Next-Generation Agents for ALK-Positive NSCLC - Episode 5

Repeat Mutation Testing at ALK-Rearranged NSCLC Progression


Shirish Gadgeel, MD: The activity of each of the next-generation ALK inhibitors was assessed in patients who were previously treated with crizotinib and had relapsed disease. In the studies that determined the activity of these drugs, ALK mutation testing was not performed, and so they demonstrated activity irrespective of such testing. As patients progress on the next-generation ALK inhibitors, it appears that one of the major mechanisms of resistance is the development of ALK mutations or ALK amplifications. This tends to occur, based on available data, in about 50% of patients, whereas ALK mutations or ALK amplification, as a resistance following crizotinib, appears to occur in about a third of patients.

As we use more and more of the next-generation ALK inhibitors, such as alectinib and ceritinib, both in the second-line setting as well as in the frontline setting, it is expected that a major mechanism of resistance will be ALK mutations. There are drugs available that can target these mutations and thus provide clinical benefit, and one such drug is lorlatinib, which has activity against a broad spectrum of ALK mutations.

And so, what is expected as we use more and more of these next-generation ALK inhibitors is that we will profile patients’ tumors to define the mechanism of resistance. If the patient’s tumor has ALK mutations or ALK amplification, we are much more likely to treat the patient with another ALK inhibitor, such as lorlatinib, because it is expected that those are the patients who will derive benefit. In patients whose tumors don’t have ALK mutation or ALK amplification as the mechanism of resistance, those patients may not benefit from another ALK inhibitor such as lorlatinib. We might choose another treatment regimen such as chemotherapy.

Even though, right now, we are not routinely doing ALK mutation testing as standard of practice at disease progression following crizotinib, as we use next-generation ALK inhibitors, we will start doing more and more of the ALK mutation testing. That is more of a common mechanism of resistance following those drugs as compared to crizotinib.

Now, I’ll move on to liquid biopsies. It is somewhat challenging to assess ALK translocations or ALK amplifications, but assessing ALK mutations is relatively easy in liquid biopsies. Liquid biopsies are clearly a much easier way of defining the molecular features of a tumor, rather than actually performing a tumor biopsy. And so, it’s quite possible that in the future, following a progression of disease on one of these next-generation ALK inhibitors, we would do liquid biopsies and attempt to define the mechanism of resistance. That might be used to determine what the next treatment is.

As is the case in patients with EGFR mutations, it is important to note that if a specific mechanism of resistance is not identified in liquid biopsy, a tumor biopsy may still be required. So, I do believe liquid biopsies will play a role in the future as we do more and more assessing of molecular mechanisms of resistance in the tumor. But at the present time, we really are moving from crizotinib to a next-generation ALK inhibitor without defining the mechanism of resistance.

Transcript Edited for Clarity