Exposure response relationship for interstitial lung disease (ILD) events following osimertinib treatment
Martin Johnson (1), Henning Schmidt (2), Mikael Sunnaker (2), Bengt Hamrén (3), Nidal Al-Huniti (4), Suman Nayak (5), Helen Tomkinson (1) and Karthick Vishwanathan (4)
(1) Quantitative clinical pharmacology, Early clinical development, AstraZeneca UK, (2) IntiQuan GmbH, Basel, Switzerland, (3) Quantitative clinical pharmacology, Early clinical development, AstraZeneca Sweden, (4) Quantitative clinical pharmacology, Early clinical development, AstraZeneca US, (5) Global Medicine Development, AstraZeneca US
Objectives: Osimertinib is indicated for the treatment of patients with T790M mutation positive advanced non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy [1]. In general, ILD incidence with TKIs is variously reported to be approximately 1.6 – 4.3%in Japanese populations and 0.3–1.0% in non-Japanese populations [2]. In this analysis, a potential relationship between systemic exposure of osimertinib and the incidence of ILD events was evaluated.
Methods: ILD event information from patients with advanced NSCLC from Phase I, Phase II, and Phase III studies (n = 1088) was used in this analysis as a categorical variable. Thirty-seven (3.40%) patients had ILD events. Occurrence of ILD was higher in the Japanese population (8.42%) than in the non-Japanese population (2.30%). A penalised logistic regression was applied to account for the separation problem due to the low number of ILD events. Ethnicity, exposure of osimertinib and other relevant covariates were used in the covariate analysis.
Results: A linear logistic regression model described the relationship between exposure and ILD events adequately (slope for change in logAUCss: 0.80 [0.308, 1.28], Intercept -10.9 [-15.7,-6.21]). Parameter estimates and predicted probabilities were represented as Median [95% confidence intervals]. Model predicted probability of a patient experiencing ILD increases with increasing osimertinib exposure as 0.0191 [0.0111 – 0.0328] for lowest quartile (steady state AUC 6361 nM*h) vs 0.0542 [0.0375 – 0.0777] for highest quartile (AUC 24460 nM*h). At the recommended 80 mg/day dose, Japanese patients are predicted to have higher (0.079 [0.042 – 0.13]) probability of experiencing ILD events compared to other ethnic populations (0.032 [0.015 – 0.052]). Estimated ILD incidence rate for non-osimertinib or placebo treatment was lower (0.0046%) than the ILD incidence rate reported in literature for placebo or chemotherapy treatment (0.9 to 2%) in NSCLC patients. When including information about ILD incidence rates for non-osimertinib or placebo treated NSCLC patients, the estimated exposure dependency of ILD events under osimertinib treatment was lower.
Conclusions: Our model-based exposure-response analysis accounted for low number of events and suggested a relationship between osimertinib exposure and ILD incidence. At 80 mg dose, Japanese population predicted to have higher probability compare to other population.
References:
[1] Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. New England Journal of Medicine 2017 376 (7) : 629–40
[2] Shah R Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas Drug Safety (2016) 39:1073–1091