Brigatinib: 'Very Promising' as First Line for ALK+ Lung Cancer

Pam Harrison

September 26, 2018

TORONTO — New clinical data are "very promising" for another targeted agent for use in the first-line treatment of ALK-positive non–small cell lung cancer (NSCLC), says the lead investigator of a head-to-head comparison trial.

The next-generation ALK-targeting agent brigatinib (Alunbrig, Ariad Pharmaceutical) was clearly superior to crizotinib (Xalkori, Pfizer), the first ALK inhibitor of its kind, in its ability to prolong time to disease progression or death, and it was also better tolerated than crizotinib.

The results, from the ALK in Lung Cancer Trial of Brigatinib in 1st Line (ALTA-1L), were presented here at the 19th World Conference on Lung Cancer (WCLC) and were simultaneously published online in the New England Journal of Medicine.

"When the study was designed, crizotinib was standard of care, and we wanted to see what happens if you try potentially the best-in-class ALK inhibitor against the standard of care in the first-line setting," lead author Ross Camidge, MD, University of Colorado Cancer Center, Aurora, told a press briefing here.

"In this first interim analysis with a very short follow-up, brigatinib reduced the risk of progression or death by 51%, and if you take a landmark [analysis] at 1 year, your chances of not having progressed or died were 67% on brigatinib vs 43% if you were on crizotinib, so this is a very promising first-line therapy," Camidge concluded.

Which Drug to Choose?

The discussant for the study, Fiona Blackhall, MD, PhD, clinical senior lecturer and honorary consultant in medical oncology, Christie Health Service Foundation Trust, Manchester, United Kingdom, noted that there are currently three approved ALK inhibitors for the first-line treatment of ALK-positive advanced NSCL.

They are crizotinib, the first agent in this class, and two second-generation ALK inhibitors, ceritinib (Zykadia, Novartis) and alectinib (Alecensa, Roche).

"Now with brigatinib, we have a fourth inhibitor for first-line use, and the big question we are asking ourselves is, Which do we chose for our patients?" she said.

She reminded the audience of recent data presented on alectinib in the first-line setting. In an updated analysis of the ALEX trial, presented at the annual meeting of the American Society of Clinical Oncology, PFS was 34.8 months for patients with untreated ALK-positive NSCLC who received alectinib regardless of baseline central nervous system (CNS) disease, compared to only 10.9 months for crizotinib. Alectinib was also well tolerated in this updated analysis.

This has prompted investigators to call for alectinib to be the new standard of care for the treatment of advanced ALK-positive NSCLC, as previously reported by Medscape Medical News.

Perhaps initiating treatment with crizotinib and then switching to a next-generation ALK inhibitor on progression is one option that physicians may consider, Blackhall suggested.

"Brigatinib is a new first-line treatment option for patients with ALK-positive lung cancer," Blackhall said.

It is going to take some time before we can determine whether there is indeed — if there ever will be — a best ALK inhibitor. Dr Fiona Blackhall

"But in the absence of direct comparisons of next-generation ALK inhibitors, it is going to take some time before we can determine whether there is indeed — if there ever will be — a best ALK inhibitor," she concluded

Study Details

ALTA-1L was a phase 3 study that compared the safety and efficacy of brigatinib to that of crizotinib in patients with ALK-positive advanced NSCLC who had not previously been treated with an ALK inhibitor.

Overall, 27% of the cohort had received prior chemotherapy, and 29% had baseline brain metastases, Camidge noted.

Patients were assigned to receive either brigatinib (n = 137) or crizotinib (n = 138).

Brigatinib was initiated at a lead-in dose of 90 mg given for 1 week, after which patients received 180 mg once a day.

Crizotinib was given at a standard dose of 250 mg twice a day.

"Of note, the median follow-up at this first interim analysis was 11 and 9.3 months for brigatinib and crizotinib, respectively," Camidge commented.

Even with the short duration of follow-up, "the primary endpoint was met," he added.

At the time of the interim analysis, median progression-free survival (PFS) had not been reached in the brigatinib arm. The median PFS in the crizotinib arm was 9.8 months, for a hazard ratio (HR) of 0.49, which was highly statistically significant (P = .0007), Camidge pointed out.

Brigatinib outperformed crizotinib in almost all subgroups as well, Camidge continued.

For example, among those who had not received previous chemotherapy, brigatinib reduced the risk for disease progression or death by 45% compared to crizotinib (HR, 0.55).

Among those who had received previous chemotherapy, brigatinib was even more effective, reducing the risk for disease progression or death by 65% compared to crizotinib (HR, 0.35; P = .0207).

Most dramatically, the risk for disease progression or death was 73% lower with brigatinib among patients with brain metastases at baseline when compared with crizotinib (HR, 0.27; P < .0001). This suggests that the effect size from brigatinib may be particularly pronounced in patients with CNS disease prior to treatment initiation, Camidge observed.

Safety Profile

Adverse events (AEs) seen in association with crizotinib were dominated by gastrointestinal side effects.

In contrast, the AEs that occurred with brigatinib were dominated by laboratory abnormalities, notably, elevations in liver and pancreatic enzyme levels.

These "paper toxicities" led to protocol-mandated dose reductions in about 20% of brigatinib-treated patients, but patients remained asymptomatic, Camidge stressed.

"Early onset of pneumonitis occurring within days of treatment initiation appears to be a unique side effect of brigatinib," Camidge said, but pneumonitis was rare, occurring at a rate of only 3% in the brigatinib arm.

No clinical cases of pancreatitis were observed in the study overall.

Brigatinib in CNS Disease

Asked by Medscape Medical News about the significance the effect that brigatinib seems to have on CNS disease, Camidge noted that it is likely just a "quirk" of the fact that brain progression occurs earlier than extracranial progression in this particular patient population.

"So with such a short follow-up, you are going to be stacked towards those who are likely to progress in the brain," he said.

Camidge added, "I think this study is almost like a movie trailer, because it is saying, 'Keep watching: something exciting might happen because those [PFS] curves may continue to separate as differences in terms of extracranial control continue to mature.' "

The senior author of the study, Sanjay Popat, MD, consultant medical oncologist at the Royal Marsden Hospital, London, the United Kingdom, agreed. "It will take some time to see what emerges in the mature datasets — this is definitely a marathon, not a sprint," he said in a statement.

The study was supported by Ariad Pharmaceuticals, a subsidiary of Takeda Pharmaceutical. Dr Camidge has received honoraria from Takeda, GI Therapeutics, Mersan Therapeutics, Roche, Genentech, AstraZeneca, Arrys/Kyn, Genoptix, Iggnyta. Daichii Sanko, Hansoh SR< Bio-Thera, Lycera, Revolution Med, Orion, Clovis, Celgene, and Novartis. He has also served as a speaker or on the advisory board for many of those companies and has received research or grant support from Ariad, Takeda, and Pfizer. Dr Blackhall has disclosed no relevant financial relationships.

19th World Conference on Lung Cancer (WCLC). Abstract PL02.03, presented September 25, 2018.

N Engl J Med. Published online September 25, 2018. Full text

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