Incidence of Adverse Events for PD-1/PD-L1 Inhibitors Underscores Toxicity Risk

Approximately two-thirds of cancer patients who received a programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor in clinical trials experienced treatment-related adverse events, according to a systematic review and meta-analysis recently published in JAMA Oncology. The study findings may facilitate discussions with cancer patients who are considering PD-1 or PD-L1 therapy.

“The vast majority of patients with advanced cancer want to be on the [PD-1 or PD-L1] therapy,” Eric H. Bernicker, MD, a thoracic medical oncologist with Houston Methodist Cancer Center, told Cancer Network. Not involved in the current study, Bernicker explained that patients perceive these therapies to have “very different” side effects and risks from chemotherapy.

While they do, Bernicker explained, it's important to underscore, which this study does, that these are not “completely innocuous” therapies. The study findings allow physicians to give numbers to patients and families when counseling them about the risks involved, he said.

The systematic review and meta-analysis is based on data from 125 clinical trials and 20,128 participants. Clinical trials were identified by systematically searching for published clinical trials that evaluated single-agent PD-1 and PD-L1 inhibitors and reported treatment-related adverse events in PubMed, Web of Science, Embase, and Scopus. The majority of trials evaluated nivolumab (n = 46) or pembrolizumab (n = 49), and the most common cancer types were lung cancer (n = 26), genitourinary cancer (n = 22), melanoma (n = 16), and gastrointestinal cancer (n = 14).

In all, 66.0% of clinical trial participants reported at least 1 adverse event of any grade, and 14.0% reported at least 1 grade 3 or higher adverse event. The most frequently reported adverse events of any grade were fatigue (18.26%), pruritus (10.61%), and diarrhea (9.47%). As for grade 3 or higher events, the most commonly reported were fatigue (0.89%), anemia (0.78%), and aspartate aminotransferase (AST) increase (0.75%).

Frequently reported immune-related adverse events of any grade included diarrhea (9.47%), AST increase (3.39%), vitiligo (3.26%), alanine aminotransferase (ALT) increase (3.14%), pneumonitis (2.79%), and colitis (1.24%). Grade 3 or higher immune-related adverse events included AST increase (0.75%), ALT increase (0.70%), pneumonitis (0.67%), diarrhea (0.59%), and colitis (0.47%).

If present, certain adverse events had increased likelihood of being grade 3 or higher, including hepatitis (risk ratio [RR], 50.59%), pneumonitis (RR, 24.01%), type 1 diabetes (RR, 41.86%), and colitis (RR, 37.90%).

“In terms of the rough percentage of side effects and the breadth of the side effects, this is pretty much what most of us see in the clinic,” Bernicker said, noting that none of the findings were particularly surprising.

Although no differences in adverse event incidence were found across different cancer types, differences were found between PD-1 and PD-L1 inhibitors in a subgroup analysis. Overall, compared with PD-L1 inhibitors, PD-1 inhibitors had a higher mean incidence of grade 3 or higher events (odds ratio [OR], 1.58; 95% CI, 1.00–2.54). Specifically, nivolumab had a higher mean incidence of grade 3 or higher events (OR, 1.81; 95% CI, 1.04–3.01) compared with PD-L1 inhibitors.

Bernicker commented that these incidence differences on the basis of drug type were “intriguing” but not clinically useful, given that PD-1 and PD-L1 inhibitors are not interchangeable. He said the finding “needs to be further looked at.”