Meta-Analysis Sheds Light on Treatment-Related AEs for PD-1 and PD-L1 Inhibitors

Yucai Wang, MD

Two in 3 patients treated with PD-1 or PD-L1 inhibitors experienced at least 1 adverse event (AE) and 1 in 7 patients experienced at least 1 grade ≥3 AE, according to a systematic review and meta-analysis of clinical trials and study updates published through December 15, 2018.¹ Investigators looked at treatment-related AEs of FDAapproved PD-1 and PD-L1 inhibitors to determine important differences between agents and cancer types. The data were compiled from 125 trials involving 20,128 patients published in PubMed, Web of Science, Embase, and Scopus.

In a breakout of 106 of the studies, 66%, or 12,277 of 18,610 patients, had at least 1 AE of any grade; in 110 of the studies, 14%, or 2627 of 18,715 patients, had at least 1 AE of grade 3 or higher severity.

The most common all-grade AEs were fatigue (18.26%), pruritis (10.61%), and diarrhea (9.47%). The most frequent grade 3 or higher AEs were fatigue (0.89%), anemia (0.78%), and aspartate aminotransferase (AST) increase (0.75%). Hypothyroidism (6.07%) and hyperthyroidism (2.82%) were the most common all-grade endocrine immune-related AEs (irAEs).

Other common irAEs related to endocrine dysfunction were hyperglycemia (1.20%; 95% CI, 0.91%- 1.55%); thyroiditis (0.75%; 95% CI, 0.52%-1.04%); and adrenal insufficiency (0.69%; 95% CI, 0.50%-0.93%).

The overall mean incidence of all-grade AEs was 1.66% (95% CI, 1.47%-1.86%), and the mean incidence of grade ≥3 AEs was 0.11% (95% CI, 0.08%-0.14%).

Compared with pembrolizumab (Keytruda), nivolumab (Opdivo) was associated with higher mean incidences of allgrade AEs (OR, 1.28; 95% CI, 0.97-1.79) and grade 3 or higher AEs (OR, 1.30; 95% CI, 0.89-2.00). Investigators said that PD-1 inhibitors had a higher mean incidence of grade 3 or higher AEs versus PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54). “The incidences of [AEs] are independent of cancer types, but different PD-1 and PD-L1 inhibitors may be associated with different incidences of [AEs],” the authors concluded.

The most common grade ≥3 irAE was pneumonitis (24.01%), which was observed to be the most common cause of treatment-related death.

Table. Mean Incidences of AEs by Cancer Type

Multiple tumor types were included in the study, and data suggested that all-grade AEs were similar across cancer types, with the highest mean of all-grade AEs observed in melanoma (1.72%; 95% CI, 1.45%-2.27%) and the lowest in lung cancer (1.55%; 95% CI, 1.23%-1.81%), with just a slim difference between the 2 (Table). In addition to pembrolizumab and nivolumab, the PD-L1 inhibitors atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) were used in all the trials included in the meta-analysis. Investigators found that among the 125 studies, 112 (89.6%) reported whether treatment-related deaths occurred. A total of 82 treatment-related deaths were reported (incidence, 0.45%), and 40 studies reported at least 1 treatment-related death.

The authors recommend that although fatigue is not likely to present as severe, because of its high incidence (1 in 5 patients), it should be disclosed as an AE to patients before therapy begins. Although less likely to present as a severe AE in patients, pruritus, diarrhea, and rash are the next most common AEs (about 1 in 10 patients) that clinicians might consider counseling patients about. The authors added that early detection of symptoms, including dyspnea, diarrhea, and alanine aminotransferase or AST, can prevent the development of more severe AEs such as pneumonitis, colitis, and hepatitis.

Wang Y, Zhou S, Yang F, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis [published online April 25, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.0393.