5783 - Immune-related adverse events (irAEs) with single-agent PD-1 vs PD-L1 inhibitors: a meta-analysis of 8,730 patients from clinical trials

Background

Six anti–PD-1/PD-L1 agents have been FDA approved for various cancers. Despite a lack of head-to-head trials, there is a perception that the irAE profiles are comparable between agents. We hypothesized that the irAE profiles vary between anti–PD-1 and anti–PD-L1 agents and among individual agents. Since prospective comparison is unlikely, we conducted a trial-level meta-analysis of irAEs reported in phase I–IV trials evaluating anti–PD-1/L1 agents in various tumor types.

Methods

We analyzed data from 35 manuscripts reporting phase I (n = 18), 2 (n = 15), 3 (n = 9) or 4 (n = 1) trials, comprising 8,730 patients treated with anti–PD-1/PD-L1 monotherapy. The incidence and odds ratios (ORs) for selected clinically relevant irAEs (colitis, elevated AST, hypothyroidism, pneumonitis or rash; any grade and grade ≥3) and irAEs overall were estimated using random-effects models for anti–PD-L1 agents atezolizumab, avelumab and durvalumab; for anti–PD-1 agents nivolumab and pembrolizumab; and as pooled estimates for anti–PD-1 and anti–PD-L1 agents.

Results

The risk of any grade (OR = 4.34) and grade ≥3 rash (OR = 4.38); grade ≥3 hypothyroidism (OR = 2.85); any grade (OR = 2.53) and grade ≥3 colitis (OR = 3.79); and any grade ≥3 irAE (OR = 1.89) was higher with anti–PD-1 vs anti–PD-L1 agents. When comparing the risk of all selected irAEs for each agent with pooled estimates for all other agents combined, atezolizumab had the lowest risk, followed by avelumab; pembrolizumab had a higher risk, except for grade ≥3 elevated AST. In pairwise comparisons, the risks associated with atezolizumab vs avelumab were not significantly different, likewise for nivolumab vs pembrolizumab. The largest decrease in risk for all grade ≥3 irAEs except elevated AST was for avelumab vs pembrolizumab.

Conclusions

Overall, the risk of grade ≥3 irAEs was higher with anti–PD-1 vs anti–PD-L1 agents. Compared with other agents, avelumab had a lower risk of individual grade ≥3 irAEs except elevated AST, whereas atezolizumab had the lowest risk of irAEs of any grade. Limitations include the retrospective nature of the meta-analysis and varied tumor types, trial designs, treatment durations and irAE evaluations.

Clinical trial identification

Editorial acknowledgement

ClinicalThinking, funded by Merck Healthcare KGaA and Pfizer Inc.

Legal entity responsible for the study

Merck Healthcare KGaA.

Funding

Merck Healthcare KGaA and Pfizer Inc.

Disclosure

G.P. Sonpavde: Honoraria (self): UpToDate; Advisory / Consultancy: Agensys; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck & Co.; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Speaker Bureau / Expert testimony: Clinical Care Options/NCCN; Speaker Bureau / Expert testimony: Onclive; Speaker Bureau / Expert testimony: Physician Education Resource; Speaker Bureau / Expert testimony: Research to Practice; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Onyx; Research grant / Funding (institution): Pfizer. P. Grivas: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biocept; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy: Driver, Inc; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Heron; Advisory / Consultancy, Research grant / Funding (institution): Merck & Co.; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: QED Therapeutics; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Oncogenex. D. Hennessy: Full / Part-time employment: EMD Serono. J.D. Hunt: Full / Part-time employment: EMD Serono. All other authors have declared no conflicts of interest.