Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2019 ASCO Annual Meeting but not presented at the Meeting, can be found online only.
Alectinib exposure-response (ER) in ALK-inhibitor naïve ALK-positive NSCLC patients: Pooled analysis across phase III studies.
Metastatic Non-Small Cell Lung Cancer
Lung Cancer—Non-Small Cell Metastatic
2019 ASCO Annual Meeting
J Clin Oncol 37, 2019 (suppl; abstr e20575)
Author(s): Kevin Smart, Joy C Hsu, Felix Jaminion, Elena Guerini, Alice Tsang Shaw, Caicun Zhou, Tony S. K. Mok, Walter Bordogna, Nicolas Frey, Peter N. Morcos; Roche Products, Welwyn, United Kingdom; F. Hoffmann-La Roche, New York, NY; Roche Innovation Center, Basel, Switzerland; Massachusetts General Hospital/Harvard Medical School, Boston, MA; Shanghai Pulmonary Hospital, Tongji University, Shanghai, China; Prince of Wales Hospital, Hong Kong, China; F. Hoffmann-La Roche Ltd., Basel, Switzerland; Roche Innovation Center, New York, NY
Background: Alectinib superiority to crizotinib has been demonstrated in ALK-inhibitor naïve ALK-positive NSCLC patients (pts) in Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132316) pts receiving alectinib 300 mg BID and global (ALEX; NCT02075840) and Asian (ALESIA; NCT02838420) pts receiving alectinib 600mg BID. ER analyses are undertaken to confirm the appropriate alectinib dosing regimen for the global population. Methods: A previous population PK analysis (Hsu et al, ASCO 2016) assessed PK of alectinib and major metabolite, M4, to identify factors influencing PK variability. ER analyses across the 3 Phase III studies investigated the relationship between alectinib and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis. PK simulations for alectinib 300 mg and 600 mg BID doses were conducted to determine the proportion of pts falling above and below an identified optimal PK threshold for PFS. ER for key safety events were investigated for alectinib 600 mg BID using logistic regression. Results: Alectinib PK is influenced only by body weight and not by race/ethnicity. CPH analysis demonstrated a statistically significant relationship between alectinib exposure and PFS across the 3 Phase III studies, with an improved PFS above an identified optimal PK threshold (Table). PK simulations indicate 49% and 7% of global alectinib treated patients would fall below the optimal PK threshold for 300 and 600mg BID, respectively. Alectinib 600mg BID ensures a distribution of exposures that maximize the PFS benefit while lower alectinib doses/exposures could result in reduced efficacy. Baseline tumor size (BSIZ) was shown to negatively impact PFS with larger BSIZ seen in global pts. No significant exposure-safety relationships were identified for alectinib 600mg BID. Conclusions: Alectinib 600mg BID is the most appropriate dose in the global ALK-inhibitor naïve population. Clinical trial information: NCT02075840; JapicCTI-132316; NCT02838420
|Patients||HR [95% CI] vs crizotinib|
|All PK pts* (n = 334)||0.46 [0.33−0.64]|
|Low Exposure (n = 44)||0.76 [0.46−1.25]|
|High Exposure (n = 290)||0.36 [0.28−0.46]|
*All PK pts = pts with post-baseline PK and efficacy data; Low and high exposure categories = defined as below or above alectinib+M4 = 1040 nM, the derived optimal PK threshold