Treatment-emergent antidrug antibodies related to PD-1, PD-L1, or CTLA-4 inhibitors across tumor types: a systematic review.

BACKGROUND

Increased understanding of how the immune system regulates tumor growth has innovated the use of immunotherapeutics to treat various cancers. The impact of such therapies, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, on the production of antidrug antibodies (ADAs) and their impact on outcomes, is poorly understood. This study aims to evaluate the clinical trial evidence on ADA incidence associated with PD-1, PD-L1, and CTLA-4 inhibitors in the treatment of cancer and to assess associations between treatment administered, ADA incidence, and treatment outcomes.

METHODS

Embase

RESULTS

After screening 4160 records and reviewing 97 full publications, a total of 34 publications reporting on 68 trials were included. A further 41 relevant clinical trials were identified on ClinicalTrials.gov and a further 32 from searches of packaging inserts. In total, 141 relevant trials covering 15 different checkpoint inhibitors and 16 different tumor types were included. Across the included trials, atezolizumab was associated with the highest incidence of ADAs (29.6% of 639 patients), followed by nivolumab (11.2% of 2,085 patients). Combination checkpoint inhibitor treatment appeared to increase the rate of ADAs versus monotherapy. Only 17 trials reported on the impact of ADAs on treatment outcomes with mixed results for the impact of ADAs on treatment efficacy, safety, and pharmacokinetics.

CONCLUSIONS

Checkpoint inhibitors for the treatment of cancer are immunogenic, with the incidence of treatment-emergent ADAs varying between individual therapies. It remains unclear what impact ADAs have on treatment outcomes.

Informations de copyright

© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: KN and ZR were an employee of Eisai, USA. CRM and GSR of Mtech Access were paid consultants to Eisai. PG has received lecture fees and honoraria from BMS, Adaptimmune, AstraZeneca, Sirtex, MSD, Eisai, Ipsen, Bayer, Roche, Lilly, Boston Scientific, and Guerbet. DJP has received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, Falk Foundation; travel expenses from BMS and Bayer Healthcare; consulting fees from Mina Therapeutics, Eisai, Roche, Ipsen, Mursla, Starpharma, Avamune, DaVolterra, and Astra Zeneca; and research funding (to institution) from MSD, GSK, and BMS. RSF has acted as a consultant to AstraZeneca, Bayer, BMS, CStone, Exelixis, Eisai, Merck, Pfizer, Roche/Genentech, and has received grants (to institution) from Bayer, BMS, Eisai, Merck, Pfizer, and Roche/Genentech.