Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis

Figures & data

Table 1 Baseline characteristics of six trials comparing PD-1 inhibitors to chemotherapy or everolimus

Study	Phase	Underlying malignancy	Treatment arm	Control arm	Treatment arm	Control arm	CTC version	Jadad score
Borghaei et al^Citation9	III	NSCLC	Nivolumab 3 mg/kg every 2 weeks	Docetaxel	287	268	4.0	3
Brahmer et al^Citation10	III	NSCLC	Nivolumab 3 mg/kg every 2 weeks	Docetaxel	131	129	4.0	3
Robert et al^Citation25	III	Melanoma	Nivolumab 3 mg/kg every 2 weeks	Dacarbazine	206	205	4.0	5
Weber et al^Citation7	III	Melanoma	Nivolumab 3 mg/kg every 2 weeks	Investigator’s choice of chemotherapy	268	102	4.0	3
Motzer et al^Citation11	III	RCC	Nivolumab 3 mg/kg every 2 weeks	Everolimus	406	397	4.0	3
Herbst et al^Citation5	II/III	NSCLC	Pembrolizumab 2 mg/kg every 3 weeks	Docetaxel	339	309	4.0	3
			Pembrolizumab 10 mg/kg every 3 weeks	Docetaxel	343

Abbreviations: PD-1, program death 1; CTC, common toxicity criteria; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma.

Figure 1 Flow chart of selection process for trials included in meta-analysis.

Abbreviations: AEs, adverse events; RCTs, randomized controlled trials.

Table 2 Direct comparison among different immune checkpoint inhibitors

Study	Phase	Underlying malignancy	Treatment arm	Control arm	Treatment arm	Control arm	CTC version	Jadad score
Larkin et al^Citation26	III	Melanoma	Nivolumab 3 mg/kg combined with placebo	Ipilimumab	313	311	4.0	5
			Ipilimumab combined with nivolumab (1 mg/kg)	Ipilimumab	313
Postow et al^Citation8	III	Melanoma	Ipilimumab combined with nivolumab (1 mg/kg)	Ipilimumab	94	46	4.0	5
Robert et al^Citation12	III	Melanoma	Pembrolizumab 10 mg/kg every 2 weeks	Ipilimumab	278	256	4.0	3
			Pembrolizumab 10 mg/kg every 3 weeks	Ipilimumab	277

Abbreviation: CTC, common toxicity criteria.

Figure 2 Forest plot for meta-analysis of incidence of all-grade elevated ALT (A) and AST (B) and high-grade elevated ALT (C) and AST (D).

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval.

Figure 3 RR of all-grade elevated ALT (A) and AST (B) and high-grade elevated ALT (C) and AST (D) for cancer patients receiving PD-1 inhibitors monotherapy compared with control.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; PD-1, program death 1; CI, confidence interval; RR, risk ratio.

Figure 4 Relative risk of all-grade elevated ALT (A) and AST (B) and high-grade elevated ALT (C) and AST (D) for cancer patients receiving a nivolumab/ipilimumab combination compared with ipilimumab control.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; PD-1, program death 1; CI, confidence interval.

Figure 5 Relative risk of all-grade elevated ALT (A) and AST (B) and high-grade elevated ALT (C) and AST (D) for cancer patients receiving PD-1 inhibitors monotherapy compared with ipilimumab control.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; PD-1, program death 1; CI, confidence interval.

BorghaeiHPaz-AresLHornLNivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancerN Engl J Med2015373171627163926412456

 PubMed Web of Science ®Google Scholar

BrahmerJReckampKLBaasPNivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancerN Engl J Med2015373212313526028407

 PubMed Web of Science ®Google Scholar

RobertCLongGVBradyBNivolumab in previously untreated melanoma without BRAF mutationN Engl J Med2015372432033025399552

 PubMed Web of Science ®Google Scholar

WeberJSD’AngeloSPMinorDNivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trialLancet Oncol201516437538425795410

 PubMed Web of Science ®Google Scholar

MotzerRJEscudierBMcDermottDFCheckMate 025 InvestigatorsNivolumab versus everolimus in advanced renal-cell carcinomaN Engl J Med2015373191803181326406148

 PubMed Web of Science ®Google Scholar

HerbstRSBaasPKimDWPembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trialLancet2016387100271540155026712084

 PubMed Web of Science ®Google Scholar

LarkinJChiarion-SileniVGonzalezRCombined nivolumab and ipilimumab or monotherapy in untreated melanomaN Engl J Med20153731233426027431

 PubMed Web of Science ®Google Scholar

PostowMAChesneyJPavlickACNivolumab and ipilimumab versus ipilimumab in untreated melanomaN Engl J Med2015372212006201725891304

 PubMed Web of Science ®Google Scholar

RobertCSchachterJLongGVKEYNOTE-006 InvestigatorsPembrolizumab versus ipilimumab in advanced melanomaN Engl J Med2015372262521253225891173

 PubMed Web of Science ®Google Scholar