Next-Generation ALK Inhibitor Prolongs Survival vs Crizotinib in ALK+ NSCLC

Best Practices in Lung Cancer – November 2018 Vol 9 —November 29, 2018

Brigatinib significantly prolonged survival compared with crizotinib (standard of care) as first-line therapy in patients with advanced anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC). Median progression-free survival was not reached in the brigatinib arm versus 9.8 months in the crizotinib arm. At 1 year, 67% of patients in the brigatinib arm were alive versus 43% of those treated with crizotinib.

Median follow-up was 11 months for brigatinib and 9 months for crizotinib. Disease progression or death occurred in 26% of those treated with brigatinib versus 46% of crizotinib-treated patients.

Median progression-free survival was not reached with brigatinib versus 9.8 months with crizotinib, a 51% reduction in the risk of progression or death favoring the next-generation ALK inhibitor (P <.001).

These results from the phase 3 ALTA-1L trial were presented at the IASLC 19th World Conference on Lung Cancer and published simultaneously in The New England Journal of Medicine.

Brigatinib is a promising new treatment for inhibitor-naive ALK-rearranged NSCLC.

“Brigatinib, a next-generation ALK/ROS1 inhibitor with broad clinical activity, is the only ALK inhibitor to demonstrate activity against multiple EGFR-mutant cell lines, and it has central nervous system penetration,” said author D. Ross Camidge, MD, University of Colorado Cancer Center, Aurora, CO. “In this first report of the ALTA-1L trial, brigatinib demonstrated the longest post-crizotinib progression-free survival of any ALK inhibitor in NSCLC.”

Fiona Blackhall, MD, PhD, University of Manchester, UK, formal discussant of this trial, had a more cautious take on where brigatinib would fit in with currently approved ALK inhibitors: “In the absence of randomized comparisons of next-generation ALK inhibitors, it will take some time to determine if there is indeed a best ALK inhibitor for our patients.”

ALTA-1L Description

The head-to-head, randomized ALTA-1L comparison of brigatinib versus crizotinib was conducted at 124 centers in 20 countries. The study enrolled 275 patients with advanced ALK-positive NSCLC not previously treated with an ALK inhibitor. Brain metastasis and up to 1 previous systemic therapy for metastatic disease were allowed.

Patients were randomized 1:1 to crizotinib versus brigatinib and stratified according to presence of central nervous system disease and prior chemotherapy. Treatment was continued until disease progression or unacceptable toxicity. Crossover from crizotinib to brigatinib occurred after progression in 35 patients.

At baseline, treatment arms were well balanced for demographics and disease characteristics. Most patients (93%) were stage IV and had adenocarcinoma (96%). Twenty-nine percent had asymptomatic brain metastases.

Intracranial Response

Subgroup analysis of progression-free survival favored brigatinib for all prespecified groups.

“The effect size for progression-free survival was greater among those with baseline central nervous system disease, with an 80% improvement in intracranial progression-free survival for brigatinib compared with 28% improvement in those without baseline brain metastasis,” Dr Camidge noted.

Estimated 1-year survival was similar with the 2 agents: 86% with crizotinib, 85% with brigatinib. Survival data are immature, and longer follow-up is needed.

Among patients with measurable brain lesions, the rate of confirmed intracranial response was 78% for brigatinib and 29% for crizotinib (P = .0028). In patients with baseline brain metastases, the intracranial response rate was 67% versus 17% (P <.0001).

Median duration of confirmed response was not reached for brigatinib versus 11.1 months for crizotinib. In patients with baseline central nervous system metastasis, the objective response rate was 78% for brigatinib versus 29% for crizotinib.

Treatment-emergent adverse events more common with brigatinib included laboratory abnormalities, or “paper” toxicities, Dr Camidge said. Gastrointestinal effects, bradycardia, peripheral edema, and visual disturbances were more frequently seen with crizotinib.

Grades 3 to 5 treatment-emergent adverse events were reported in 61% of the brigatinib arm and 55% of the crizotinib arm. Pneumonitis occurred in 4% and 2%, respectively.

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