TKI-naïve Advanced ALK-positive NSCLC (ALTA 1L Study)

The efficacy of ALUNBRIG was demonstrated in a randomized (1:1), open-label, multicenter trial (ALTA 1L, NCT02737501) in adult patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. The study required patients to have an ALK rearrangement based on a local standard of care testing. Eligible patients were allowed to have up to 1 prior regimen of chemotherapy in the locally advanced or metastatic setting and were required to have an ECOG Performance Status of 0-2. Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible. Patients with a history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis were excluded. The major efficacy outcome measure was progression-free survival (PFS) as evaluated by a Blinded Independent Review Committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional efficacy outcome measures included confirmed overall response rate (ORR), duration of response (DOR), intracranial ORR, and intracranial DOR as evaluated by BIRC, and overall survival (OS).

A total of 275 patients were randomized to receive ALUNBRIG 180 mg orally once daily with a 7-day lead-in at 90 mg once daily (n = 137) or crizotinib 250 mg orally twice daily (n = 138). Of the 275 enrolled patients, 239 had positive results using the companion diagnostic test, the Vysis ALK Break Apart FISH Probe Kit; central results were negative for 20 patients and unavailable for 16 patients. Crossover from the crizotinib arm to the ALUNBRIG arm was permitted following disease progression.

Randomization was stratified by CNS metastases (present vs absent) and prior chemotherapy use for locally advanced or metastatic disease (yes, no).

Baseline demographic characteristics of the overall study population were: median age 59 years (range: 27 to 89, 32% 65 and over), 59% White and 39% Asian, 55% female, 39% ECOG PS 0 and 56% ECOG PS 1, and 58% never smokers. The disease characteristics of the overall study population were: 93% with Stage IV disease; 27% received chemotherapy in the locally advanced or metastatic setting; 14% had received CNS radiation; 31% had bone metastases; and 20% had liver metastases. CNS metastases were present in 35% (n = 96) of patients; 41 of those patients had measurable CNS lesions.

ALTA 1L demonstrated a statistically significant improvement in PFS by BIRC. Efficacy results from this study are described in Table 7 and Figure 1.

Figure 1: Kaplan-Meier Plot of Progression-Free Survival by BIRC in ALTA 1L

At the final analysis of overall survival, conducted approximately 3 years after the last patient enrolled, there were 92 deaths (33% of all patients) including 41 deaths on the ALUNBRIG arm and 51 deaths on the crizotinib arm; median OS was not reached on either arm.

BIRC assessment of confirmed intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 41 patients with measurable CNS metastases (≥10 mm in longest diameter) at baseline are summarized in Table 8. Duration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth ≥20% from nadir, or unequivocal progression of intracranial nontarget lesions) or death.

ALK-positive Advanced or Metastatic NSCLC Previously Treated with Crizotinib

The efficacy of ALUNBRIG was demonstrated in a two-arm, open-label, multicenter trial (ALTA, NCT02094573) in adult patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who had progressed on crizotinib. The study required patients to have a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit test. Key eligibility criteria included an ECOG Performance Status of 0-2 and progression on crizotinib. Neurologically stable patients with central nervous system (CNS) metastases were permitted to enroll. Patients with a history of interstitial lung disease or drug-related pneumonitis or who had received crizotinib within 3 days of the first dose of brigatinib were excluded. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR.

A total of 222 patients were randomized to receive ALUNBRIG either 90 mg once daily (90 mg arm; n = 112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (90→180 mg arm; n = 110). Randomization was stratified by CNS metastases (present vs absent) and best prior response to crizotinib (complete or partial response vs any other response/unevaluable).

Baseline demographic characteristics of the overall study population were: median age 54 years (range: 18 to 82, 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, and 95% never or former smokers. The disease characteristics of the overall study population were: Stage IV disease in 98%, adenocarcinoma histology in 97%, prior systemic chemotherapy in 74%, CNS metastases in 69% (61% had received prior CNS radiation), bone metastases in 39%, and liver metastases in 26% of patients. Sixty-four percent of patients had an objective response to prior crizotinib.

The median duration of follow-up was 8 months (range: 0.1 to 20.2). Efficacy results from ALTA are summarized in Table 9.

IRC assessment of intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 44 patients with measurable CNS metastases (≥10 mm in longest diameter) at baseline are summarized in Table 10. Duration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth ≥20% from nadir, or unequivocal progression of intracranial nontarget lesions) or death.