Therapeutic Options at Progression of ALK-Rearranged NSCLC

Corey J. Langer, MD: This patient was treated appropriately with crizotinib. Tremendous radiographic and symptomatic response was observed. It lasted about 9 months, and then the patient developed progressive fatigue and recurrent low-back pain. Interval scanning showed an enlargement of the right-upper-lobe mass, increasing bone metastases. A brain scan showed new intracranial metastases, and this scenario is not unusual. The median progression-free survival for crizotinib in the treatment-naive individual is about 10 months, maybe 11 months, and that has been seen consistently. It has been seen originally in the phase III trial, which was led by Tony Mok and colleagues, comparing it with platinum and pemetrexed. It has been seen in subsequent phase III trials comparing either ceritinib or alectinib with crizotinib. And that 10 months’ figure is remarkably similar across all these trials.

So, for the patient population, even if it’s different ethnicities—whether it’s East Asia, European, or North American—the governing paradigm here is theALKtranslocation. Ethnicity and gender really have very little interplay with median progression-free survival or, for that matter, prognosis. Progression in the brain is not unusual.ALK-positive non—small cell sadly has a propensity for CNS progression, and I think the brain, to some extent, is a sanctuary site. And, certainly, the first-generation agent, crizotinib, does not work as well in the brain as the second- or third-generation drugs do.

Second-line treatments are now available. They’ve been available since about 2012 or 2013. Ceritinib was the first agent approved in this setting. It clearly has superiority compared with chemotherapy in the second-line setting. It also has a fair amount of toxicity, particularly GI toxicity, which can make it a bit of a challenge to manage. The standard dose is 750 mg daily, but many of us start out at 450 mg, or 600 mg at least, in an attempt to mitigate the GI toxicity. In some cases, we can work up. For most individuals, we really can’t. Alectinib was the next agent approved in this setting, again based on very credible phase I and phase II data showing response rates in the 50%, 60%, or 70% range in the second-line setting. Both agents, particularly alectinib, had an inherent advantage over crizotinib in CNS control.

These agents alone, even in the absence of brain irradiation—either whole-brain or stereotactic RT—were shown to stabilize or improve CNS metastases with 30%, 40%, or 50% response rates. And disease-control rates within the brain were far higher. Remember, those who were stable aren’t considered a response, but if the tumor is not progressing within the brain, that would count toward disease control rates. And there, the percentage was 70% to 80%. I would say when we look at anecdotal evidence, cross-trial comparisons, alectinib looks a bit superior to ceritinib. Again, this is my own bias or general impression. There has never been, to my knowledge, a direct head-to-head comparison of alectinib versus ceritinib.

The newest approval since April of 2017 is brigatinib. It, too, has generated response rates in the 50% range in the second-line setting. Median progression-free survival, for a lower dose of 90 mg daily, in a randomized phase II study is about 9.2 months, as good as or better than we had seen with other agents. And for a somewhat higher dose, 90 mg over a week and then a step up to 180 mg daily, median progression-free survival in the initial report was nearly 13 months. And updated reports now point toward about 15 months. So, again, for cross-trial comparisons, you have to be very careful when you do this, but the numbers for brigatinib looked as good as if not better than we’ve seen with either alectinib or ceritinib in this setting. And likewise, we see a high rate of intracranial control, with intracranial response rates approaching 60% to 70% for the higher dose. Disease control rates within the brain in individuals with established CNS metastases are about 75% to 80%.

So, it’s almost an embarrassment of riches. We have 3 separate agents to choose from in this setting. I think based on activity alone, response rates, and PFS, alectinib and brigatinib are probably the preferred approaches, at least in my practice. And lately, I’ve been prescribing brigatinib based in part on the PFS and intracranial control rates.

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