Brigatinib at Disease Progression of ALK-Rearranged NSCLC

Corey J. Langer, MD: In the second-line setting, we have 3 available agents: ceritinib, which was the first approved; alectinib, more recently about 2 years ago; and now as of the early part of 2017, brigatinib. This patient was treated specifically with brigatinib, starting off at 90 mg daily and then escalating to 180 mg after 1 week. There’s a critically important clinical trial called ALTA, which was presented at ASCO in 2016, that looked at 2 different dosing strategies for brigatinib. One is a stable dose of 90 mg daily and then a second arm, looking at a step up from 90 mg, going up to 180 mg daily.

It’s a fairly big trial. A little over 200 patients were accrued. Response rate was numerically higher for the step-up dose, about 54% compared with 45% for the lower dose. Progression-free survival was superior for the higher dose, approaching 13 months compared with just over 9 months for the lower dose. And more recent studies suggest that that PFS may be even better, close to 15 months. CNS response rates were also higher, approaching 70% compared with about 42%. Intracranial progression-free survival was a year or more for both arms, which was quite impressive considering we’re talking about drug treatment alone for CNS involvement. If patients were relatively asymptomatic and had minimal vasogenic edema, I think it’s perfectly reasonable in those individuals to try the TKI first to defer or avoid either whole-brain or stereotactic radiation. We still have that as an option. Obviously, if they’re having significant CNS symptoms or the tumors are surrounded by a lot of vasogenic edema, we really need a radiation strategy. But for an increasing proportion of patients, we can treat these individuals with TKIs alone. Why choose brigatinib ahead of ceritinib, ahead of alectinib? Again, these are all cross-trial comparisons, but the data for brigatinib were clearly good, if not better than we’ve seen with some of the other agents, particularly insofar as PFS and intracranial control are concerned.

The standard approved dose for brigatinib now is 90 mg daily for 1 week with a step-up in the absence of significant toxicity to 180 mg daily. And the data for that are based on the ALTA trial, which frankly, at least numerically, showed superiority for the higher dose and did show somewhat higher toxicity. But for the most part, toxicity was quite manageable. And the majority of patients are able to tolerate that step-up in dose and are able to maintain that stepped-up dose for a protracted period.

Brigatinib, for the most part, is a fairly nontoxic drug. Compared with ceritinib, it has far less GI toxicity. Historically and anecdotally in my own experience, it seems to generate a lot less myalgia and arthralgia compared with alectinib. It does have, however, 1 relatively rare but significant toxicity, and that’s pulmonary toxicity. Up to 6% will develop some acute pulmonary compromise, usually right off the bat within the first week of treatment, frequently within the first couple of days of treatment. In 3% or so, it’s grade 3 or higher. The ALTA trial identified this risk. Intriguingly, this risk was seen just in that first week. It was not seen after the step-up occurred after the second cohort in arm B of the ALTA trial. And at least half these patients were successfully rechallenged with brigatinib usually after a course of steroids. So, it can be acute, sometimes quite alarming, but it’s relatively rare. And, as I said, 50% of patients can be successfully rechallenged.

Of all the toxicities we discussed with brigatinib, the potential for pulmonary toxicity is the one we clearly zero in on. Most of the other toxicities are either rare or readily managed. This toxicity, should it occur, usually manifests within the first few days of treatment. It can occur quite acutely. I make sure that patients have access to both me and my nurses, that they’ve been instructed to report immediately if they have a change in their breathing, if they feel short of breath. If it becomes unmanageable, they need to go to the ER. And we also make sure that the lines of communication are completely open and that steroids are available for these patients. Simply by stopping the drug and going on steroids, for the most part, we can abort this toxicity. And the symptoms generally go away quite quickly, within 24 to 48 hours.

Transcript edited for clarity.

August 2016

• A 51-year-old female presents to her physician with symptoms of fatigue, intermittent chest pain, and lower back pain
• PMH: hypertension managed on a calcium channel blocker; osteoarthritis
• No history of smoking
• CT of the chest showed a 4.5-cm mass in the upper right lobe and enlarged hilar lymph nodes
• Bronchoscopy and transbronchial lung biopsy were performed:
  • Pathology revealed a grade 2 adenocarcinoma, consistent with a lung primary tumor
  • Molecular testing:
    • FISH: positive forALKtranslocation
    • NGS: negative forEGFR, ROS1, RET, BRAF, KRAS
    • IHC: PD-L1 expression in 0% of cells
  • Staging with PET/CT showed¹⁸F-FDG uptake in the lung mass, hilar nodes, and lumbar spine (L4/L5)
  • Brain MRI, negative for intracranial metastases
• The patient was started on therapy with crizotinib
• Follow-up imaging at 3 and 6 months showed marked regression of the lung mass, nodal spread, and bone lesions

June 2017

• After 9 months on crizotinib, the patient reported worsening fatigue and back pain
• CT showed increased size of the pulmonary mass and bone lesions
• Brain MRI showed disseminated small lesions
• Crizotinib was discontinued and the patient was started on brigatinib