Comparative risk of serious and fatal treatment-related adverse events caused by 19 immune checkpoint inhibitors used in cancer treatment: a network meta-analysis

Abstract

Background: This network meta-analysis assessed the comparative risk of grade 3-5 and grade 5 treatment-related adverse events (TRAEs) for immune checkpoint inhibitors (ICIs), either alone or in combination with other modalities, for cancer treatment.

Methods: PubMed, Embase, Cochrane Library, Web of Science, and recent predominant oncology congresses were searched for relevant phase II and phase III randomized controlled trials (RCTs). As outcomes, grade 3-5, and grade 5 TRAE outcomes were reported as odds ratios and 95% confidence intervals.

Results: In 67 RCTs involving 36,422 patients and 19 ICIs, the incidence of grade 3-5 and grade 5 TRAEs was 17.9% and 0.8% with ICI monotherapy and 46.3% and 1.4%, respectively, with combinatorial therapy. Pneumonitis was the most common cause of grade 5 TRAEs following either monotherapy (16.3%) or combinatorial therapy (11.4%). Regarding grade 3-5 TRAEs, atezolizumab + chemotherapy (CT) and antiangiogenic therapy (AT) (atezolizumab + CAT), pembrolizumab + CT, ipilimumab + CT, and atezolizumab + CT were more toxic than any ICI monotherapy, pembrolizumab or nivolumab + radiotherapy (RT), and ICIs dual therapy (durvalumab + tremelimumab and nivolumab + ipilimumab). Tremelimumab, ipilimumab, durvalumab, and pembrolizumab were, however, associated with higher grade 5 TRAEs than combinatorial treatments. Atezolizumab + CAT was the most toxic and nivolumab + RT was the least toxic of combinatorial treatments; among monotherapies, tremelimumab and avelumab were the most and least toxic, respectively. The toxicity ranking changed with type of grade 3-5 TRAEs.

Conclusions: Compared with combinatorial therapy, ICI monotherapy caused lower grade 3-5 TRAEs, but some monotherapies resulted in a higher incidence of fatal TRAEs. Atezolizumab + CAT and nivolumab + RT were the most and least toxic of combinatorial treatments, respectively, and tremelimumab and avelumab were the most and least toxic of the monotherapies, respectively.

Keywords: antiangiogenic therapy; chemotherapy; immune checkpoint inhibitor; network meta-analysis; radiotherapy; treatment-related adverse events.

Figure 1.

Literature search and selection. FDA, United States Food and Drug Administration; ICIs, immune checkpoint inhibitors; RCTs, randomized control trials; TRAEs, treatment-related adverse events.

Figure 2.

Network of eligible comparisons for the network meta-analysis. (A) Grade 3–5 TRAEs. (B) Grade 5 TRAEs. AT, antiangiogenic therapy; Ate, atezolizumab; Ave, avelumab; CAT, CT+AT; CT, chemotherapy; Dur, durvalumab; Ipi, ipilimumab; Niv, nivolumab; Pem, pembrolizumab; RT, radiotherapy; TRAEs, treatment-related adverse events; Tre, tremelimumab.

Figure 3.

Treatments are reported in order of risk of grade 3–5 TRAEs ranking from high to low according to SUCRAs. Comparisons should be read from left to right. Data are ORs (95% CI) in the column-defining treatment compared with the row-defining treatment. An OR over 1 favors the row-defining treatment. Significant results are in bold and underlined. AT, antiangiogenic therapy; Ate, atezolizumab; Ave, avelumab; CAT, CT+AT; CI, confidecned interval; CT, chemotherapy; Dur, durvalumab; Ipi, ipilimumab; Niv, nivolumab; OR, odds ratio; Pem, pembrolizumab; RT, radiotherapy; SUCRA, surface under the cumulative ranking; TRAEs, treatment-related adverse events; Tre, tremelimumab.