1487PD - Intracranial and extracranial efficacy of lorlatinib in the post second-generation ALK tyrosine kinase inhibitor (TKI) setting

The selective, potent, brain-penetrant 3rd-generation (gen) ALK TKI lorlatinib is approved for the treatment of patients (pts) with ALK+ metastatic non-small cell lung cancer (NSCLC) whose disease has progressed following 2nd-gen ALK TKIs. In this ongoing ph 2 study (NCT01970865), 139 pts with ALK+ advanced NSCLC with ≥1 prior 2nd-gen ALK TKI, ± chemotherapy (CT), were enrolled in expansion cohorts—EXP3B, EXP4 and EXP5—based on treatment history. Overall, intracranial (IC) and extracranial (EC) antitumor activity were assessed by independent central review, per modified RECIST v1.1. Recurrent event analysis on within-patient time to progression (TTP) was conducted comparing TTP on lorlatinib with TTP on the last prior 2nd-gen ALK TKI. Of the 139 pts with ≥1 prior 2nd-gen ALK TKI (EXP3B–5), 28 had 1 prior 2nd-gen ALK TKI as their only ALK TKI (EXP3B), 65 had 2 prior ALK TKIs (EXP4) and 46 had 3 prior ALK TKIs (EXP5). As of data cutoff (02 Feb 2018), the ORR in EXP3B–5 was 40% (95% CI 32–49), median duration of response (DOR) was 7.1mo (95% CI 5.6–24.4) and median PFS was 6.9mo (95% CI 5.4–8.2). Responses were observed in pts who had also received prior CT (n/N=40/93; ORR 43% [95% CI 33–54]) as well as in CT-naïve pts (n/N=16/46; ORR 35% [95% CI 21–50]). IC- and EC-ORR in EXP3B–5 and individual cohorts are shown in the table. In EXP3B–5, median IC DOR was 12.4mo (95% CI 5.8–NR) and median EC DOR was 9.7mo (95% CI 6.1–NR). Based on 121 evaluable pts, no significant differences were observed in terms of TTP between lorlatinib and last prior 2nd-gen ALK TKI (HR 0.86, 95% CI 0.64–1.16).Table1487PDTableIC ORREC ORRN*% (95% CI)N% (95% CI)EXP3B–55754 (41–68)13937 (29–46)EXP3B967 (30–93)2832 (16–52)EXP42458 (37–78)6538 (27–51)EXP52446 (26–67)4639 (25–55)EC, extracranial; IC, intracranial; ORR, objective response rate*Patients with ≥1 measurable CNS metastases at baseline In the post 2nd-gen ALK TKI setting, lorlatinib showed clinically meaningful antitumor activity in both IC and EC compartments, with a trend towards elevated IC vs EC ORR particularly in pts with fewer lines of therapy. Despite pts having a worse prognosis at a later line, lorlatinib showed a similar TTP compared with the last 2nd-gen ALK TKI. NCT01970865. Jade Drummond of inScience Communications, Springer Healthcare, Chester, UK; funded by Pfizer Inc. Pfizer Inc. Pfizer Inc. D.R. Camidge: Honoraria (self): Roche; Honoraria (self): G1 Therapeutics; Honoraria (self): Mersana; Honoraria (self), Resea