Joy C. Hsu (1), Felix Jaminion (2), Elena Guerini (2), Eveline Nueesch (2), Bogdana Balas (2), Ali Zeaiter (2), Peter N. Morcos (1), Nicolas Frey (2)
(1) Roche Pharma Research and Early Development, Roche Innovation Center, New York, NY, USA, (2) Roche Innovation Center, Basel, Switzerland
Introduction: Alectinib is a tyrosine kinase inhibitor that targets Anaplastic Lymphoma Kinase (ALK) and REarranged during Transfection (RET), thereby inhibiting intracellular signaling pathways involved in tumor cell proliferation and survival. It is a potent and selective CNS-active ALK inhibitor in oral formulation. Alectinib was first approved in Japan in 2014 at 300 mg BID dose for treatment of ALK-positive, unresectable, recurrent or advanced non-small cell lung cancer (NSCLC) for crizotinib-naïve patients (i.e. first-line therapy). In 2015, the U.S. Food and Drug Administration granted approval for the 600 mg BID dose regimen for ALK-positive metastatic NSCLC in patients who had progressed on or were intolerant to crizotinib (i.e. second-line therapy).
Objectives: To confirm the appropriateness of alectinib 600mg BID dose regimen as a first-line therapy for the global patient population by applying knowledge from prior pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses on alectinib second-line therapy data to alectinib first-line therapy data collected in a global Phase 3 study ALEX following 600 mg BID regimen and in a Japanese Phase 3 study J-ALEX (conducted by Chugai Pharmaceuticals Co. Ltd.) following 300 mg BID regimen.
Methods: The PK of alectinib and its major active metabolite M4 were characterized previously using population PK models developed on Alectinib second-line therapy data [1]. A Bayesian feedback analysis was conducted by using those PK models to the PK data collected in ALEX (randomized, open-label study with PK data from 143 patients treated with 600 mg BID alectinib and 151 patients treated with crizotinib) and PK data collected in J-ALEX (randomized, open-label study with PK data from 96 patients treated with 300 mg BID alectinib and 104 patients treated with crizotinib). A total of 1518 alectinib and 1516 M4 plasma concentrations were analyzed.
Effects of exposure on main efficacy measures systemic best overall response (BOR), CNS BOR, progression free survival (PFS), and time to CNS progression were evaluated graphically for ALEX. A Cox proportional-hazards (CPH) analysis was conducted to investigate the relationship between exposure and PFS (RECIST 1.1), utilizing data from ALEX and J-ALEX. Potential influence of additional factors such as baseline disease status covariates (e.g., tumor size, Eastern Cooperative Oncology Group score, CNS-metastases status, prior chemotherapy) and demographic covariates (e.g., body weight, age, gender, race, ethnicity, smoking status) were investigated. To investigate the exposure-safety relationship between exposure and safety parameters serious adverse event (SAE) and any adverse events (AE) Grade 3 or above, logistic regressions were conducted.
Results: Bayesian feedback analysis showed that the PK characteristics of alectinib and M4 in patients who were ALK inhibitor-naïve are consistent with that in patients previously treated with crizotinib. Body weight was confirmed to be the only significant covariate for the PK of alectinib and M4, as identified in the previous population PK analyses [1]. Administration of 600 mg BID regimen ensures that all patients across the entire body weight range in global population would achieve steady-state exposure which is not inferior to that achieved following 300 mg BID regimen in J-ALEX.
Results of the graphical exposure-efficacy showed that variability in alectinib exposure at 600 mg BID does not explain the variability in efficacy. Across the dose range of 300-600 mg BID for alectinib, results of the CPH analysis indicated that greater PFS benefits were found for patients treated with alectinib compared to crizotinib, with the most PFS benefit identified for patients in the high exposure category. The PFS benefit was found to decrease with increasing baseline tumor size. Simulations using the CPH model for PFS showed that the 600 mg BID dose regimen would provide greater PFS benefit over crizotinib compared to the 300 mg BID dose regimen. No significant exposure-safety relationship was identified following 600 mg BID in ALEX.
Conclusions: Results of these analyses demonstrated that alectinib 600mg BID is the appropriate dose regimen for all the ALK-inhibitor naïve ALK-positive NSCLC global patient population.
References:
[1] Hsu J, et al., Population Pharmacokinetics and Exposure-Efficacy and Safety Analyses of Alectinib in Crizotinib-Progressed or Intolerant Population, American Conference on Pharmacometrics 7, 2016.
Reference: PAGE 27 (2018) Abstr 8697 [www.page-meeting.org/?abstract=8697]
Poster: Drug/Disease Modelling - Oncology