Selecting Second-Line Therapy for ALK+ NSCLC

Robert C. Doebele, MD, PhD:Following repeat testing withMETgene amplification identified as a resistance mechanism, this patient was started on crizotinib. She experienced some diarrhea and visual disturbances, which are known adverse effects of this drug. Imaging at 3 and 6 months showed a partial response.

Imaging at 10 months demonstrated both progression in the central nervous system [CNS], with brain metastases, and progression in the lung. A repeat biopsy and genotyping of the lung biopsy demonstrated anALKL1196M mutation.

Our second-line options following alectinib are a bit more limited than our second-line options following crizotinib. Right now, the only FDA-approved drug for post alectinib progression is lorlatinib. However, there are other options. Brigatinib has now been shown in 2 studies to have a response rate of approximately 40% to 50% following alectinib or other second-generation inhibitors.

The choice of crizotinib here is a bit unique and probably is worth discussing a bit. Crizotinib is a first-line inhibitor and would not necessarily be thought of as a great option following alectinib. However, crizotinib has a unique property compared with all the other ALK inhibitors. It also is a very potent MET inhibitor. And so I think the choice of crizotinib in this particular case, because of theMETgene amplification, does make sense, although not obvious based on the indications for these drugs. One downside, of course, of crizotinib in this case is that although it covers bothALKandMET, which is important for this patient, it is not a very good CNS-penetrating inhibitor. As we saw in this case, the patient progressed after a relatively short time, both in the CNS and the lung.

We mentioned earlier that this patient’s PD-L1 status, or PD-L1 TPS [tumor proportion score], was 20%. One question that might come up is, would we consider immunotherapy? Immunotherapy agents have become a very exciting option for a lot of lung cancer patients. However, in this case, I would definitely not use a checkpoint inhibitor, or an immunotherapy. There are multiple reasons for this. First, the patient has a low TPS score—20%. However, it’s important to note that even if this patient had a very high score of 80%, or 90%, or 100%, I would still not use an immunotherapy.

This patient is a never-smoker. Immunotherapies tend to work far less well in never-smokers. Retrospective data and some prospective data also suggest that immunotherapy inALK-positive patients is particularly ineffective, with very low response rates. And so I would not recommend using an immunotherapy in this case.

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