Relapsed ALK-Rearranged NSCLC - Episode 6

Treating NSCLC Patients With a Next-Generation ALK TKI

September 16, 2019

Robert C. Doebele, MD, PhD:Currently, brigatinib is not approved post alectinib. However, there is a rationale and clinical trial data to support the use of brigatinib post alectinib. There were 2 clinical trials presented at ASCO [the American Society of Clinical Oncology Annual Meeting] this year. One that I participated in was brigatinib after any second-generation inhibitor. For that study, which is still ongoing, we presented preliminary results, with a response rate of approximately 40%. There was a second study, somewhat larger, from France, in which patients had to have 2 prior ALK inhibitors, which would include a next-generation inhibitor. In that clinical trial, they showed a similar response rate, slightly better, of approximately 50%. And so, there’s clear rationale from 2 independent trials for the use of brigatinib post alectinib or other second-generation inhibitors in this setting.

Brigatinib, overall, is very well tolerated. It has some similar toxicities and some toxicities. Thinking about the toxicities, in the initial trials of brigatinib, it was observed that patients had shortness of breath and pulmonary toxicities—these transient opacities and shortness of breath that would occur within the first few days or weeks of dosing. In the initial clinical trials, that was estimated at 7%. In later trials, that has decreased to approximately 3%. It’s rare, but it is an important adverse effect to be aware of. That’s what led to the dosing schedule of 90 mg for the first week followed by the 180 mg dose following this. That may have actually led to the decrease in incidence of these pulmonary toxicities. I think the important thing to note is to warn our patients that if they get short of breath, they need to call their doctor and be evaluated. However, if they’re fine during that first week—with the 90-mg dose—they can be escalated to the 180-mg dose with safety.

Other toxicities: There can be CPK [creatine phosphokinase] elevation and muscle aches with this. That’s actually similar to alectinib. There are GI [gastrointestinal] toxicities with almost all the ALK inhibitors, but usually they are quite manageable. As with most tyrosine kinase inhibitors, fatigue is an adverse effect that can occur not only with ALK inhibitors but also with EGFR inhibitors and others.

Specifically regarding the pulmonary events, these have been termed EOPEs, or early-onset pulmonary events. Again, these have been observed at a higher frequency in the early trials when 180 mg was initiated. They were reduced by using the staggered dosing of 90 mg followed by 180 mg. It’s important for physicians, nurses, and patients to be aware that if they become short of breath, they need to call their physician immediately, hold the dose, and be evaluated. This could be a sign of one of these early-onset pulmonary events. The good news is that typically, if they’re not having significant breathing problems, these will resolve within a day or 2, and patients can resume dosing.

Fortunately, patients who areALKpositive can experience a very good quality of life on these therapies compared with older therapies, such as chemotherapy. But even considering different tyrosine kinase inhibitors, one important feature of brigatinib is that it showed not only an improvement of progression-free survival in the early analysis but also an improvement of quality-of-life metrics compared with crizotinib, which is a very well-tolerated drug. I think this is an important thing for patients to understand.

I think most patients and physicians understand that, in general, these tyrosine kinase inhibitors have far better tolerability and can result in an improvement in quality of life compared with chemotherapy. Even thinking about that, brigatinib is more tolerable and leads to a better quality of life than crizotinib—not just improved progression-free survival and, hopefully, overall survival but quality of life, as well.

Transcript edited for clarity.


Case: A 53-Year-Old Woman WithALK-Rearranged NSCLC

  • A 53-year-old woman presented with dyspnea, persistent cough with bloody sputum, and intermittent pain in right side of her chest
  • Relevant PMH:
    • Nonsmoker, had childhood exposure to second-hand smoke
    • No history or presence of pneumonia or bronchitis
    • No history of diabetes, cardiovascular disease, or renal disease
  • PE: lungs, clear; no palpable masses or visible lesions; patient is of average height and weight, appears physically fit
  • Diagnostic workup:
    • Chest X-Ray: revealed multiple small solid lesions in right lung
    • CT with contrast chest/abdomen/pelvis: several hyperattenuated tumors in right lung
    • Biopsy confirmed lung adenocarcinoma
    • Molecular testing:
      • Genetic testing;EGFR, BRAF, RET,KRAS, HER2wild-type,ROS1FISH
      • IHC;ALK-rearrangement
      • PD-L1 TPS; 20%
    • Brain MRI: revealed extensive CNS involvement
  • Treatment:
    • Started on alectinib; achieved partial response
    • Developed fatigue, grade 1 constipation, and nausea; continued treatment
    • Imaging at 12 months showed disease progression
    • Tumor testing of a lung lesions demonstrated MET FISH+
  • She was started on crizotinib
    • Imaging at 3 and 6 months showed a partial response
    • Developed grade 2 diarrhea and visual disturbance; continued treatment
    • Imaging at 10 months showed progression in the CNS lesions and the lung
    • Repeat biopsy of the lung lesions and genotyping showed ALK L1196M mutation
  • She was started on brigatinib at 90 mg once daily; she tolerated therapy well and after 1 week, dose was increased to 180 mg once daily
    • Achieved partial response, including in CNS metastases
    • Had fatigue, but was able to resume some exercise
    • Remains on treatment 16 months later