The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

Abstract

Purpose: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK þ ) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. Experimental Design: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib-ALK co-structure was determined.Results: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK þ cell lines, brigatinib inhibited native ALK (IC 50 , 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK þ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. Conclusions: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK þ , crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials.

Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial

“…However, any differences among these drugs in their ability to suppress clinically relevant ALK mutations, including those that may not be dominant initially but could emerge later, are more likely to be reflected in PFS or duration of response. [12][13][14][15][16]21 In preclinical models, brigatinib had broader predicted mutation coverage, compared with ceritinib and alectinib. 21 Consistent with this observation, in the phase I/II trial of brigatinib, the median PFS of patients with advanced ALK-positive NSCLC who previously received crizotinib (most of whom received 180 mg per day, with or without lead-in at 90 mg) was recently reported as 12.9 months, across all doses tested.…”

“…[12][13][14][15][16]21 In preclinical models, brigatinib had broader predicted mutation coverage, compared with ceritinib and alectinib. 21 Consistent with this observation, in the phase I/II trial of brigatinib, the median PFS of patients with advanced ALK-positive NSCLC who previously received crizotinib (most of whom received 180 mg per day, with or without lead-in at 90 mg) was recently reported as 12.9 months, across all doses tested. 22 This extended PFS, relative to ceritinib 12-14 and alectinib 15,16 results, is substantiated by the median PFS of .…”

“…20 In preclinical models, brigatinib potently inhibited all ALK resistance mutations tested, including G1202R, and overcame mechanisms of resistance to other ALK inhibitors at clinically achievable brigatinib levels. 21 In an ongoing phase I/II clinical trial (NCT01449461), brigatinib yielded promising antitumor activity (confirmed ORR, 62%; median PFS, 12.9 months) in patients with advanced ALK-positive NSCLC previously treated with crizotinib. 22 However, during dose escalation and an initial phase II expansion at 180 mg once daily, a small proportion of patients had moderate or severe pulmonary adverse events (AEs) with early onset (usually within 24 to 48 hours) that were observed more frequently at higher starting doses.…”

Targeting ALK: Precision Medicine Takes on Drug Resistance

“…In the interim, brigatinib has received breakthrough therapy designation by the FDA for the treatment of crizotinib-resistant, ALK -rearranged NSCLC. Some preclinical studies of brigatinib suggest activity against the G1202R mutation in cell lines and mouse models (128, 130), and a confirmed response to brigatinib has been reported in a patient with G1202R-mutant NSCLC (129). However, G1202R has also been detected in 43% (3/7) of ALK -positive NSCLC biopsies post-brigatinib (78).…”

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

“…Preclinical work showed that brigatinib was more potent and maintained activity against 17 secondary ALK mutations, with superior inhibitory activity compared to crizotinib, ceritinib, and alectinib [32]. The phase I/II trial showed an ORR of 72% in previously crizotinib-treated ALK -rearranged NSCLC patients with an intracranial response rate of 53% [33].…”