Safety and Tolerability of PD‐1/PD‐L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta‐Analysis

Abstract Background Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor‐1 (PD‐1) inhibitors nivolumab and pembrolizumab and the programmed death‐ligand 1 (PD‐L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta‐analysis to compare safety and tolerability between PD‐1/PD‐L1 inhibitors and chemotherapy. Methods PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single‐agent U.S. Food and Drug Administration–approved PD‐1/PD‐L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all‐grade (1–4) or high‐grade (3–4) adverse events (AEs), all‐ or high‐grade treatment‐related symptoms, hematologic toxicities and immune‐related AEs, treatment discontinuation due to toxicities, or treatment‐related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated. Results A total of 3,450 patients from 7 RCTs were included in the meta‐analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non‐small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD‐1/PD‐L1 inhibitors had a significantly lower risk of all‐ and high‐grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all‐grade anorexia, nausea, and constipation, any all‐ and high‐grade AEs, and treatment discontinuation. There was an increased risk of all‐grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all‐ and high‐grade pneumonitis with PD1/PD‐L1 inhibitors. Conclusion PD‐1/PD‐L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD‐1/PD‐L1 inhibitors. Implications for Practice We conducted a systematic review and meta‐analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitors and chemotherapy. PD1/PD‐L1 inhibitors were associated with a lower risk of treatment‐related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune‐related adverse events (AEs). Summary toxicity endpoints favor PD1/PD‐L1 inhibitors (any all‐ and high‐grade AEs and treatment discontinuation). PD1/PD‐L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well‐balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer.