Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors – A systematic review and meta-analysis

• Published in: Cancer treatment reviews Vol. 92; p. 102134
• Main Authors: Hussaini, Syed, Chehade, Rania, Boldt, Ronald Gabriel, Raphael, Jacques, Blanchette, Phillip, Maleki Vareki, Saman, Fernandes, Ricardo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2021
• Subjects: Checkpoint inhibitors; Efficacy; Humans; Immune Checkpoint Inhibitors - adverse effects; Immune Checkpoint Inhibitors - therapeutic use; Immune-related adverse events; Immunotherapy; Immunotherapy - methods; Ipilimumab; Melanoma; Neoplasms - drug therapy; Neoplasms - immunology; Nivolumab; Non-small cell lung cancer; Pembrolizumab; Survival Analysis; Toxicity; ILD; Checkpoint inhibitors; PR; Toxicity; Ipilimumab; ICIs; PICOS; ORR; mOS; SD; TTP; Pembrolizumab; Immunotherapy; PD-L1; CTLA-4; PFS; BMI; mPFS; Immune-related adverse events; OS; NSCLC; GA/GEJ; Melanoma; Efficacy; MeSH; HCC; CR; RCC; PD; CRC; Nivolumab; HNSCC; Non-small cell lung cancer; irAEs; MSI-H
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2020.102134

•Immune checkpoint inhibitors can induce immune-related adverse events (irAEs), potentially life-threatening.•There is evidence suggesting a potential association between toxicities and clinical benefit.•This systematic review showed that there appears to be an association between the development of irAEs and anti-tumor effect by ICI.•This systematic review provides real-world data showing increased likelihood of response to ICI and improved progression free-survival, overall survival and response rate in patients who experienced an irAE, across all solid tumors and regardless of type of ICI. The use of immune checkpoint inhibitors (ICIs) has become standard therapy in many tumor sites. The aim of this study is to systematically review the literature to determine whether the incidence of immune-related adverse events (irAEs) after the use of ICIs is associated with clinical outcomes in all solid malignancies. Embase and PubMed were searched from January 1st, 2000 until March 14, 2020 for relevant studies assessing the relationship between irAEs and treatment efficacy. Outcome measures of interest included: incidence of irAEs, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Of 3384 unique citations, 51 studies met inclusion criteria. Studies included melanoma (n = 21), lung (n = 19), renal (n = 4), urothelial (n = 1), head and neck (n = 2) and gastrointestinal cancers (n = 1). In patients with metastatic melanoma (n = 1474), the development of irAEs (irAE + versus irAE-) was associated with better weighted average OS (15.24 months (95% CI 9.95 to 20.5) versus 8.94 months (95% CI 7.76 to 10.1), HR = 0.46 (n = 640, CI 0.35–0.62, p < 0.00001), PFS (17.61 months (95% CI 10.1 to 25.1) versus 2.23 months (95% CI 1.77 to 2.68), HR = 0.51 (n = 1763, CI 0.42–0.63, p < 0.00001), and ORR (37.67% (95% CI 32.8 to 42.5) versus. 23.44% (95% CI 17.8 to 29.1). Similarly, in lung cancer patients, the ORR (irAE + versus. irAE-) was 41.49% (95% CI 36.5 to 46.5) versus 18.01% (95% CI 13.5 to 22.6). The weighted average PFS and OS were 8.97 months (95% CI 7.14 to 10.8) versus 3.06 months (95% CI 2.4 to 3.72) with HR = 0.46 (n = 1575, CI 0.39–0.54, p < 0.00001) and 19.07 months (95% CI 14.3 to 23.8) versus 7.45 months (95% CI 5.34 to 9.56) HR = 0.40 (n = 1085, CI 0.30–0.51, p < 0.00001), respectively. Improved treatment efficacy in patients who developed irAEs was also seen in renal cell carcinoma, urothelial and head and neck cancers. Notably, grade 3 or 4 irAEs were associated with increased ORR but worse OS. A positive association was noted between the development of irAEs and ORR, PFS, and OS in patients treated with ICIs, irrespective of disease site, type of ICI and irAE. Grade 3 or higher toxicities resulted in better ORR, but worse OS.