Treatment-related adverse events of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors in clinical trials: a meta-analysis

Figures & data

Figure 1. Flow diagram of the study selection process.

Figure 2. Methodological quality assessed by the quality assessment of diagnostic accuracy studies.

Figure 3. Mean incidences of overall all-grade adverse events (anti-PD-1/PD-L1 plus anti-CTLA-4 therapy).

Table 1. Study design characteristics of the included studies.

Study	Year	Cancer type	Number	Number of AE	Number of 3 or higher AE	Dose	Median overall survival (month)
Anti-PD-1 plus anti-CTLA-4
D’Angelo et al. [9]	2018	Sarcoma	42	42	NA	niv 3 mg/kg + ipi 1 mg/kg	14.3
Armand et al. [23]	2021	Lymphoma	65	51	19	niv 3 mg/kg + ipi 1 mg/kg	NA
Blank et al. [7]	2018	Melanoma	10	10	NA	niv 1 mg/kg + ipi 3 mg/kg	NA
Gubens et al. [11]	2019	NSCLC	51	35	NA	pem 2 mg/kg + ipi 1 mg/kg; pem 10 mg/kg + ipi 1 mg/kg	10.9
Hodi et al. [24]	2016	Melanoma	95	86	52	niv 1 mg/kg + ipi 3 mg/kg	NA
Larkin et al. [25]	2015	Melanoma	314	299	215	niv 1 mg/kg + ipi 3 mg/kg	11.5
Patel et al. [26]	2020	Neuroendocrine neoplasm	32	27	16	niv 240 mg + ipi 1 mg/kg	11
Perets et al. [12]	2021	NSCLC	173	144	63	qua 25mg + pem 200 mg; qua 75 mg + pem 200 mg; qua 200 mg + pem 200 mg; qua 25 mg + pem 200 mg; qua 75 mg + pem 200 mg	NA
Pollack et al. [10]	2018	Melanoma	80	80	NA	niv 1 mg/kg + ipi 3 mg/kg; pem 2 mg/kg + ipi1mg/kg	NA
Scherpereel et al. [27]	2019	Pleural mesothelioma	61	54	16	niv 3 mg/kg + ipi 1 mg/kg	15.9
Schoenfeld et al. [28]	2020	Oral cavity squamous cell carcinoma	15	NA	NA	niv 3 mg/kg + ipi 1 mg/kg	NA
Wolchok et al. [29]	2013	Melanoma	53	52	NA	niv 0.3 mg + ipi 3 mg; niv 1 mg + ipi 3 mg; niv 3 mg + ipi 1 mg; niv 3 mg/kg + ipi 3 mg/kg	NA
Antonia et al. [30]	2016	SCLC	115	88	28	niv 1 mg/kg + ipi 3 mg/kg; niv 3 mg/kg + ipi 1 mg/kg	13.7
Hellmann et al. [8]	2019	NSCLC	576	442	189	niv 3 mg/kg + ipi 1 mg/kg	17.1
Motzer et al. [31]	2019	Renal cell carcinoma	574	514	255	niv 3 mg/kg + ipi 1 mg/kg	NA
Tawbi et al. [32]	2018	Melanoma	94	91	52	niv 1 mg/kg + ipi 3 mg/kg	NA
Janjigian et al. [33]	2018	Esophagogastric cancer	100	80	NA	niv 1 mg/kg + ipi 3 mg/kg; niv 3 mg/kg + ipi 1 mg/kg	NA
Zimmer et al. [34]	2020	Melanoma	55	55	NA	niv 1 mg/kg + ipi 3 mg/kg	NA
Anti-PD-L1 plus anti-CTLA-4
Antonia et al. [13]	2016	NSCLC	184	82	NA	dur 3 mg/kg + tre 1 mg/kg; dur 10 mg/kg + tre 1 mg/kg; dur 15 mg/kg + tre 1 mg/kg; dur 20 mg/kg + tre 1 mg/kg; dur 10 mg/kg + tre 3 mg/kg; dur 15 mg/kg + tre 3 mg/kg; dur 20 mg/kg + tre 3 mg/kg; dur 15 mg/kg + tre 10 mg/kg	NA
Boileve et al. [14]	2021	Biliary tract carcinoma	10	7	NA	dur 1500 mg + tre 75 mg	NA
Calabro et al. [15]	2018	Pleural or peritoneal mesothelioma	40	30	NA	dur 20 mg/kg + tre 1 mg/kg	16.6
Chen et al. [35]	2020	Colorectal cancer	118	75	75	dur 1500 mg + tre 75 mg	6.6
Siu et al. [36]	2019	Neck squamous cell carcinoma	133	77	21	dur 20 mg/kg + tre 1 mg/kg	7.6
Powles et al. [37]	2020	Urothelial carcinoma	342	255	93	dur 1500 mg + tre 75 mg	15.1
Gao et al. [38]	2020	Urothelial carcinoma	28	26	6	dur 1500 mg + tre 75 mg	NA
Ferris et al. [39]	2020	Head and neck squamous cell carcinoma	247	150	40	dur 20 mg/kg + tre 1 mg/kg	7.8

AE: adverse event; SCLC: small cell lung cancer; NSCLC: non-small cell lung cancer; PD-1 inhibitor: niv: nivolumab; pem: pembrolizumab; PD-L1 inhibitor: dur: durvalumab; CTLA-4 inhibitor: ipi: ipilimumab, tre: tremelimumab, qua: quavonlimab; NA: not available.

Figure 4. Pooled ORs of the most common all-grade and grade 3 or higher adverse events.

Figure 5. Pooled ORs of the most common all-grade and grade 3 or higher immune-related.

Figure 6. Mean incidences of overall all-grade adverse events by combination types.

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Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.