Emerging Targets in NSCLC Treatment

Transcript:Mark A Socinski, MD: One class of drugs that has had some level of interest in the ALK population, other than the tyrosine kinase inhibitors, has been the Hsp90 inhibitors. All proteins, for their confirmation to be effective, require a scaffolding effect, and that’s what Hsp90 is. So, when you inhibit the scaffold that holds together the protein in its functional capacity, the protein becomes nonfunctional. All of these oncogenic drivers require Hsp90 for their function. But one of the ones that seems to be most sensitive is the ALK oncoprotein, and some of the initial trials noted quite a high response rate with several Hsp90 inhibitors. And it was pretty consistent across the data with ganetespib—data with AUY922, and other Hsp90 inhibitors—that in the ALK population you see objective responses that are actually quite notable. The Hsp90 inhibitors are a class of drugs that have not yet been successful in an FDA-approval strategy. I think the interest in these agents somewhat dissipated with the increasing numbers of tyrosine kinase inhibitors—alectinib, brigatinib, ceritinib, and those sorts of drugs.

There are some data combining Hsp90 inhibitors with ALK inhibitors. These data are very early. We don’t have a good read on it yet, but that’s one strategy where perhaps the combination of an ALK inhibitor in refractory disease would be a viable strategy. I would also think that if I had an ALK patient who was refractory to a series of tyrosine kinase inhibitors, I might look for a clinical trial with an Hsp90 inhibitor to enroll that patient in. So that’s something that I would think about in an ALK-positive patient.

The age of immunotherapy is upon us. We have FDA-approved options for patients right now. One of the interesting observations about immunotherapy is that there seems to be a link between the effectiveness of immunotherapy and the mutational load we see in the cancer. If you look at mutational load in all cancers, the two highest ones are melanoma and lung cancer. That’s where immunotherapy has been successful. So there’s a suggestion that the more mutations you have, the more neoantigens you may have, the more immunogenic your tumor may be, and the more successful immunotherapy may be.

Now, let’s look at the other end of the spectrum. It’s very clear that never-smokers, which comprise the population of EGFR-mutants, ALK-positive patients, and those sorts of things, have a much lower mutational load. And I must admit, the early data, not so much in ALK-positive patients but in EGFR mutation—positive patients, when you look at the differential benefit from immunotherapy versus standard chemotherapy, there really isn’t an incremental benefit, suggesting that immunotherapeutic agents may not be any more effective than standard chemotherapy. They may be better tolerated, but they aren’t more effective.

Whereas if you look at patients with a smoking history or a higher mutational load, there’s a clear advantage of the immunotherapeutic agents over standard chemotherapy. That brings us to, what role is immunotherapy going to play in the oncogenic driver subset, such as EGFR mutations, ALK translocations, ROS1? How should we combine them with the available TKIs? I think these are important research questions, but I think many of us have a much, much more cautious level of optimism than that the immunotherapeutic agents are going to be home-run for these populations of patients. The data are very early. The data are not completely compelling that immunotherapy is going to be a home-run for these patients, but it may be that during the life cycle of the tumor, that changes within the tumor allow it to be more immunogenic and immunotherapy may be an option either by itself or in combination with TKIs.

There have actually been very little data presented to date on the combinations in the oncogenic driver subsets of patients. So we have to draw our initial impressions from the phase III data, such as the CheckMate trials. In CheckMate-057, the never-smokers and EGFR-mutants really didn’t have a benefit relative to docetaxel. So I think many of us are a little cautious about what role these agents may play, either as monotherapy or in combination in the oncogenic driver subsets.

Alice T. Shaw, MD, PhD: There’s a lot of excitement about potential combinations of ALK inhibitors with immunotherapies, with the hopes that we may be able to induce even longer remissions for patients by incorporating an immunotherapy into their regimen. I think it’s too early to know. These trials have just started. These are all phase I trials, and there are a number of them. Ceritinib and nivolumab are being combined in a phase I study. Alectinib and atezolizumab are also being combined in a phase I study, and the newest ALK inhibitor, lorlatinib, is also being combined with a PD-L1 inhibitor.

So, there are a number of approaches to trying to combine ALK TKIs with immunotherapies. We don’t yet know how active these combinations will be, if they really will make a difference. But I think there is that potential concern for toxicity with these combinations. We’ve already heard about potential increased pneumonitis with the combination of EGFR inhibitors with checkpoint inhibitors. So, with these phase I trials now launching of ALK inhibitors and immunotherapies, we’re really going to be on the lookout for any increased or unexpected toxicities.

Transcript Edited for Clarity