Next-Generation Agents for ALK-Positive NSCLC - Episode 6

Treatment of Relapsed/Refractory ALK+ NSCLC


Mohammad Jahanzeb, MD: The question is, how do we sequence these drugs when the resistance develops? We have the luxury to access 3 compounds in the second-line setting. I would basically talk about ALK, because for ROS1, we have had approval for crizotinib, but not for these other drugs yet. So, I would biopsy the patient and see what type of resistance has emerged. It’s heartening to know that brigatinib covers multiple resistance mutations. So, it’s a very attractive drug to use in patients who have progressed on crizotinib.

In fact, the randomized ALTA study, which was a randomized phase II study of brigatinib for crizotinib failures that led to its approval, shows very impressive activity—actually, a progression-free survival in the higher-dose arm up to 15 months, which is unprecedented. So, I think that it’s going to be a very promising drug. It’s going to be a matter of trial and error in some patients, because patients with ALK mutations are not like patients with EGFR mutations, where half of their resistance is due to T790M. Here, you have a smattering of different mechanisms; there’s no single predominant mechanism. They could have ALK amplification or they could have a resistance mutation. Or they could have path reactivation. So, in that regard, I think it’s comforting to know that it covers multiple resistance mutations.

The question is, how do you choose between the 3 agents—crizotinib, alectinib, and brigatinib—with a pattern of relapse including CNS metastases? In the case of CNS metastases, you obviously would want drugs that have excellent penetrance into the CNS, and in my view, alectinib and brigatinib have better penetrance. Among those 2, you could go either way. Alectinib is multiple pills—4 pills, to be exact—twice a day. Brigatinib is once a day. That could dictate whether you go for one or the other. It is also something that you may base on your biopsy and resistance pattern mutation. So, I think those factors go into decision making for a physician, as well as what drugs you have access to, what you can get more easily for the patient, etc. A lot of considerations go into that, and you individualize your decision.

The question is, how do we select among the 3 agents in the second-line setting based on their toxicity profile dosing schedule, etc? I already alluded to excessive gastrointestinal toxicity in full doses of ceritinib. That’s where lower doses with food are now being studied before the FDA label can be amended. I think it’s a huge advantage to have a drug once a day versus twice a day in the case of ceritinib and brigatinib, where alectinib is the twice-a-day option.

A lot of my patients who previously took crizotinib in the first-line setting twice a day said it becomes a production: “I take my nausea pill, then I take the drug, then I eat something, and the whole exercise takes 2 to 3 hours, and I have to do this exercise twice a day. It takes half of my day to be compliant with this medication.” So, in that regard, drugs that are better tolerated, have less gastrointestinal side effects, and are taken once a day are preferable over other options. I think that’s what really is important to the patient and the prescribing physician.

Corey J. Langer, MD: It’s a very difficult decision on which second-line agent to use. Alectinib has really displaced ceritinib, at least up until the spring or summer of 2017, when it comes to a standard second-line agent. Brigatinib, in my opinion, looks as good, if not superior, to ceritinib—at least in the second-line setting in individuals whose disease has progressed on crizotinib. If we look just at PFS, the data are just as good, maybe a little bit better for 90 mg stepped up to 180 mg. The CNS penetrance seems to be equivalent. The toxicities are generally equivalent. I tend to see a bit more myalgias and fatigue with alectinib, and of course, we’re a bit more concerned about pulmonary toxicity with brigatinib. But we’re not seeing the degree of myalgias and fatigue with brigatinib that I’ve observed with alectinib. It’s a very tough decision, brigatinib and alectinib. It really depends on very nuanced factors, within each individual patient, in terms of which agent to use. One additional advantage, at least for brigatinib, is the schedule. Unlike alectinib, it’s once-daily. Alectinib, of course, is twice-daily. Both of these agents have a major advantage over ceritinib, which features a lot more in the way of gastrointestinal toxicity.

Shirish Gadgeel, MD: Ceritinib does have activity in patients with ROS1 mutations, but brigatinib and alectinib, as best as I know, do not have activity in ROS-positive patients. I know alectinib does not have ROS1 activity, but I’m not certain about brigatinib. Ceritinib is not a very effective ROS1 inhibitor, and the likelihood is that it won’t be a major drug utilized for the management of patients with ROS1 mutations. As far as selecting between these 3 drugs, I think we can approach this in 2 different settings. One is, of course, in patients who have previously received crizotinib and have developed disease progression. And the other clinical setting is choosing one of these drugs as frontline therapy.

If we look at the clinical setting where patients have received crizotinib and, subsequently, developed disease progression, as far as efficacy is concerned, the overall response rates with each of these drugs appear very similar. The only standout feature, as far as efficacy is concerned, is that the median progression-free survival of brigatinib was the longest at 15.6 months, whereas the median progression-free survival with alectinib is in the range of 8 months. With ceritinib, it is in the range of 6 to 7 months. Now, these are cross-trial comparisons, and they have to be viewed with a level of caution, but that’s the only measure of efficacy that does stand out among the 3 drugs. If we just went based on efficacy, one may consider brigatinib as the preferred agent, but we do not have a head-to-head comparison.

The mutation profile targeted by each of these drugs does appear to be different in preclinical studies, but the relevance of that in managing patients who have been treated with crizotinib and, subsequently, developed disease progression is unclear. It is possible that in the future, for specific mutations, a specific drug may be chosen for patients who have progressed after crizotinib, but we don’t have those data.

As far as frontline treatment is concerned, each of these drugs appears to be an extremely potent ALK inhibitor, and each of these drugs appears to have activity in the CNS. At the present time, I don’t think one can determine which particular drug to use as frontline therapy. We also have to consider another drug called lorlatinib, which is not yet approved, but we do have clinical data on it. It does appear to have the broadest mutation activity as compared to the other 3 drugs. And so, it is unclear, when that drug becomes available, what role each of these drugs will have. This is an evolving field. I can summarize by saying that, at the present time, we don’t determine which drug to use based on mutation profile, but do so much more on tolerability and efficacy.

Transcript Edited for Clarity