Updates in the Management of Lung Cancer Associated Brain Metastases With Targeted Agents

PracticeUpdate: What have been some of the most significant changes in the management of lung cancer associated brain metastases with targeted agents over the past year?

Dr. Ahluwalia: We know that lung cancer is the most common cause of brain metastases. Any large series that you see, 50% of patients with brain metastases have lung origin. Now, we also know that in the last decade or so, that lung cancer is not one disease. Non-small cell lung cancer can be divided into a number of oncogenic-driven mutations, which impact those tumors. There has been a lot of interest in immunotherapy in those tumors, which are not oncogenic-driven.

There have been the targets which are druggable or actionable, like EGFR, ALK, more recently RET, MET and ROS. Then there are the ones which are like KRAS which were felt to be undruggable, but now we have interesting drugs, which are looking promising. Then there's the immunotherapy space where single-agent drugs like pembrolizumab, have response rates in the ballpark of 30%. The combinations with anti-CTLA-4 that have been recently reported, which look exciting as well.

PracticeUpdate: Which key data would you like to highlight for PracticeUpdate users?

Dr. Ahluwalia: I would particularly like to highlight a few abstracts, publications, presentations that have come out in the last year. The one which was very interesting out of the ASCO 2020 and stood out to me was the selpercatinib trial, where intercranial activity of selpercatinib, LOXO-292, which is a drug that targets the RET fusion lung cancer was reported. In this trial, 22 patients who had measurable CNS disease were treated with selpercatinib. We saw very impressive response rates of 82%. Out of which 23%, five of the 18 responses, were complete responses. Partial responses were seen in 59% of the patients. Four of the 22 patients, or 18%, were stable disease. The median duration of response in this patient population was 9.5 months. Very impressive response rates with this new agent, selpercatinib and a fairly durable responses, which are north of 9 months.

This is a great development, and this follows some of the very exciting data that has been generated in oncogenic driven tumors in recent times. Similarly, osimertinib now has become the drug of choice for EGFR-mutant lung cancer patients who frequently have brain metastasis and osimertinib has had response rates, again in the ballpark of 60-70% in upfront disease, making it the drug of choice for patients with newly diagnosed EGFR-mutant lung cancer with brain metastasis.

PracticeUpdate: What other targetable mutations show promise?

Dr. Ahluwalia: The ALK space has been also been very exciting. There has been a lot of data generated. There are numerous drugs, which are FDA approved: alectinib, brigatinib, crizotinib, more recently the lorlatinib, and then the ceritinib. A number of these drugs have had impressive response rates. The first-generation drugs like crizotinib with limited blood-brain barrier penetration, reduce response rates in the ballpark of 20-30%. However, the more recent studies with either ceritinib, brigatinib, and alectinib have shown response rates in the ballpark of 50% to 70%. Lorlatinib has been an exciting drug, as well, which continues to work if patients progressed in the earlier generation ALK inhibitors. I think this space has been very amenable to a drug therapy and drug therapy only, because in the past, patients with brain metastasis were typically not treated by chemotherapy because they had only limited penetration in the brain, and they were mostly managed with radiation or surgery. But now, with these impressive drugs, especially in the ALK space, a lot of these patients are being managed with drug only.