Metastatic NSCLC: Recent Developments on ALK, ROS1, and NTRK - Episode 12

Future of ALK-rearranged mNSCLC


Balazs Halmos, MD: We need to look back and realize that what we’ve achieved in the management of ALK translocation-positive non–small cell lung cancer is magical on a certain level. We just learned a couple of months ago that long-term outcomes on the ALEX study suggest that 5-year overall survival of our patients is more than 50%. The average patient with ALK translocated lung cancer at the time of diagnosis, despite having stage IV disease, can anticipate living at least 5 years. That 5 years is improving as we introduce novel drugs and agents. We’ve achieved a lot, but why not stay greedy and try to achieve more? We need to continue to focus on advancing research. Advancing research in this field can be in terms of learning more about and overcoming acquired resistance with novel agents—matching the alterations, secondary mutations, or bypass mechanisms.

Also, invest in the up-front treatment setting, where the sequencing of agents has been very successful; maybe we could achieve more by combinations up front. There are a number of studies investigating that—combining ALK inhibitors with VEGF inhibition, other targeted agents, MEK inhibitors, etc. The science is definitely expanding to offer us scientifically based alternatives for up-front management.

Lastly, testing in terms of the ctDNA [circulating tumor DNA] platforms now enhances and facilitates patient care. We want to continue to invest in those, not just in terms of understanding molecularly defined subsets but also how we use ctDNA to monitor the progress of the patient. Could we use that as an early surrogate to look for response? Could we monitor a patient in terms of tumor dynamics, with the potential for recurrence after definitive treatment, early stage disease, things of that nature? There’s still a lot to do, but this is a field where we have accomplished a lot, and our patients are doing so much better than in the past. It’s just wonderful to witness and participate in this progress as a team.

Lyudmila A. Bazhenova, MD: The most recent ALK TKI approved is the drug lorlatinib. This is what we call third-generation ALK TKI; this is the medication that has the most evidence of using it after failure of second-generation ALK TKI, such as brigatinib, alectinib, and lorlatinib. In a lorlatinib clinical trial, the overall response rate was approximately 30%. Your response was higher if you had an on-target ALK mutation as a resistant mechanism to previous ALK TKI.

Jonathan W. Riess, MD: In terms of newer developing agents in ALK-rearranged non–small cell lung cancer changing the landscape of treatment, there are a couple of exciting developments on the horizon. Lorlatinib, which is approved after progression of prior ALK TKI, is being studied in the CROWN trial as first-line therapy, so it will be interesting to see those results. It may have some more activity against some of those ALK-resistance mutations that we talked about previously and bring that up to the front line.

It also has some potential adverse effects as well in terms of tolerability in first line. It would be interesting to see how that plays out. Targeting those mutations and bringing it up front could potentially detect and target bypass track mutations, such as MET amplification. We have a trial, and colleagues at UCSF [University of California San Francisco] are looking at MEK inhibition on top of ALK inhibition and targeting bypass tracks as well and then potentially bringing these up front. There are other trials with other ALK inhibitors, such as repotrectinib and others, that are exciting to look at.

The main takeaway is in terms of ROS1, ALK, and NTRK fusion non–small cell lung cancer, we’ve made a tremendous amount of progress where we now can match patients whose tumors harbor these molecular aberrations to highly effective drugs. Some of the principles I look at that we discussed are forestalling and treating CNS [central nervous system] metastatic disease and not doing so in a way where you’re bringing in radiation therapy early on—particularly whole brain—to maximize quality of life and prevent those neurocognitive adverse effects as patients are living, as we start with the updates to the ALEX trial.

Even in the crizotinib arm, median progression-free survival was almost 5 years. At 5 years, 62% of alectinib patients undergoing first-line treatment were still alive. I really want to emphasize those types of things, and the high response rates and activity of these next-generation inhibitors has really changed the landscape of how we treat these oncogene-driven tumors.

Transcript Edited for Clarity