MA07.11 Safety and Efficacy of Lorlatinib (PF-06463922) in Patients with Advanced ALK+ or ROS1+ Non-Small-Cell Lung Cancer (NSCLC)

Patients with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC often become resistant to tyrosine kinase inhibitor (TKI) therapy; central nervous system (CNS) relapse is common. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI, active against most known resistance mutations. In Ph I of the ongoing Ph I/II study NCT01970865, patients had ALK+ or ROS1+ NSCLC ± brain metastases and were treatment naïve or had disease progression after ≥1 TKIs. Patients received lorlatinib on day –7 and then once or twice daily from day 1. Primary objective was identification of MTD and recommended Ph II dose (RP2D). Other objectives were safety and efficacy by RECIST v 1.1 including intracranial activity. Of 54 patients treated in Ph I (cutoff Jan 15, 2016), 41 were ALK+, 12 ROS1+, and 1 had mutation status unconfirmed for ALK+ or ROS1+. Patients were heavily pretreated: 27 had received ≥2 prior TKIs and 20 had 1 prior TKI; 39 patients had CNS metastases at baseline. Patients were treated across 10 dose levels (total daily dose of 10–200 mg). Response rates were:Tabled 1nCRPRuCRuPROverall RR (CR + PR)n (%)ORR in ALK+ and ROS1+533(6)22(42)-1(2)25(47)ORR in ALK+ with 1 prior TKI141(7)7(50)--8(57)ORR in ALK+ with ≥2 prior TKI262(8)9(34)-1(4)11(42)IC ORR (target + non-target lesions) in ALK+ and ROS+3910(26)4(10)1(3)2(5)14(36)IC ORR (target lesions) in ALK+ and ROS+237(30)4(17)-2(9)11(47)ORR, objective response rate; IC ORR, intracranial objective response rate; CR, complete response; PR, partial response; RR, response rate; u, unconfirmed Open table in a new tab ORR, objective response rate; IC ORR, intracranial objective response rate; CR, complete response; PR, partial response; RR, response rate; u, unconfirmed Median duration of response was 10.5 months (95% CI 2.9– not reached [NR]) and 12.4 months (95% CI 6.5–NR) for ALK+ and ALK+/ROS1+ pts, respectively. 26 patients remain on treatment. The most common treatment-related adverse events (TRAEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade ≥3 TRAE. No patient discontinued due to a TRAE. Analyses of ALK resistance mutations in archival tumor tissue and plasma circulating free DNA collected before lorlatinib treatment are ongoing. Lorlatinib was well tolerated and demonstrated durable responses, including intracranial responses, in ALK+ and ROS1+ NSCLC, most of whom had CNS metastases and ≥1 prior TKIs. The RP2D was identified as 100 mg once daily. Ph II is ongoing.