Brigatinib is another treatment option for patients diagnosed with advanced ALK-positive non-small-cell lung cancer who are treatment-naïve or who have progressed on or are intolerant to crizotinib

The Editor

Current Oncology

11 December 2018

We recently published an article in Current Oncology titled “Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer”¹. Since that article was submitted to Current Oncology, new phase III data for brigatinib from the alta-1L study were presented at the International Association for the Study of Lung Cancer’s 19th World Conference on Lung Cancer (September 2018) and published in the New England Journal of Medicine². Those data have changed our evidence-based perspective concerning the place of brigatinib as a treatment option in Canada (Figure 1).

FIGURE 1.

Revised treatment algorithms for ALK-positive non-smallcell lung cancer. ^aNot yet approved by Health Canada for first-line therapy. ^bHas received a Notice of Compliance with conditions from Health Canada based on the phase II ALTA study (full approval pending Health Canada review of the phase III ALTA-1L study). TKI = tyrosine kinase inhibitor.

The phase III alta-1L study compared brigatinib (180 mg once daily) with crizotinib (250 mg twice daily) in ALK-positive patients with non-small-cell lung cancer who had not previously received an alk inhibitor (n = 275). The primary endpoint was progression-free survival as assessed by an independent review committee. At a median follow-up of 11.0 months (range: 0–20.0 months) for brigatinib and 9.3 months (range: 0–20.9 months) for crizotinib, the results from the first pre-specified interim analysis showed a hazard ratio of 0.49 [95% confidence interval (ci): 0.33 to 0.74; p < 0.001] for disease progression or death favouring brigatinib². The objective response rate (orr) was 71% (95% ci: 62% to 78%) for brigatinib and 60% (95% ci: 51% to 68%) for crizotinib. The intracranial orr was 78% (95% ci: 52% to 94%) for brigatinib and 29% (95% ci: 11% to 52%) for crizotinib. The cumulative incidence of intracranial disease progression was 9% (12 of 137 patients) for brigatinib and 19% (26 of 138 patients) for crizotinib, with a hazard ratio for time to progression of intracranial disease of 0.30 (95% ci: 0.15 to 0.60), with relatively short follow-up.

The phase II alta study randomized 222 crizotinib-refractory patients 1:1 to receive either brigatinib 90 mg once daily (n = 112) or brigatinib 180 mg once daily (n = 110)³. Patients could have received chemotherapy before receiving crizotinib, and in the 180 mg arm, 74% of the patients had received at least 1 prior line of chemotherapy. The primary endpoint was investigator-assessed confirmed orr, and the key secondary endpoints were progression-free survival and independent review committee–assessed intracranial orr. The study met its primary endpoint, and at the latest data cut-point⁴, it showed confirmed orrs of 56% (97.5% ci: 45% to 67%) and 46% (97.5% ci: 35% to 57%). The independent review committee–assessed median progression-free survival was 16.7 months (95% ci: 11.6 months to 21.4 months) in the 180 mg arm and 9.2 months (95% ci: 7.4 months to 12.8 months) in the 90 mg arm. The median overall survival for patients in the 180 mg arm was 34.1 months (95% ci: 27.7 months to not reached). Brigatinib was approved by the European Commission on 27 November 2018 for patients previously treated with crizotinib⁵, and it received a Notice of Approval with conditions from Health Canada on 30 July 2018⁶.

The phase III data from alta-1L and the phase II data from alta provide a sound rationale for recommending brigatinib as a treatment option both for alk-inhibitor, treatment-naïve patients and for patients previously treated with crizotinib.