Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial.

In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor-naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee-assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35-0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53-1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21-0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.

Camidge DR ，Kim HR ，Ahn MJ ，Yang JCH ，Han JY ，Hochmair MJ ，Lee KH ，Delmonte A ，Garcia Campelo MR ，Kim DW ，Griesinger F ，Felip E ，Califano R ，Spira AI ，Gettinger SN ，Tiseo M ，Lin HM ，Liu Y ，Vranceanu F ，Niu H ，Zhang P ，Popat S ... -  《-》

Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial.

Camidge DR ，Kim HR ，Ahn MJ ，Yang JCH ，Han JY ，Hochmair MJ ，Lee KH ，Delmonte A ，García Campelo MR ，Kim DW ，Griesinger F ，Felip E ，Califano R ，Spira A ，Gettinger SN ，Tiseo M ，Lin HM ，Gupta N ，Hanley MJ ，Ni Q ，Zhang P ，Popat S ... -  《-》

Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial.

Yang JC ，Liu G ，Lu S ，He J ，Burotto M ，Ahn MJ ，Kim DW ，Liu X ，Zhao Y ，Vincent S ，Yin J ，Ma X ，Lin HM ，Popat S ... -  《-》

Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer.

Camidge DR ，Kim HR ，Ahn MJ ，Yang JC ，Han JY ，Lee JS ，Hochmair MJ ，Li JY ，Chang GC ，Lee KH ，Gridelli C ，Delmonte A ，Garcia Campelo R ，Kim DW ，Bearz A ，Griesinger F ，Morabito A ，Felip E ，Califano R ，Ghosh S ，Spira A ，Gettinger SN ，Tiseo M ，Gupta N ，Haney J ，Kerstein D ，Popat S ... -  《-》

Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK-Inhibitor-Naive ALK+ Non-Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study.

Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non-small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial. This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor-naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases. Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients. Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients.

Ahn MJ ，Kim HR ，Yang JCH ，Han JY ，Li JY ，Hochmair MJ ，Chang GC ，Delmonte A ，Lee KH ，Campelo RG ，Gridelli C ，Spira AI ，Califano R ，Griesinger F ，Ghosh S ，Felip E ，Kim DW ，Liu Y ，Zhang P ，Popat S ，Camidge DR ... -  《-》