Subsequent Lines of Therapy in ALK-rearranged mNSCLC

Balazs Halmos, MD: What do we do with acquired resistance? Do we rebiopsy? Do we retest? We’ve learned so much in this field. We started with the EGFR paradigm, and we’ve learned that retesting can help because some patients will have secondary mutations that can guide us to overcome that resistance with new generation molecules. Some patients will have bypass resistance mechanisms. Some patients will have other types of alterations, ie, small cell transformation. I view retesting as helpful in both treating the patient in front of you and in terms of how we educate ourselves with the next generation of studies in the overall field. I do promote retesting but not blindly for everyone.

Some patients could benefit with what’s called locally ablative therapy, adding radiation to ongoing treatment to a few sites of illness. Maybe the same treatment can continue. In some patients, biopsy is not safe to pursue. Think about CNS [central nervous system] progression; ctDNA is there for us to utilize as well. It’s an additional tool before we perform a tissue biopsy since it seems that the secondary ALK mutations can be detected quite well from ctDNA [circulating tumor DNA]. We want to look at each patient carefully.

What do we do with the information? Realistically, in the field of ALK-translocated lung cancer, lorlatinib in the secondary setting is effective and is realistically the only choice for many of our patients. Many of the paths will converge toward lorlatinib, but there are novel drugs in development, some very potent ALK inhibitors that we could also guide our patients toward. There are definitely treatment alternatives, and we do not want to forget that our conventional tools, such as chemotherapy and radiation, can provide additional benefit to our patients through their treatment continuum.

Lyudmila A. Bazhenova, MD: Even though decisions on what you give to our patients with ALK-rearranged metastatic non–small cell lung cancer are relatively simple—you have to give them ALK TKI—we are still struggling as to what we should tell patients once they progress. The way I approach postprogression therapy in patients with ALK-rearranged lung cancer is very similar to how I approach the issue of oncogenic-driven tumors. First, you need to establish where your patient is progressing. Is it a CNS-only progression? Is it a diffuse systemic progression or localized progression? If it’s a localized progression, such as CNS or a single site, it is appropriate to do local therapy of those parts, such as radiation. However, if your progression is systemic, then we need to switch therapies. Where we are struggling at this point is how to decide the best therapy and the role of postprogression biopsy for those patients.

I personally believe in the benefit of postprogression biopsy. There is a rare occasion where your ALK-rearranged lung cancer can transform into small cell; the treatment will be different, and you can determine the likelihood of response to a third-generation ALK TKI, such as lorlatinib, based on the presence or absence of ALK domain mutation. I currently put all my patients in a clinical trial, which we call ALK master protocol. It’s NRG-LU003.

In that protocol, patients who progressed on ALK TKI will get a postprogression biopsy, and the treatment assignment depends on what was found in the postprogression biopsy. For example, if your patient was found to have a MET amplification, then their appropriate treatment would be crizotinib, which, in addition to having ALK inhibition, also inhibits MET. I believe in doing clinical trials for our patients because that’s how we can improve. We strongly encourage you look at where the nearest site for ALK NRG-LU003 is and refer your patients to that clinical trial.

Jonathan W. Riess, MD: In general, there have been some great advances in targeting ALK-rearranged non–small cell lung cancer, specifically targeting these resistance mechanisms, because alectinib and/or brigatinib as first-line treatment shows great activity. There was also meaningful improvement in PFS [progression-free survival] and OS [overall survival] that we saw in recent updates with alectinib. Invariably, these patients still develop resistance. They still progress. The main, broad overview of resistance mechanisms are histologic transformations, so adeno going to squamous or to neuroendocrine small cell-type histologies.

That happens infrequently, but it happens on target ALK-resistance mutations, bypass tracks, and on-target resistance mutations—as mentioned with ROS1—but even more pertinent to ALK is that we are able to gauge differences in terms of spectrum and frequency by whether it’s crizotinib, alectinib, etc, based on a heat map of ALK resistance mutations to potentially match to other ALK inhibitors that could be successful.

For example, lorlatinib is approved and has activity against some of these resistance mutations that others don’t. There are new drugs in development, such as repotrectinib and others, that may have additional activity beyond that. Lorlatinib is now approved after progression on prior ALK TKI for these patients, with about a third of patients having a good response.

There are also bypass tracks that may not respond as well to a change in direct ALK inhibitors, such as MET amplification; you could potentially go back to crizotinib because it was initially developed not only in ALK but as a MET inhibitor and has some activity there. There’s RAS/RAF and MET kinase alterations, such as KRAS mutations and amplifications that may also signal around ALK. The main one that we are concerned with is the G1202R, which is resistant to many ALK inhibitors. We’re looking at additional clinical trials to try to address that.

Transcript Edited for Clarity