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.
U.S. Food and Drug Administration. YERVOY® (ipilimumab): Highlights of prescribing information 2011 [Available from: https://packageinserts.bms.com/pi/pi_yervoy.pdf.
Wilkins JJ, Brockhaus B, et al. Time-Varying Clearance and Impact of Disease State on the Pharmacokinetics of Avelumab in Merkel Cell Carcinoma and Urothelial Carcinoma. CPT: Pharmacometrics and Systems Pharmacology. 2019;8(6):415–27.
U.S. Food and Drug Administration. BAVENCIO® (avelumab): Highlights of prescribing information 2019 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761049s006lbl.pdf.
Zucali PA, Lin CC, et al. Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: Results from a phase I/II open-label, multicenter study. Journal for ImmunoTherapy of Cancer. 2022;10(1) (no pagination)(e003697).
U.S. Food and Drug Administration. LIBTAYO® (cemiplimab-rwlc): Highlights of prescribing information 2021 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761097s007lbl.pdf.
Lu S, Bowsher RR, et al. An Integrated Analysis of Dostarlimab Immunogenicity. AAPS Journal. 2021;23(5) (no pagination)(96).
U.S. Food and Drug Administration. JEMPERLI (dostarlimab-gxly): Highlights of prescribing information 2021 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761174s000lbl.pdf.
Papadopoulos KP, Autio K, et al. Phase I study of MK-4166, an anti-human glucocorticoid-induced tnf receptor antibody, alone or with pembrolizumab in advanced solid tumors. Clinical Cancer Research. 2021;27(7):1904–11.
Agrawal S, Statkevich P, et al. Evaluation of Immunogenicity of Nivolumab Monotherapy and Its Clinical Relevance in Patients With Metastatic Solid Tumors. Journal of Clinical Pharmacology. 2017;57(3):394–400.
U.S. Food and Drug Administration. OPDIVO (nivolumab): Highlights of prescribing information 2018 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf.
van Vugt MJH, Stone JA, et al. Immunogenicity of pembrolizumab in patients with advanced tumors. Journal for Immunotherapy of Cancer. 2019;7(1):212.
U.S. Food and Drug Administration. KEYTRUDA® (pembrolizumab): Highlights of prescribing information 2019 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514Orig1s054lbl.pdf.
Liu R, Li W, et al. Phase I study of pucotenlimab (HX008), an anti-PD-1 antibody, for patients with advanced solid tumors. Therapeutic Advances in Medical Oncology. 2021;13(no pagination).
Johnson ML, Braiteh F, et al. Assessment of Subcutaneous vs Intravenous Administration of Anti-PD-1 Antibody PF-06801591 in Patients with Advanced Solid Tumors: A Phase 1 Dose-Escalation Trial. JAMA Oncology. 2019;5(7):999–1007.
Shemesh CS, Chanu P, et al. Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer. Journal for ImmunoTherapy of Cancer. 2019;7(1) (no pagination)(314).
Peters S, Galle PR, et al. Evaluation of atezolizumab immunogenicity: Efficacy and safety (Part 2). Clinical and Translational Science. 2022;15(1):141–57.
Wu B, Sternheim N, et al. Evaluation of atezolizumab immunogenicity: Clinical pharmacology (part 1). Clinical and Translational Science. 2022;15(1):130–40.
U.S. Food and Drug Administration. TECENTRIQ®(atezolizumab): Highlights of prescribing information 2022 [Available from: https://www.gene.com/download/pdf/tecentriq_prescribing.pdf.
U.S. Food and Drug Administration. IMFINZI® (durvalumab): Highlights of prescribing information 2017 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf.
Hellmann MD, Bivi N, et al. Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors. Clin Cancer Res. 2021;27(10):2773–81.
Patnaik A, Yap TA, et al. Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial. Clin Cancer Res. 2021;27(5):1267–77.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.