Dose dependence of treatment-related adverse events for immune checkpoint inhibitor therapies: a model-based meta-analysis

Figures & data

Table 1. Subgroup analysis of AE rates and ICI dose/exposure.

Target		Total trAE		Total Grade 3/4 trAE		Gastrointestinal imAE		Hepatic imAE		Skin imAE		Endocrine imAE		Pulmonary imAE
Dose/Exposure Subgroup		Lower	Higher	Lower	Higher	Lower	Higher	Lower	Higher	Lower	Higher	Lower	Higher	Lower	Higher
PD-1	AE %	71	74	17	19	1.3	3.4	1.9	0.04	1.1	1.3	0.38	0.4	0.8	1.2
	CI	68–75	70–77	15–19	15–22	0.9–2.0	1.3–8.8	1.4–2.5	0–80	0.8–1.6	0.3–6.2	0.2–0.9	0–19	0.4–1.5	0.2–8
	N	7506	2377	8899	2402	3557	227	3557	227	3644	247	2838	227	3577	247
PD-1 dose difference		p = .34		p = .41		p = .08		p = .42		p = .87		p > .9		p = .66
CTLA-4	AE %	83	89	23	37	9.5	13	1.1	7.0	1.4	2.9	2.6	4.3	0.14	1.0
	CI	75–89	85–92	18–28	32–42	7.2–12	10–16	0.4–3.2	5.3–9.1	0.5–3.4	1.8–4.5	1.6–4.2	2.6–7.0	0.02–1.0	0.5–2.0
	N	1934	4907	1934	4931	1549	2701	1652	2615	1652	2701	1652	2104	719	817
CTLA-4 dose difference		p = .12		p < .001		p = .09		p < .001		p = .165		p = .15		p = .06
CTLA-4 + PD-1 (CTLA-4 dose)	AE %	83	92	35	53	6.4	20	9.5	18	3.8	6.3	3.8	5.3	1.8	1.6
	CI	76–88	86–95	30–41	46–59	3.1–13	14–20	7.1–13	15–22	2.9–5.1	4.5–8.6	2.9–5.1	3.7–7.6	0.9–1.6	0.8–3.1
	N	2064	654	2106	654	1183	509	1183	509	1203	544	1203	509	1203	509
CTLA-4 + PD-1 dose difference (CTLA-4 dose)		p = .016		p < .001		p = .008		p < .001		p = .02		p = .17		p = .8

Abbreviations: AE, adverse event; CI, confidence interval; CTLA-4, cytotoxic T lymphocyte–associated antigen 4; ICI, immune checkpoint inhibitor; imAE, immune-mediated adverse event; PD-1, programmed cell death-1; trAE, treatment-related adverse event.

p < 0.05 was considered statistically significant for dose/exposure dependence.

Figure 1. Forest plots of grade 3/4 AEs for (a) CTLA-4 inhibitors and (b) CTLA-4 inhibitor + PD-1 inhibitor.

Figure 2. Dependencies of grade AEs upon ICI drug dose/exposure for (a) total trAEs, (b) gastrointestinal imAEs, and (c) hepatic imAEs.

Figure 3. Dependencies of AEs on ICI dose/exposure and baseline characteristics.