Resistance to ALK TKIs


Robert C. Doebele, MD, PhD: When we think about resistance to ALK TKIs [tyrosine kinase inhibitors], we think about several types of resistance. There is primary resistance. We find that very rarely, fortunately. The vast majority of patients who are ALK-fusion positive, especially if they’ve been tested appropriately with a good test and a good evaluation, the primary resistance is quite rare. Meaning there’s no clinical benefit. It sometimes occurs. I don’t think we fully understand why that happens, and I think we also are not able to fully predict which patients are likely to fail up front. As I mentioned, these patients are quite rare.

One situation where we sometimes see primary resistance is in the rare situation of dual oncogene drivers. That’s a situation where the patient may have an ALK gene rearrangement but also an EGFR or KRAS mutation. Fortunately, that’s quite rare. I think for patients who have dual oncogene mutations, we should proceed with caution and close surveillance if we’re going to choose 1 of the other tyrosine kinase inhibitors to treat those patients with, because I think they’re probably the most likely to have primary resistance and early failure of these drugs.

In terms of secondary resistance for ALK-positive disease, we’ve learned a lot over the last decade in terms of how patients become resistant. And although there are subtle variations for different drugs in terms of what types of resistance emerges, I think we can group these into 2 general patterns. Patients become resistant via secondary kinase domain mutations and ALK. For example, the gatekeeper mutation of L1196M or the solvent front mutation at G1202R are very common mutations that we might observe with a number of different ALK inhibitors.

Those are the patients I think that are most likely to benefit from switching to a next-generation ALK inhibitor or different ALK inhibitor. Because they’ve maintained the ALK dependence in their cancer cells, their cancer cells have figured out a way to become resistant to a particular drug.

The second way in which patients become resistant to ALK inhibitors is through a mechanism called bypassing signaling, and that’s very different. In this case patients’ cancer cells often activate other pathways that no longer would be responsive to an ALK inhibitor. Those are both more difficult to detect by modern testing methods, even by NGS [next-generation sequencing], and often more difficult to treat. It might involve switching to a completely different class of drugs or having to combine drugs, and we don’t really have any FDA-approved options for patients who may develop MET, for example, as a mechanism of resistance to alectinib. We may be able to detect it in some cases, but currently there are no FDA-approved options.

In those situations, or if a patient is resistant to alectinib, for example, and we find evidence of MET gene amplification, 1 potential option is to switch them back to crizotinib, or to crizotinib for the first time, because crizotinib inhibits not only the ALK tyrosine kinase but also the MET tyrosine kinase. That’s not necessarily an approved use, but it is an option for our patients. I think that’s still an emerging area of research to better understand not only how to diagnose patients with bypass signaling but then how best to treat them.

For patients who are ALK positive and treated with TKIs, we can often understand how their cancer cells become resistant via biopsy of a progressing lesions. We can do a biopsy of a lung metastasis that’s growing or a liver metastasis that’s growing and do next-generation sequencing to understand if their tumors have acquired a secondary mutation in the ALK kinase domain. That may help us choose the next ALK inhibitor.

We know from many years of both clinical data and laboratory data that we can often predict sensitivity and resistance to different drugs based on the type of resistance mutation that occurs. For example, alectinib can become resistant via an I1171 mutation that may be responsive to ceritinib. You may have a gatekeeper mutation, 1196M, that generates resistance to crizotinib but then becomes sensitive to many of the next-generation inhibitors, including ceritinib, alectinib, and brigatinib.

We know that if you acquire a G1202R mutation, perhaps the best drug is lorlatinib, a newer-generation drug, but brigatinib may have some activity in that setting too. Doing the serial biopsies may help us understand that.

What’s really revolutionized the way we track disease progression in ALK-positive patients are liquid biopsies, or ctDNA [circulating tumor DNA] analyses. Obviously, it’s far less invasive than a tumor biopsy, lower risk, because we’re just drawing blood, which we’re often doing with our patients anyway, often with very short turnaround times of a week. So we can very easily monitor how the disease is progressing at multiple time points. I think that’s an important point. If patients have received multiple prior ALK TKIs, I think sometimes it can be hard to interpret resistance if you haven’t been tracking it all along.

Now having said all this, although ctDNA and liquid biopsy are a very useful way to track disease progression and perhaps select next therapies, I want to emphasize that it’s not FDA approved, and it’s not necessary for any of these drugs to do that.

One of the very important trials that has just activated is the ALK Master Protocol. And this will really help us understand whether it makes sense to choose our drugs based on the type of resistance that’s observed. Initially, this is going to be done by both tumor biopsy and liquid biopsy and will help us understand how well those 2 types of monitoring corollate. Ultimately it will tell us if it makes clinical sense to pick our drugs based on the type of resistance that we’re observing in the tumor, whether that’s done by tumor testing or liquid biopsy.

Transcript Edited for Clarity

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