Third-Line TKI Therapy in ALK+ NSCLC

Robert C. Doebele, MD, PhD:Following progression on crizotinib and the identification of anALKL1196M mutation, this patient was initiated on brigatinib at a dosage of 90 mg per day for 1 week. The patient did well during that time, with no respiratory issues, and was dose escalated to 180 mg of brigatinib.

This patient achieved a partial response in both the lung lesions and in the CNS [central nervous system]. She experienced some fatigue but was able to maintain some exercise. Importantly, her response was still ongoing at 16 months.

In thinking about this particular patient with anALKL1196M resistance mutation, she really has several options. Ceritinib, brigatinib, and lorlatinib have all shown in vitro activity againstALKL1196M, and there are clinical data to support the use of those drugs against that particular mutation. And so, any of those would be a reasonable choice.

When thinking about treatment following crizotinib, brigatinib has the longest progression-free survival—approximately 15 to 16 months—whereas ceritinib and alectinib after crizotinib only have progression-free survival rates in the range of about 6 to 8 months. And so I think brigatinib is a very reasonable choice here. This patient has brain metastases. Brigatinib is a very good option for a patient with progression in both the brain and the lungs and has a very long progression-free survival.

We know that brigatinib has good potency across a number ofALKresistance mutations, includingALKL1196M. We know that in the clinical setting, post crizotinib, it has very significant activity in terms of response rate and progression-free survival. Importantly, it also has CNS activity and long progression-free survival specifically related to CNS metastases. That’s now been backed up by multiple trials post crizotinib.

Alectinib and ceritinib both have activity against several crizotinib-resistance mutations. In this particular case, the patient had already received alectinib, so using alectinib again probably doesn’t make much sense. Ceritinib has activity againstALKL1196M, and some mutations that are specific to alectinib, likeALKI1171, so that might be a good option for particularALKmutations. But again, if we just look at the clinical data in terms of progression-free survival and intracranial activity, brigatinib really stands out compared with ceritinib and alectinib as treatment post crizotinib.

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