Future Directions for ALK+ NSCLC

Transcript:Alice Shaw, MD, PhD: Brigatinib is another second-generation inhibitor. This class—alectinib, ceritinib, brigatinib—was developed around the same time, and they were all developed really as more potent ALK inhibitors. At the time they were developed, it wasn’t realized how brain penetrable they would be, but, in fact, particularly alectinib and brigatinib turned out to have very potent CNS activity. The third-generation class, which includes lorlatinib, the reason we separate that out is because lorlatinib really was designed to overcome all the resistance mutations and was actually designed to be very CNS penetrable as well. And so, that’s why that one is considered more of a third-generation inhibitor.

We anticipate that brigatinib—which has now been tested in phase I and II studies, in crizotinib-resistant patients—will actually gain accelerated approval for crizotinib-resistant patients in the United States this spring. And that will be yet another option for ALK-positive patients who relapse on crizotinib. The efficacy data with brigatinib look very good in crizotinib-resistant patients. And, again, we can only do cross-trial comparisons because there are no head-to-head trials comparing second-generation inhibitors to each other. But in the single arm trials of brigatinib, the efficacy was very high in terms of the response rate. And the median progression-free survival in the phase I setting was beyond 12 months, which is longer than what we saw for either ceritinib or alectinib.

So, brigatinib is very exciting from that standpoint. I would say the main concern about brigatinib has to do with a very unusual side effect that this particular ALK inhibitor has, which is early pulmonary toxicity. And this was first reported in the phase I study, but actually has been seen in the phase II as well, where patients can have a pulmonary reaction to even a single dose of brigatinib. They can develop mild symptoms—mild cough or mild shortness of breath—but they could also develop more significant symptoms, even respiratory failure. And so, we don’t understand very much about who’s at risk for developing this unusual or rare side effect, but it can be very significant and it can even be life-threatening. I would say that’s the main issue of concern with brigatinib, that there is a pulmonary toxicity reaction that happens very early. It’s a small percentage of patients, but we don’t yet know which patients are most at risk for that.

Lorlatinib is a third-generation inhibitor. It has been developed to target all of the known resistance mutations, including G12O2R, and also to penetrate into the brain at high levels. Lorlatinib has shown very impressive activity in patients who have already failed multiple ALK inhibitors. I think what’s particularly exciting though is looking at lorlatinib in the first-line setting, so there will be a randomized phase III trial comparing lorlatinib versus crizotinib in advanced ALK-positive lung cancer. I should also mention that some of the other ALK inhibitors like brigatinib—also another one called ensartinib—will also all be compared to crizotinib in the first-line setting.

David Spigel, MD: When you have very active agents such as the TKIs in the ALK treatment space, one of the questions that has come up is, could you combine these drugs with other more classic agents used in the treatment of lung cancer—so things like chemotherapy? And actually, the bigger story right now is with immunotherapy. In short, we don’t know. Immunotherapy and ALK TKI combination studies are in progress. They’re very early in development. We don’t expect any overlapping toxicity—perhaps pneumonitis, a side effect we sometimes see with immune checkpoint inhibitors—although it’s important to reference that with brigatinib, that could be a potential overlapping toxicity. But whether it makes sense to even add anything to an ALK inhibitor really is a question we don’t have an answer to.

We have to remember these drugs are quite active. They’re quite effective at inducing responses, maintaining durable responses, long-term control of patients, but also temper that with the fact that we’re not curing patients. And so, we do need better therapies. But should that be as a combination approach where the side effect profile could go up? Or should it be in sequence? Should a patient, for example, receive a very effective TKI, maybe 2 or 3 in a row, and then move on to a strategy where they get immunotherapy, chemotherapy, or the combination? Those are the kind of studies that are being designed now.

Tony Mok, MD: ALK was only discovered in 2007. We actually have multiple agents on hand that actually may improve the efficacy for the patients. In other words, the patients may go on one TKI and then possibly another one; just using so-called tyrosine kinase inhibitor alone to have a rather prolonged duration of control. Now, of course, we still are facing a lot of difficulty with the brain metastases. However, I think they’re hopeful that in the future, we’re going to have new agents that can also control the CNS very effectively. So, overall, I’m very much encouraged by this discovery, and also it has a full impact on the patient with the ALK-transformed lung cancer.

Transcript Edited for Clarity