Emerging ALK/ROS1 TKIs for NSCLC

Transcript:David Spigel, MD: The drug development space for helping patients with ALK-rearranged lung cancer has really been expanding over the last years. So, there are many new drugs, or next-generation agents, being developed in this space, and it’s great to see that all of them appear to be very active. This includes patients who have been previously treated not just with drugs like crizotinib, but even next-generation drugs like ceritinib or alectinib.

One of the agents that is not yet approved—but we’ve been seeing data on over the last couple of years at least, and certainly at the World Lung Meeting in Vienna—is brigatinib. This is an agent that has been a little bit behind in its development. It’s considered a next-generation ALK inhibitor, a very potent drug at inhibiting ALK. I have referenced that ceritinib and alectinib are very active agents compared with crizotinib. We know that drugs like ceritinib and alectinib are better because they target ALK in a more specific way, a more effective way, and brigatinib should be viewed the same way. It’s a next-generation drug that is very potent and appears to be more potent than crizotinib. And we don’t have head-to-head studies of brigatinib against crizotinib, but those studies certainly are planned.

Now we have yet a fourth potential agent that’ll come into the treatment of ALK-rearranged lung cancer, initially as an agent following first-line use. So, a drug like ceritinib, alectinib, or even crizotinib in the first-line setting would be an effective therapy. And then, as patients progress, brigatinib potentially would be the next line of therapy. One day, brigatinib will try to get into the first-line setting as well. But I regard this as a fourth, very active agent that appears to be very safe as well, and effective at controlling cancer not only in the body but in the brain.

One of the things to mention about brigatinib though has been a safety profile that is very good, but we watch for something called “pneumonitis.” It’s quite rare, but we want to make sure patients are followed carefully for inflammation of the lungs—not an unusual side effect that we see with other therapies we use in lung cancer these days.

Brigatinib’s mechanism of action’s a little bit different. It’s very potent at targeting ALK. Actually, its structure was originally designed to have an EGFR moiety—so targeting EGFR—but that’s not thought to be a part of its activity. Some people might, in the past, refer to this as a dual ALK EGFR agent, but really, this should be viewed as a classic ALK inhibitor.

So, brigatinib is not yet approved, but the pivotal trials have enrolled, and we are seeing data now emerge that look every bit as good as the data we’ve seen with ceritinib and alectinib in the settings where those drugs got approved. I think we all expect brigatinib to be a new standard of care in ALK-rearranged lung cancer.

Tony Mok, MD: Lorlatinib is actually considered to be the third-generation drug because it has the ability of actually inhibiting of some of the resistant genes, namely the G1202R. At the same time, they also have to be very high quality to penetrate the brain due to the molecular structure. So, those are the 2 benefits that we are looking into for this third-generation TKI. Now, at this moment, they have data coming out from the phase I/II extension study, suggesting the response rates to be good but, again, it’s early. Toxicity wise, apart from some of the standard toxicity, there is also an interesting one where they may have a CNS effect, meaning that it will change the mentality of the patient sometimes, and also some patients may have somnolence as well. This is one of the so-called CNS effects that had been closely evaluated.

Now the drug is actually entering the phase III study of the frontline, lorlatinib compared with crizotinib. So, in other words, there will be a new option of a third-generation drug comparing to the standard first-generation of TKI if this study turns out to be positive. However, this is in the relatively early development of the phase III. I do not have a specific timeline when this study will be completed. Of course, I think the regulation probably will be looking at this particular study as the so-called registrational data.

Transcript Edited for Clarity