Treatment of Newly Diagnosed ALK-Rearranged NSCLC

Corey J. Langer, MD: The prognosis for patients with oncogenic drivers, for the most part, is better than for patients who have wild-type tumors. A patient with anALKrearrangement on crizotinib or 1 of the newer agents, ceritinib or alectinib, can expect to have a progression-free interval minimum of 8 to 10 months with frontline therapy; the newer agents can approach 2 years or more. And their overall survival, median survival, is in the range of 3 to 4 years, and there are clearly some patients who are alive now a decade after diagnosis. And this is despite having metastatic cancer. So, in general, the prognosis—certainly the median survival—is 2- to 3-fold higher than we typically observe in wild-type non—small cell lung cancer in an individual who does not have an oncogenic driver.

              

Up until 2016, crizotinib was the standard approach in this sort of patient. In fact, it was the only approach. We had credible prospective, randomized phase III trials that showed a clear-cut response in PFS advantage compared with standard platinum doublet chemotherapy in this setting. More recently, ceritinib has shown a similar, even more profound, advantage compared with standard chemotherapy with median progression-free survival not 10 or 11 months but 16 months or more. And last year, 2016, at ASCO, and now this year at ASCO 2017, we’ve seen 2 separate trials showing a profound advantage for alectinib, another second- or third-generation TKI targetingALK, compared with crizotinib. So, I think those studies will ultimately lead to a formal approval for alectinib in this setting. Currently, it is not yet FDA approved, at least as of mid-July 2017, but I’m speculating here. I suspect in the next month, 2 months, or 3 months, that approval will be forthcoming, and the data are really quite impressive.

              

In the J-ALEX trial, which compared alectinib with crizotinib in treatment-naïveALK-positive non—small cell, the median progression-free survival for alectinib had not even been reached. The lower end of the confidence intervals was more than 20 months compared with fairly standard 10 months or so for crizotinib. Response rates were at least as good. Intracranial response and progression-free survival was clearly superior for alectinib, and toxicity was less. So, on every point and every objective of that trial, alectinib was superior to crizotinib.

And this year at ASCO in June of 2017, we saw a similar trial, Global ALEX—essentially the same design, although the dose of alectinib was higher; it was 600 mg twice daily instead of the Japanese dose at 300 BID—with essentially the same outcome measures. Median progression-free survival was at least 25 months compared with 10 months for crizotinib. Response rates were again edging out crizotinib, although I don’t believe the differences were statistically significant there. Again, we were starting off with a response rate of over 70% and inching up to 80%—far less toxicity, significantly less toxicity overall. Intracranial progression-free survival was far superior. The chance of having brain metastases in the control arm was about 40% or so for crizotinib. It dropped to less than 10% for alectinib.

              

So, the new-generation TKIs—and this applies not just to alectinib but also to ceritinib and to brigatinib and to other agents—actually have a protective effect on the CNS. And at the end of the day, CNS progression unfortunately is often the terminal event that occurs in these patients. We’ll often observe excellent extracranial control, but the CNS is the site where the disease ultimately progresses and can spell the patient’s demise.

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