Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer

Abstract

Background: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients.

Patients and methods: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology.

Results: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses.

Conclusions: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.

Clinicaltrialsgov registry: NCT01295827.

Keywords: PD-L1; exposure–response; immunotherapy; non-small-cell lung cancer; pembrolizumab; tumor size modeling.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Best percentage change from baseline in sum of the longest diameters of target lesions by PD-L1 TPS. (A) Patients treated with pembrolizumab 2 mg/kg every 3 weeks. (B) Patients treated with pembrolizumab 10 mg/kg every 3 weeks. (C) Patients treated with pembrolizumab 10 mg/kg every 2 weeks. Change from baseline in tumor size was assessed in patients with measurable disease at baseline by RECIST v1.1 per central review and ≥1 evaluable postbaseline tumor assessment who had known PD-L1 TPS. PD-L1, programmed death ligand 1; TPS, tumor proportion score.

Figure 2.

Observed percentage change from baseline in tumor size at 18 weeks by pembrolizumab exposure. The analysis population was patients with previously treated NSCLC who had both tumor size and exposure data at week 18 (n = 170). AUCss–6weeks is presented in µg·day/ml. The sample size per group is shown. Lines extending vertically from the boxes (whiskers) indicate variability outside the 25th and 75th quantile. The ends of the whiskers correspond to the 5th and 95th quantiles of the observed data. All patients treated at 2 mg/kg are in the left-most bin. AUCss–6weeks, area under the concentration–time curve at steady state over a 6-week interval; CI, confidence interval.

Figure 3.

Median simulated response rates by pembrolizumab dose spanning the observed range of NSCLC exposure (1000 simulated trials, each with 1000 patients). (A) Patients with PD-L1 expression in ≥50% of tumor cells at week 27. (B) PD-L1 expression in 1%–49% of tumor cells at week 27. PD-L1 expression was assessed using a clinical trial immunohistochemistry assay. Error bars represent the 90% confidence intervals around the estimates. Response was defined as a ≥30% decrease from baseline in SLD, stable disease was defined as a