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Brigatinib Superior to Standard of Care Crizotinib in ALK+ NSCLC

Kristie L. Kahl
Published Online:2:02 PM, Wed September 26, 2018

D. Ross Camidge, MD, PhD

Adult patients with ALK-positive, locally advanced or metastatic non–small cell lung cancer (NSCLC) who had not received a prior ALK inhibitor experienced a more than 50% reduction in the risk of disease progression or death with treatment with brigatinib (Alunbrig), compared with the first-line standard of care, crizotinib.

Brigatinib demonstrated superior progression-free survival (PFS) compared with crizotinib, corresponding to a 51% reduction in the risk of disease progression or death (HR, 0.49; 95% CI, 0.33-74; P = .0007), according to first interim analysis results presented at the 19th World Conference on Lung Cancer1 and simultaneously published in the New England Journal of Medicine.2

“Brigatinib is a next-generation ALK inhibitor with excellent central nervous system (CNS) penetration, preclinical activity against a wide range of crizotinib resistance mutations in ALK, as well as being the only ALK inhibitor with marked preclinical activity against EGFR-mutant cell lines,” explained D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center In Aurora.

“It has already shown significant activity…where it has consistently demonstrated the longest reported median PFS of any licensed, experimental ALK inhibitor, including ceritinib (Zykadia), alectinib (Alecensa), and lorlatinib,” he added.

ALTA-1L is a global, randomized, open-label, comparative, multicenter trial, designed to evaluate efficacy and safety of brigatinib compared with crizotinib in 275 patients with stage IIIB/IV ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor, but may have received up to one prior regimen of chemotherapy in the advanced setting.

PFS as assessed by blinded independent central review served as the primary endpoint, and secondary endpoints included objective response rate (ORR) and intracranial response.

The investigators randomized patients 1:1 to receive either 180 mg brigatinib once daily (n = 137), with a 7-day lead-in period at 90 mg, or 250 mg crizotinib twice daily (n = 138). Of note, crossover from the crizotinib arm to receive brigatinib was permitted at blinded independent central review of PFS.

The median age was 59 years, and 55% of patients in the trial were female. Twenty-nine percent had brain metastases at baseline with comparable pre-enrollment CNS radiotherapy rates among both cohorts. Overall, 27% of patients had prior chemotherapy in the locally advanced or metastatic setting.

At data cutoff on February 19, 2018, median follow-up was 11 months (range, 0-20) in the brigatinib arm and 9.3 months (range, 0-20.9) in the crizotinib arm, which included 95 (69%) and 59 (43%) patients, respectively, who remained on study treatment.

The first interim analysis included a total of 99 PFS events. The trial met its pre-specified threshold for superiority in the primary endpoint at the first interim analysis: Investigator-assessed median PFS was not reached (95% CI, NR-NR) in the brigatinib arm and 9.2 months (95% CI, 7.4-12.9 months) in the crizotinib arm (estimated 12-month PFS, 67% [95% CI, 56-75] vs 43% [95% CI, 32-53]; HR, 0.45; 95% CI, 0.20-0.68; P = .0001).

Based on treatment with prior chemotherapy in the locally advanced or metastatic setting, those in the brigatinib arm demonstrated superior PFS compared with crizotinib when previously treated with chemotherapy (estimated 12-month PFS, 75% [95% CI, 50-74] vs 48% [95% CI, 28-53]; HR, 0.55; 95% CI, 0.34-0.88), as well as those who were not treated with chemotherapy (estimated 12-month PFS, 63% [95% CI, 50-74] vs 41% [95% CI, 28-53]; HR, 0.55; 95% CI, 0.34-0.88).

PFS rates were consistent across all other subgroups; however, of note, the PFS dataset was more mature among patients with baseline CNS disease than those without (PFS events, 46% vs 26%). “Consequently, this first interim analysis may be preferentially emphasizing drug efficacy differences within the subgroup, when the earliest progression events are occurring,” Camidge added.

Confirmed ORR was 71% (95% CI, 62%-78%) with brigatinib and 60% (95% CI, 51%-68%) with crizotinib (odds ratio [OR], 1.59; 95% CI, 0.96-2.62; P = .0678).

The confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52%-94%) and 29% (95% CI, 11%-52%), respectively (OR, 10.42; 95% CI, 1.90-57.05; P = .0028). When the investigators included any brain metastases at baseline, brigatinib was even more likely to improve intracranial response (67% [95% CI, 51%-81%] vs 17% [95% CI, 8%-31%]; OR, 13; 95% CI, 4.38-38.61; P <.0001).

No new safety concerns were noted. Any grade treatment-emergent adverse events (TEAEs) that occurred with brigatinib compared to crizotinib included increased blood creatine phosphokinase (39% vs 15%), cough (25% vs 16%), hypertension (23% vs 7%), and increased lipase (19% vs 12%).

Grade 3 to 5 TEAEs occurred in 61% of the patients in the brigatinib arm and 55% of the patients in the crizotinib arm. Most common grade 3 or greater TEAEs in the brigatinib arm included increased blood creatine phosphokinase (16%), increased lipase (13%), hypertension (10%), and increased amylase (5%); and for crizotinib were increased alanine aminotransferase (9%), increased aspartate aminotransferase (6%), and increased lipase (5%). Interstitial lung disease/pneumonitis at any time occurred in 4% of patients in the brigatinib arm and 2% in the crizotinib arm.

“Brigatinib represents a promising new first-line treatment option for ALK-positive non-small cell lung cancer,” Camidge added.

In a follow-up discussion, Fiona Blackhall, MD, PhD, a medical oncologist at the Christie NHS Foundation Trust, noted these results may have implications on future randomized studies, for which crizotinib may or may not serve as the control arm.

“In the absence of direct comparisons of next-generation ALK inhibitors, it is going to take some time before we can determine if there is indeed, or if there ever will be, a best ALK inhibitor for our patients,” she added.
  1. Camidge R, Kim HR, Ahn M, et al. Brigatinib vs crizotinib in patients with ALK inhibitor-naïve advanced ALK+ NSCLC: first report of a phase 3 trial (ALTA-1L). Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.03.
  2. Camidge R, Kim HR, Ahn M, et al. Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1810171.

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