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Abstract
Background Treatment-emergent anti-drug antibodies (ADAs) are postulated to reduce the efficacy of immune checkpoint inhibitors. A systematic review (SR) was conducted to evaluate the incidence of treatment-emergent ADAs with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and their impact on treatment outcomes in patients with cancer.
Methods Electronic database searches of MEDLINE, EMBASE and the Cochrane Library (conducted February 2022), supplemented by interrogation of grey literature were conducted to identify studies reporting incidence of ADAs and the impact of immunogenicity on treatment efficacy in oncology patients treated with PD-1, PD-L1, or CTLA-4 checkpoint inhibitors.
Results Of the 4,612 articles identified, 34 publications reporting on 68 trials were included. An additional 41 and 32 records were identified from clinicaltrials.gov and packaging inserts respectively.1–25 In total, 141 trials of 15 checkpoint inhibitors and 16 tumour types were included. There was considerable variability in the reporting of ADAs, and comparisons between trials were challenging due to intra-study heterogeneity. The incidence of ADAs ranged from 0 to 74% (table 1 and figure 1). Across trials, in analyses with the largest sample sizes, atezolizumab was associated with the highest incidence of ADAs (29.6%), then nivolumab (12.2%), followed by the remaining treatments (0–4.4%). Combination checkpoint inhibitor treatment appeared to increase the rate of ADAs versus monotherapy (eg. the incidence of ADAs in durvalumab and tremelimumab was 0% and 3.98% respectively when administered as a monotherapy in trials with the largest sample sizes; however the incidence was higher at 9.6% and 18.5% respectively when administered in combination). The same effect was also observed for ipilimumab + nivolumab. The incidence of neutralising antibodies (nAbs) mirrored ADA distribution, being highest for atezolizumab (4.3–27.5%) vs other treatments. Only 17 trials reported on ADA impact on treatment outcomes. Of 11 trials examining efficacy, two reported a negative effect of ADAs, eight reported no measurable effect, and another had insufficient patient numbers. The impact of ADAs on treatment safety, and pharmacokinetics was also inconclusive.
Conclusions Treatment-emerging ADAs are inconsistently reported across trials and documented in up to 30% of subjects treated with checkpoint inhibitors across indications. Emergence of nAbs follows but does not perfectly mirror ADA titers, raising questions around the functional meaning of different ADAs. Standardised reporting of ADAs and nAbs should be advocated to facilitate more conclusive immunologic and clinical insight as to the relationship with ADAs and response.
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Incidence of treatment-emergent ADAs across treatments
Incidence of treatment-emergent ADAs across all trials identified in the SLR
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