Background Durvalumab, an immune checkpoint inhibitor (ICI) targeting PD-L1, has demonstrated clinical activity with or without tremelimumab, a CTLA-4 inhibitor, in Phase 3 studies in multiple tumor types.1-3 The occurrence of anti-drug antibodies (ADA) could potentially negatively impact ICI safety and efficacy.4 This analysis assessed the immunogenicity of durvalumab using pooled pan-tumor data.
Methods Durvalumab immunogenicity was assessed using pooled data from 18 clinical studies of 7826 participants with lung cancer (MYSTIC, ATLANTIC, NEPTUNE, Study 6, ARCTIC, PACIFIC), hepatocellular carcinoma (HIMALAYA, Study 22), bladder cancer (DANUBE, Study 10), head and neck cancer (KESTREL, HAWK, CONDOR, EAGLE, Study 11), gastric or gastroesophageal junction adenocarcinoma (Study 21) or advanced solid tumors (Study 1108, Japan Study 2). ADA and neutralizing ADA (nAb) to durvalumab were detected using validated solution-phase bridging electrochemiluminescence immunoassays. Impact of durvalumab ADA on safety was assessed using pan-tumor data from the pool of 18 studies. Impact of ADA on durvalumab pharmacokinetics was assessed using a pooled dataset from Study 1108, PACIFIC, ATLANTIC, CASPIAN, POSEIDON, HIMALAYA, and Study 22. Due to differences in cancer settings of the studies, the impact of durvalumab ADA on efficacy was not assessed.
Results The proportion of durvalumab ADA-positive participants at any visit (ADA prevalence) was 6.2% with durvalumab monotherapy (D), 6.8% with T75+D, and 7.3% with T300+D (STRIDE) (table 1). The proportion of treatment-emergent ADA–positive participants (ADA incidence) was low and similar across data pools: 2.7% with D, 3.4% with T75+D, and 2.8% with T300+D (table 1). Median ADA titers were ≤16 across all ADA categories in all pools (table 1). The proportion of transiently ADA-positive participants out of those with ADA prevalence was 32/191 with D, 22/146 with T75+D, and 3/26 with T300+D. The proportion of participants who tested positive for durvalumab nAb at any visit was 0.5% with D, 0.6% with T75+D, and 1.4% with T300+D (table 1). Incidence of infusion-related reactions was low in ADA-positive participants across treatment regimens (1% with D, and 0% with T75+D and T300+D); there was no marked impact of durvalumab ADA presence on categorical AE data (table 2). Durvalumab ADA presence did not have a clinically meaningful impact on durvalumab exposure metrics.
Conclusions Although incidences of ADA vary greatly among ICI 4, analysis of this large, multi-study, pooled pan-tumor dataset demonstrates that durvalumab has a low-risk immunogenicity profile as monotherapy or in combination with tremelimumab. Immunogenicity of durvalumab appeared to have no marked impact on safety or exposure.
Acknowledgements Medical writing support, under the direction of the authors, was provided by Claire Tinderholm, PhD, of CMC Connect, McCann Health Medical Communications, with funding from AstraZeneca, in accordance with Good Publications Practice (GPP3) guidelines.
Trial Registration MYSTIC: NCT02453282
Study 6: NCT02000947
Study 22: NCT02519348
Study 10: NCT02261220
Study 11: NCT02262741
Study 21: NCT02340975
Study 1108: NCT01693562
Japan Study 2: NCT01938612
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Oh D-Y, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary trance cancer. NEJM Evid. 2022. Doi: https://doi.org/10.1056/EVIDoa2200015.
Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22:51–65.
Enrico D, Paci A, Chaput N, Karamouza E, Besse B. Antidrug antibodies against immune checkpoint blockers: impairment of drug efficacy or indication of immune activation? Clin Cancer Res. 2020;26:787–792.
Ethics Approval The trial protocol was approved by local institutional review boards.
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