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Newer ALK Inhibitor Tops Standard in NSCLC

— Significant improvement in PFS with brigatinib after short follow-up

Last Updated October 16, 2018
MedpageToday

TORONTO -- Progression-free survival (PFS) in advanced ALK-positive non-small cell lung cancer (NSCLC) improved by 50% in patients treated with brigatinib (Alunbrig) instead of the current standard of care, early data from the randomized ALTA-1L trial showed.

Median PFS had yet to be reached in patients treated with brigatinib versus a median PFS of 9.8 months among patients treated with crizotinib (Xalkori). Brigatinib-treated patients had a 12-month event-free rate of 67% as compared with 43% with crizotinib.

The brigatinib advantage extended across all prespecified patient subgroups, including an 80% improvement in intracranial PFS in patients who had brain metastases at enrollment, D. Ross Camidge, MD, of the University of Colorado at Aurora, reported here at the .

"The trial design emphasized a real-world setting, permitting patients to enter after being diagnosed by any local ALK-testing methodology, and prior chemotherapy was permitted," said Camidge. "Utilizing a blinded independent review committee, and with a median follow-up of only 9 to 11 months, the study has already met its primary endpoint, with brigatinib reducing the chances of progression or death, compared with crizotinib, by 51%."

"Although PFS favored brigatinib across all subgroups -- and as CNS progression among those with baseline CNS disease may be a very early event -- the relatively short median follow-up time is likely to explain why a greater differential drug effect was seen among those with baseline CNS disease versus those without. Additional follow-up will allow the full differential impact of the two drugs on both early- and later-onset progression events to be assessed."

Invited discussant Fiona Blackhall, MD, PhD, of the University of Manchester in England, agreed with Camidge's conclusion that the results make brigatinib a new first-line option for patients with ALK-positive NSCLC, but said the results also are part of an ongoing story.

At the American Society of Clinical Oncology meeting in June, Camidge reported from the randomized ALEX trial, comparing the ALK inhibitor alectinib (Alecensa) with brigatinib in ALK-positive NSCLC. With a median follow-up of about 2 years, the trial showed an "unprecedented" median PFS of 34.8 months among patients treated with alectinib versus 10.9 months for the crizotinib group, Blackhall noted.

"For ALTA-1L, although the early first interim analysis is highly provocative, the median follow-up is substantially less," she said. "Further follow-up will be needed to determine how close, or whether indeed brigatinib can beat alectinib in progression-free survival."

At this point, no one can say with certainty what is the best ALK inhibitor, Blackhall continued. The growing number of agents in the class also has raised questions about the choice of first-line ALK inhibitor therapy, sequencing of the agents, and the impact of treatment choices on evolution of resistance mutations and mechanisms. For example, a documented resensitization to crizotinib following emergence of a resistance mutation in a patient treated with the investigational ALK inhibitor loratinib.

ALTA-1L involved patients with stage IIIb/IV ALK-positive NSCLC and no prior exposure to ALK inhibitor therapy and no more than one prior line of chemotherapy. Patients were randomized to brigatinib or crizotinib and followed until disease progression, development of unacceptable toxicity, or other reasons for discontinuation. The primary endpoint was PFS, as determined by BIRC. Secondary endpoints included objective response, intracranial response, intracranial PFS, overall survival (OS), safety, and tolerability.

At the first planned interim analysis, a significant PFS advantage had emerged in favor of the brigatinib arm. Data analysis included 275 randomized patients. Camidge said 35 patients who discontinued crizotinib because of disease progression crossed over to brigatinib.

Statistical considerations for the trial included the assumption of a 10-month median PFS in the crizotinib arm, a 6-month median PFS with brigatinib, and a hazard ratio of 0.625. Although neither the upper nor lower limit of median PFS had been reached in the brigatinib arm, the hazard ratio at the interim analysis showed a statistically significant difference (HR 0.49, 95% CI 0.33-0.74, P=0.0007).

A preliminary analysis of overall survival showed no difference in the estimated probability of survival at 1 year (85% with brigatinib, 86% with crizotinib). Camidge noted that survival data remain immature and a definitive survival analysis will be performed after longer follow-up.

Brigatinib demonstrated an advantage in patients previously treated with chemotherapy (HR 0.35, 95% CI 0.14-0.85, P=0.0207) and in those with no prior chemotherapy (HR 0.55, 95% CI 0.34-0.88, P=0.0095).

A total of 81 patients had brain metastases at baseline, and brigatinib treatment was associated with an 80% reduction in the hazard ratio (95% CI 0.09-0.46). The hazard ratio for patients without central nervous system disease at baseline favored brigatinib but did not achieve statistical significance (HR 0.72, 95% CI 0.44-1.18).

The most common adverse events (all grades) in the brigatinib arm were diarrhea (49%), increased creatine phosphokinase (CPK) (39%), nausea (26%), cough (25%), increased aspartate transaminase (AST) (23%), and hypertension (23%). Grade ≥3 adverse events included increased CPK (16%), increased lipase (13%), and hypertension (10%).

In the crizotinib arm, the most common adverse events were nausea (56%), diarrhea (55%), constipation (42%), vomiting (39%), and increased alanine aminotransferase (ALT) (32%). Grade ≥3 adverse events were led by increased ALT (9%), increased AST (6%), and increased lipase (5%).

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ֱ in 2007.

Disclosures

The ALTA-1L trial was supported by Ariad Pharmaceuticals.

Camidge disclosed relationships with AstraZeneca, Takeda, Arrys/Kyn, Genoptix, G1 Therapeutics, Mersana Therapeutics, Roche/Genentech, Ignyta, Daichii Sankyo, Hanso SRC, Bio-Thera DSMB, Lycera, Revolution Med, Orion, Clovis, Celgene, Novartis, and Ariad/Takeda.

Blackhall disclosed relationships with AstraZeneca, Novartis, Pfizer, Amgen, Regeneron, Medivation, AbbVie, Takeda, Roche, CellMedica, Merck Sharp & Dohme, and Boehringer Ingelheim.

Primary Source

World Conference on Lung Cancer

Camidge DR, et al “Brigatinib vs crizotinib in patients with ALK inhibitor-naive advanced ALK+ NSCLC: First report of a phase III trial (ALTA-1L)” WCLC 2018. Abstract PL02.03.