Next-Generation Agents for ALK-Positive NSCLC - Episode 4
Corey J. Langer, MD: The ALTA II trial was a unique randomized phase II effort evaluating 2 separate doses of brigatinib: a standard dose of 90 mg/daily versus a step-up dose, where individuals started at 90 mg/daily and escalated after 1 week, in the absence of intolerance, to 180 mg/daily. This clinical trial in the setting of crizotinib resistance confirmed the activity of brigatinib—roughly a 45% response rate in the lower-dose group and about 55% in the higher-dose group. PFS was just over 9 months in the lower-dose group in the initial reports and nearly 13 months in the higher-dose group. More recent reports suggest that it may be higher: 1- and 2-year survival rates that look quite promising and seem to be roughly equivalent. Intracranial disease control rates were quite good, in the mid-80% range.
The brain, the CNS, is the sanctuary site in ALK-positive non—small cell disease. Within a year or 2, the vast majority of these individuals will manifest CNS metastases. Brigatinib, like other second or third-generation ALK TKIs, seems to have tremendous penetrance into the CNS, such that we are seeing response rates in measurable tumors, untreated CNS metastases measuring at least a centimeter or more, in the order of 50% to 60%. Particularly in this case, at higher doses of brigatinib, intracranial control rates approach 75% to 80%. So, it’s extremely promising.
We are able, in these individuals, to put off brain radiation—be it stereotactic CyberKnife or more conventional whole brain radiation. Obviously, if someone presents with fulminant CNS involvement and is highly symptomatic with a lot of vasogenic oedema, you need to deal with that individual locally, either surgically or with radiation. In patients who have more indolent progression in the brain or who are relatively asymptomatic with minimal vasogenic oedema, TKIs, like brigatinib, appear to work quite well.
Brigatinib will likely join alectinib and ceritinib as one of our standard second-line agents. For now, crizotinib still has sole FDA approval in the frontline. There may come a time, based on the J-ALEX and global ALEX trials, that alectinib will displace crizotinib. Nevertheless, for the huge cohort of patients who have already been on crizotinib, or have been on crizotinib and then chemotherapy, brigatinib will be one of our go-to agents. In my personal experience, it seems to be as well tolerated as alectinib. I see a lot less muscle cramping and much fewer myalgias with brigatinib. Both of these agents, brigatinib and alectinib, are better tolerated than ceritinib, with far less gastrointestinal toxicity, nausea, vomiting, and diarrhea, which is really one of the bête noires of ceritinib.
A major concern with brigatinib is pulmonary toxicity. If we go back to the ALTA trial, the randomized phase II trial, and the incidence of pulmonary syndrome—which is usually acute onset and involves shortness of breath and, in some cases, hypoxemia or wheezing—about 6%, only 3% total, were grade 3 or worse. All of this happened at the initial dose, not at the 180-mg step-up, so it does not seem to be a dose-related phenomena. At least half of these patients were able to be re-challenged with the use of steroids and actually continue with brigatinib.
Mohammad Jahanzeb, MD: The question is, where does brigatinib fit in? It’s very interesting that we already had 2 agents approved prior to brigatinib, crizotinib, and alectinib. Crizotinib has had gastrointestinal issues at full doses. I actually don’t use a full dose of crizotinib in any patient, anymore. You have to adjust the dose in a vast majority of patients. Alectinib is better tolerated, but it requires 4 pills, twice-a-day. Brigatinib is once-daily dosing, which is more convenient. So, I think it clearly has a role and an advantage in that regard. There’s also a rational dose escalation, where you start at 90 mg for a week and then you up it to the full dose of 180 mg. The other drugs are not built like that. And brigatinib does carry the advantage of having better penetrance in the CNS compared to crizotinib, from a separate study of the trials—there has been no head-to-head comparison in CNS metastases. But from my reading, brigatinib has better penetrance in the central nervous system and a better response rate.
Corey J. Langer, MD: Brigatinib, like the other TKIs in this setting, covers the broad spectrum of ALK mutations, acquired mutations, with IC50s that rival or exceed those seen with either alectinib or ceritinib. Like both of those agents, this is a clear-cut ALK inhibitor, unlike crizotinib, which is actually a very poor ALK inhibitor. It really started out in development as a MET inhibitor.
Shirish Gadgeel, MD: I can start off by saying that the treatment landscape of ALK-positive non—small cell lung cancer is changing quite rapidly. It’s very clear where brigatinib fits in right now, but I think it’s going to be somewhat more challenging to say what the role of the drug will be in 6 months or a year from now. Let me explain why I say that. At the present time, the drug has clearly shown efficacy in patients who were treated with crizotinib and who subsequently had disease progression. In those patients, its efficacy is well established. But in the near future, it is expected that crizotinib may not be the first ALK inhibitor used in patients with advanced ALK-positive non—small cell lung cancer. There is a very good chance drugs such as alectinib or ceritinib would be used as frontline therapy.
We don’t have any data to know what the efficacy of brigatinib will be in patients who were previously treated with a drug like alectinib or ceritinib, rather than crizotinib. Preclinical data suggest that brigatinib is one of the most potent ALK inhibitors, and it appears to have activity against several ALK mutations that can be resistant to many of these next-generation ALK inhibitors. That raises the possibility, at least based on preclinical data, that brigatinib may provide clinical benefit in patients who have been treated with either alectinib or ceritinib. But at this point, that’s just a matter of speculation. So, it is quite possible that practitioners might use brigatinib in that setting.
If alectinib is approved as is expected—ceritinib just got approved as frontline therapy for ALK-positive non—small cell lung cancer, and it is expected that alectinib will also be approved in the near future—my suspicion is that practitioners may treat patients who have been treated with either alectinib or ceritinib in the frontline setting with brigatinib in the second-line setting, though we don’t have clear data. What I can say is that there are studies ongoing, evaluating the efficacy of brigatinib in patients who have been previously treated with alectinib, and such studies will truly define its role.
Transcript Edited for Clarity