. Extending the dosing intervals of nivolumab: model-based simulations in unselected cancer patients. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02659-x

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