Incidence of Cutaneous Immune-Related Adverse Events and Outcomes in Immune Checkpoint Inhibitor-Containing Regimens: A Systematic Review and Meta-Analysis

Abstract

Immune checkpoint inhibitors (ICIs) are used to treat many cancers, and cutaneous immune-related adverse events (cirAEs) are among the most frequently encountered toxic effects. Understanding the incidence and prognostic associations of cirAEs is of importance as their uses in different settings, combinations, and tumor types expand. To evaluate the incidence of cirAEs and their association with outcome measures across a variety of ICI regimens and cancers, we performed a systematic review and meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) ICIs, both alone and in combination with chemotherapy, antiangiogenic agents, or other ICIs in patients with melanoma, renal cell carcinoma, non-small cell lung cancer, and urothelial carcinoma. Key findings of our study include variable cirAE incidence among tumors and ICI regimens, positive association with increased cirAE incidence and response rate, as well as significant association between increased vitiligo incidence and overall survival. Across 174 studies, rash, pruritis, and vitiligo were the most reported cirAEs, with incidences of 16.7%, 18.0%, and 6.6%, respectively. Higher incidence of cirAEs was associated with ICI combination regimens and with CTLA-4-containing regimens, particularly with higher doses of ipilimumab, as compared to PD-1/L1 monotherapies. Outcome measures including response rate and progression-free survival were positively correlated with incidence of cirAEs. The response rate and incidence of pruritis, vitiligo, and rash were associated with expected rises in incidence of 0.17% (p = 0.0238), 0.40% (p = 0.0010), and 0.18% (p = 0.0413), respectively. Overall survival was positively correlated with the incidence of pruritis, vitiligo, and rash; this association was significant for vitiligo (p = 0.0483). Our analysis provides benchmark incidence rates for cirAEs and links cirAEs with favorable treatment outcomes at a study level across diverse solid tumors and multiple ICI regimens.

Keywords: anti-angiogenic; autoimmune toxicities; chemotherapy; cutaneous immune-related adverse events; immune checkpoint inhibitors; melanoma; meta-analysis; non-small cell lung cancer; renal cell carcinoma; urothelial carcinoma.

Figure 1

PRISMA flowchart of included studies.

Figure 2

Overall incidence of rash by drug class groupings via random-effects modeling of 142 studies reporting rash. Highest incidence of rash was seen for IO combination (25.1%) followed by IO + antiangiogenic combination (24.9%), CTLA-4 monotherapy (24.8%), and IO + chemotherapy (22.3%). Rash was less frequent in anti-PD-1 (11.0%) and PD-L1 monotherapy (7.9%) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190].

Figure 3

Overall incidence of pruritis by drug class groupings via random-effects modeling of 131 studies reporting pruritis. Highest incidence of pruritis was seen in the IO combination group at 28.6%, followed by CTLA-4 monotherapy (25.2%), IO + chemotherapy (20.1%), IO + antiangiogenic (16.1%), PD-1 monotherapy (14.5%), and PD-L1 monotherapy (8.8%) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190].

Figure 4

Overall incidence of vitiligo by drug class groupings via fixed-effect modeling of 31 studies reporting vitiligo. Incidence of vitiligo was highest in the IO combination (10.1%) and PD-1 monotherapy (7.9%) groups, followed by the IO + chemotherapy (3.7%), CTLA-4 monotherapy (3.2%), and PD-L1 monotherapy (0.54%) groups. No studies on IO + antiangiogenic combination regimens reported vitiligo [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190].

Figure 5

Bubble plot demonstrating the estimated regression slope for incidence of rash and duration of treatment (median months). Rash and median treatment duration were positively correlated, with an expected rise in incidence of 0.01% per month of treatment duration (p = 0.0116).

Figure 6

Bubble plot demonstrating the estimated regression slope for incidence of rash (A), pruritis (B), and vitiligo (C), as well as response rate. Response rate was positively correlated with the incidence of pruritis, vitiligo, and rash, with an expected rise in incidence of 0.17% (p = 0.0238) for pruritis, 0.40% (p = 0.0010) for vitiligo, and 0.18% (p = 0.0413) for rash per percentage increase in response rate.

Figure 7

Bubble plot demonstrating the estimated regression slope for incidence of rash (A), pruritis (B), and vitiligo (C), as well as overall survival. Overall survival was positively correlated with the incidence of pruritis, vitiligo, and rash, and this association was significant for vitiligo (p = 0.0483), with an expected rise in incidence of vitiligo of 0.003% per additional month of overall survival.