PD-1 and PD-L1 Inhibitors Yield a Higher Risk of AEs in Combination With Chemotherapy vs Targeted Therapy or Immunotherapy

The toxicity profiles of PD-1 and PD-L1 inhibitors displayed unique characteristics when combines with other agents such as chemotherapy, targeted therapy, and immunotherapy.

PD-1 or PD-L1 inhibitors, when combined with other classes of drugs such as chemotherapy, immunotherapy, and targeted therapy, resulted in toxicity profiles with distinct characteristics, according to the results of a meta-analysis published in Lancet Oncology.

The overall incidence of treatment-related adverse effects (TRAEs) of any among patients treated with a chemotherapy combination was 97.7% (95% CI, 96.4%-98.5%; I2 = 75%), with grade 3 TRAEs occurring in 68.3% of patients (95% CI, 90.7%-96.8%). Among those treated with a targeted therapy combination, the overall incidence of TRAEs of any grade was 94.5% (95% CI, 90.7%-96.8%; I2 = 86%) and 47.3% (95% CI, 37.3%-57.5%) had grade 3 or higher AEs. Additionally, patients who received an immunotherapy combination had an incidence rate of 86.8% (95% CI, (80·9%-91·1%; I² = 94%) for any grade TRAEs and 35.9% (95% CI, 29.5%-42.9%; I2 = 92%).

“A high proportion of patients had at least 1 [AE] with all 4 classes; grade 3 or higher toxicity was also not rare, especially for patients receiving both PD-1 or PD-L1 inhibitors and chemotherapy,” investigators of the study wrote.

Investigators identified 2540 records, among which 161 studies that included 17,197 participants met the inclusion criteria and were selected for the quantitative analysis. Of these, 159 studies with 17,116 patients were included for the profile of TRAEs. The trials were categorized into anti–PD-1 or anti–PD-L1 plus chemotherapy (n = 44), plus targeted therapy (n = 51), plus immunotherapy (n = 58), and plus radiotherapy (n = 8).

Across all the included combinations, the most common any grade AEs were anemia (45.4%; 95% CI, 32.4%-59.1%) and alopecia in 45.1% (95% CI, 29.6%-61.7%). Common grade 3 or higher AEs included neutropenia (19.6%; 95% CI, 13.5%-27.7%) and anemia (11.4%; 95% CI, 8.2%-15.6%).

Among patients who received a targeted therapy combination, the most common any grade AEs were fatigue (34.3%; 95% CI, 27.5%-41.9%) and diarrhea (31.7%; 95% CI, 23.3%-41.6%), and the most common grade 3 or higher AEs were hypertension (9.3%; 95% CI, 5.7-14.9) and hyponatremia (3.6%; 95% CI, 2.3%-5.7%). For those who received an immunotherapy combination, the most common any grade AEs were fatigue (26.4%; 95% CI, 19.2%-35.2%) and diarrhea (21.1%; 95% CI, 17.0%-25.8%); grade 3 or higher AEs included lipase increase (7.2%; 95% CI, 5.2%-9.9%) and colitis (3.6%; 95% CI, 2.4%-5.5%). In the radiotherapy combination group, the most common any grade AEs were dysphagia (30.0%; 95% CI, 18.7%-44.5%) and nausea (24.9%; 95% CI, 11.8%-45.3%), and grade 3 or higher AEs included lymphopenia (10.3%; 95% CI, 4.5%-21.8%) and dysphagia (8.8%; 95% CI, 4.2%-17.5%).

Of the 156 trials—which included 16,554 patients—that reported of treatment-related deaths, investigators reported a total of 180 treatment-related deaths, including 1.49% (n = 91) in the chemotherapy group, 0.85% (n = 34) in the targeted therapy group, and 0.87% (n = 55) in the immunotherapy group. There were no treatment-related deaths reported in the radiotherapy group (n = 173).

The post-hoc subgroup analysis indicated that patients receiving anti–PD-1 or anti–PD-L1 therapy plus chemotherapy had a significantly higher risk of experiencing TRAEs. Those receiving anti–PD-1 or anti-PD-L1 with a targeted therapy were more prone to TRAEs than those receiving an immunotherapy combination. Additionally, TRAEs were not significantly different between the chemotherapy and targeted therapy combination arms.

“This meta-analysis showed that the toxicity profile of combination therapies presented higher incidences than anti-PD-1 or anti-PD-L1 monotherapy reported elsewhere. A large portion of the most frequent adverse events were likely caused by an additive effect of PD-1 and PD-L1 inhibitors plus combination agents, including fatigue, pyrexia, diarrhea, skin toxicity, thyroid dysfunction, pneumonitis, liver enzyme elevation, and lipase increase,” the investigators concluded.


Zhou X, Yao Z, Bai H, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis. Lancet Oncol. 2021;22(9):1265-1274. doi:10.1016/S1470-2045(21)00333-8