12138 Background: Pembrolizumab 400 mg every 6 weeks (Q6W) was approved based on population pharmacokinetic (pop-PK) modeling rather than direct pharmacokinetic measurements, leaving its real-world concentrations insufficiently characterized. The impact of concentration changes when switching from 200 mg every 3 weeks (Q3W) to Q6W on immune-related adverse events (irAEs) remains unclear. Methods: We retrospectively identified patients with advanced non-small cell lung cancer who switched pembrolizumab from Q3W to Q6W between March 2017 and September 2023. Serum concentrations were quantified by liquid chromatography–tandem mass spectrometry; pop-PK analysis estimated maximum concentration (eCmax) and trough concentration (eCtrough). Inter-cycle variability was expressed as percentage coefficient of variation (%CV) using all available Q3W cycles. Early irAEs were defined as events within 126 days. In exploratory analysis, associations between pop-PK metrics and after switching irAEs (including pneumonitis) were evaluated using Wilcoxon rank-sum tests and multivariable logistic regression. Clinical correlates of %CV-eCmax were examined using multivariable stepwise linear regression. Results: Seventy-nine patients switched, and pop-PK analysis was feasible in 66. Median age was 70 years, 50 were male and 62 had a smoking history. Median Q3W cycles were 6 (range, 1–37) and median follow-up after switching was 463 days. After switching, 42 patients developed new or worsened irAEs, with 16 pneumonitis, and 22 had early irAEs, with 12 early pneumonitis. First-dose 400 mg eCmax and cross-regimen exposure ratios were not associated with the occurrence of irAEs. Among 64 patients who received ≥2 cycles of Q3W, those who developed irAEs after switching showed higher %CV-eCmax during Q3W (p = 0.036). Similar associations were observed for early irAEs (p = 0.024), pneumonitis (p = 0.023), and early pneumonitis (p = 0.007). %CV-eCtrough during Q3W was not associated with irAEs after switching (irAEs, p = 0.24; early irAEs, p = 0.13; pneumonitis, p = 0.16), with an association observed only for early pneumonitis (p = 0.044). High %CV-eCmax during Q3W was associated with increased odds of irAEs (odds ratio OR 8.4, p = 0.02), pneumonitis (OR 14.3, p = 0.03), early irAEs (OR 15.2, p = 0.017), and early pneumonitis (OR 30.0, p = 0.03). No significant associations were observed between %CV-eCtrough and irAEs or early irAEs. Higher platelet count and renal dysfunction were independently associated with increased %CV-eCmax. Conclusions: Higher inter-cycle variability in eCmax during 200 mg Q3W was associated with an increased risk of new or worsened irAEs, particularly pneumonitis, after switching to 400 mg Q6W. These findings suggest that inter-cycle variation in Cmax may be an important safety consideration when transitioning to a 400 mg Q6W regimen.
Masui et al. (Wed,) studied this question.