Safety and pharmacokinetics of crizotinib in patients (pts) with hepatic impairment (HI) and advanced cancer

2552 Background: Crizotinib is a kinase inhibitor approved for treating ALK+ and ROS1+ advanced non-small cell lung cancer. Since crizotinib undergoes hepatic metabolism, this phase 1 study evaluated the pharmacokinetics (PK) and safety of crizotinib in pts with liver dysfunction. Methods: Crizotinib-naïve pts with different types of advanced cancer (ALK and ROS1 status unknown), ≥ 18 yr old, and ECOG PS 0–2 were enrolled. Pts were assigned to groups A1 – D based on liver function: normal (A1/A2) = both AST and TB ≤ the upper limit of normal (ULN); mild impairment (B) = AST > ULN and TB ≤ ULN, or TB > 1.0 – 1.5 × ULN; moderate (C1/C2) = TB > 1.5 – 3 × ULN; severe (D) = TB > 3 × ULN. Starting dose was based on HI. Pts in A1 and A2 were matched for weight, age, gender, race and ECOG PS to pts in B and C2, respectively. Study objectives included PK, safety and antitumor activity. Results: 88 pts were enrolled in A1 (n=11), A2 (n=15), B (n=20), C1 (n=10), C2 (n=16) and D (n=16). The geometric means of PK parameters at steady-state (Cycle 2 Day 1) are shown below. 75% of pts experienced treatment-related AEs (TRAEs), 9 (81.8%), 14 (93.3%), 15 (75.0%), 6 (60.0%), 11 (68.8%) and 11 (68.8%) in groups A1, A2, B, C1, C2 and D, respectively. 25% of pts experienced Grade 3/4 TRAEs, 3 (27.3%), 3 (20.0%), 3 (15.0%), 1 (10%), 7 (43.8%), 5 (31.3%) in groups A1, A2, B, C1, C2 and D, respectively. Three (3.4%) pts, all in A2, experienced treatment-related SAEs. Two pts (10%) in B and 1 (6.3%) in C2 required dose reductions for TRAEs. TRAEs associated with permanent discontinuation of treatment occurred in 1 pt in A1, A2, C2 and D. Overall, 3 pts had partial responses with durations of 96, 17 and 17 wks; 25 pts had stable disease. Conclusions: Systemic exposures of crizotinib in pts with mild HI receiving 250 BID and in pts with moderate HI receiving 200 mg BID are comparable with that of pts with normal hepatic function at 250 mg BID. All TRAEs were manageable across the various levels of hepatic function. Clinical trial information: NCT01576406. [Table: see text]