Improving tolerability of pembrolizumab with weight based dosing: A meta-analysis.

Abstract

2639 Background: Pembrolizumab, a PD-1 immune checkpoint inhibitor (ICI), has demonstrated significant clinical activity in various cancers. Despite a favorable toxicity profile, discontinuation due to adverse events including immune related adverse events (irAE) has been reported. We conducted a meta-analysis of published clinical trials to evaluate the tolerability of pembrolizumab in cancer patients. Methods: A systematic review was conducted of relevant studies from the databases of PubMed and abstracts presented at American Society of Clinical Oncology (ASCO) from June 2015 until September 2020. Eligible studies included prospective clinical trials that reported a discontinuation rate due to adverse effects. Incidence, relative risk and 95% confidence intervals (CI) were calculated by employing fixed or random effects models. Results: A total of 6,380 patients with a variety of hematologic and solid malignancies from 20 studies of pembrolizumab were included for analysis. The overall rate of pembrolizumab discontinuation due to adverse events was 8.2% (95% CI: 6.4-10.4%). The discontinuation rate of pembrolizumab was not significantly lower than the chemotherapy controls, with RR of 0.84 (95% CI: 0.58-1.12, p = 0.33). However, the discontinuation rate of pembrolizumab was significantly higher compared to placebo control with RR of 2.20 (95% CI: 1.36-3.54, p < 0.001), and significantly lower compared to ipilimumab with RR of 0.58 (95% CI: 0.34-0.99, p = 0.04) respectively. The discontinuation rate varied widely among different tumor types with the lowest rate of 0.8% (95% CI: 0.2-3%) in gastric cancer, and the highest of 13.5% (95% CI: 10.8-16.8%) in head and neck squamous cell carcinoma. Interestingly, the discontinuation rate varied with pembrolizumab dosing, with the fixed dosing of 200mg being 9.2% (95% CI: 6.9-12%) and the weight-based dosing being 6.5% (95% CI: 4.8-8.8%). The weight-based dosing was associated with a significantly lower discontinuation rate compared to controls with RR of 0.62 (95% CI: 0.47-0.81, p < 0.0001), while the fixed dosing had similar discontinuation rate with RR of 1.03 (95% CI: 0.89-1.20, p = 0.67). Conclusions: The tolerability of pembrolizumab may be comparable to chemotherapy in cancer patients and may vary with its dosing. Future studies are warranted to evaluate the impact of different dosing.

Pembrolizumab weight based dosing – A call for policy change

“…Interestingly, in this meta-analysis, pembrolizumab discontinuation rate was higher (9.2%; 95% CI: 6.9–12%) in flat 200 mg dose as compared with weight-based dosing schedule (6.5%; 95% CI: 4.8–8.8%). 17…”