Pharmacokinetic variability with pembrolizumab dosage switching and its impact on immune-related adverse events in patients with non-small cell lung cancer
Ryoko Inaba Higashiyama, Tatsuya Yoshida, Shigehiro Yagishita, Mayu Ohuchi, Yoshihiro Masui, Ken Masuda, Yuki Shinno, Yuji Matsumoto, Tomonori Mizutani, Yusuke Okuma, Yasushi Goto, Hidehito Horinouchi, Shohei Koyama, Noboru Yamamoto, Akinobu Hamada, Yuichiro OheBackground
Pembrolizumab 400 mg every 6 weeks (Q6W) was approved based on population pharmacokinetic (pop-PK) modeling rather than pharmacokinetic measurements, leaving 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. This study aimed to evaluate the association between the change in pembrolizumab dosage and irAE occurrence.
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; pop-PK analysis estimated maximum concentration (eC max ) and estimated trough exposure (eC trough ). Intercycle variability was expressed as percentage coefficient of variation (%CV) using all available 200 mg Q3W cycles. Early irAEs were defined as events within 126 days.
Associations between pop-PK metrics and irAEs (including pneumonitis) after switching were explored. Clinical correlates of %CV-eC max were also assessed.
Results
79 patients switched, and pop-PK analysis was feasible in 66 patients. The median age was 70 years, 50 were male, and 62 had a smoking history. The median Q3W cycles were 6, and the median follow-up period after switching was 463 days. After switching, 45 events occurred new or worsened irAEs, with 19 pneumonitis, and 22 had early irAEs, with 13 early pneumonitis.
Among the 64 patients who received ≥2 cycles of Q3W, those who developed irAEs after switching showed higher %CV-eC max during Q3W. Similar associations were observed for early irAEs, pneumonitis, and early pneumonitis.
%CV-eC trough during Q3W was not associated with irAEs after switching, with an association observed only for early pneumonitis.
High %CV-eC max during Q3W was associated with increased odds of irAEs, pneumonitis, early irAEs, and early pneumonitis. No significant associations were observed between %CV-eC trough and irAEs or early irAEs.
Higher platelet count and renal dysfunction were independently associated with increased %CV-eC max .
Conclusions
High intercycle eC max variability during 200 mg Q3W is associated with an increased risk of new or worsened irAEs, particularly pneumonitis, after switching to 400 mg Q6W, suggesting that intercycle variation in C max may be an important safety consideration when switching to 400 mg Q6W.