Relapsed ALK-Rearranged NSCLC - Episode 4
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 score20%. 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