Phase I trial of lorlatinib in patients with ALK-driven refractory or relapsed neuroblastoma: A New Approaches to Neuroblastoma Consortium study.

Abstract

10504 Background: Lorlatinib, a potent ALK inhibitor, exerts unprecedented activity against neuroblastoma (NB) derived xenografts harboring common crizotinib-resistant ALK mutations, leading to a first in child phase I study. Methods: R/R NB patients (pts) > 12 months, with ALK mutations/amplification and prior ALK inhibitor (ALKi) treatment were eligible. Lorlatinib was administered in 28-day courses (C). For pts < 18 years, 5 dose levels (DL) (45, 60, 75, 95, 115 mg/m2/day) were assessed. DL5 (115 mg/m2/day) expansion is enrolling (cohort A1). For patients > 18 years, two DL (DL3a the adult RP2D of 100 mg/day and DL4a at 150mg/day) were assessed (cohort A2). Primary endpoint was dose-limiting toxicity (DLT) during C1 and neurocognitive toxicity through C2. Blood samples for circulating tumor DNA (ctDNA) were matched to radiologic restaging. Results: From 9/2017 to 1/2019, 33 eligible patients enrolled (13 with prior ALKi therapy), with median age (range) 5.5 years (2-17) on A1, 21.5 years (15-50) on A2. In A1, 3 pts each enrolled onto DL1-3, with no DLT’s. 5/10 pts enrolled on DL4, with no DLT’s. 1/3 on DL5 had a DLT of grade 3 diarrhea, with expansion ongoing. In cohort A2, 5 patients enrolled at 100 mg/day with no DLT’s; 6 enrolled at 150 mg/day, with one DLT (grade 4 reversible psychosis). Most common treatment-related adverse events were weight gain (90%, grade 1-3), hyperlipidemia (90%, grade 1-3), concentration/memory impairment (23%, grade 1-2), peripheral neuropathy (13%; grade 1-2, A2 only), and peripheral edema (10%; grade 1, A2 only). Lorlatinib steady state exposure at DL3 and DL4 was in the range of exposures seen in adult lung cancer patients at the 100 mg and 200 mg DLs. In A1, 1/18 had partial response (PR), 3/18 had minor responses (MR), and 4/18 had stable disease (SD). Of pts with MR, 2/3 had PR of soft tissue and 1/3 had complete response (CR) by MIBG. In A2 pts, 1/10 had CR, 3/10 PR, and 3/10 MR; Notably, 2/3 with PR had CR by MIBG. Of the pts with MR, one had PR and one CR by MIBG. Responses occurred across dose levels, ALK mutations, and in ALKi pre-treated pts with median courses of 2 (1-24) on A1 and 10.5 (2-28) on A2. Serial ctDNA results showed mutant ALK variant allele frequency trajectories that correlated with clinical response and emergence of novel ALK mutations in cis that corresponded with disease progression. Conclusions: Inhibition of ALK-driven NB with lorlatinib occurs with manageable toxicity and objective anti-tumor activity. Prospective ctDNA allows for monitoring of disease and evolution of resistance. Clinical trial information: NCT03107988.