Targeted Therapy Resistance Mechanisms in ALK+ NSCLC


Robert C. Doebele, MD, PhD:This patient, who was started on frontline alectinib, had imaging at 12 months that demonstrated disease progression in multiple lung lesions. A biopsy of 1 of these lesions via an interventional radiology CT [computed tomography]—guided technique was sent for testing and, interestingly, showed MET-FISH [fluorescence in situ hybridization] positivity, indicatingMETgene amplification.

I would characterize this patient’s response as somewhat suboptimal. As I mentioned, the progression-free survival on alectinib is typically quoted as somewhere from 26 to 35 months. This is on the short side. Of course, we know that not every patient falls around the median, and we do sometimes see a shorter progression-free survival on these drugs.

We know that all patients will eventually become resistant to an ALK tyrosine kinase inhibitor, and these generally fall into 2 classes of resistance mechanisms: 1, secondary kinase domain mutations; and 2, bypass signaling mechanisms. We’ve become very good at treating secondary kinase domain mutations with newer-generation ALK inhibitors. They’re also very easy to detect on routine sequencing assays.

Bypass signaling has been both harder to detect, in some cases, and also more difficult to treat. In theory, it would typically require the addition of a second drug or a drug that covers bothALKand the new bypass signaling mechanism.

The question of whether to perform a repeat biopsy on patients at disease progression is a controversial one. I’ll start by saying that in terms of necessity for treating with another ALK inhibitor, it’s not necessary. It’s not mandated by any of the guidelines. It’s not part of the FDA approval or label for any of the drugs. However, it can be very informative, and we’re learning more and more about how patients become resistant and which patients respond to which therapies based on what we find on those biopsies. In my practice, we try to routinely do repeat biopsies at progression. We now have a new option, in addition to a biopsy: ctDNA [circulating tumor DNA] testing. This is a blood-based biopsy for which we can determine some mutations off a simple blood draw. I think that has helped us revolutionize how we analyze mechanisms of resistance at progression.

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
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