Future Directions for Precision Medicine in Advanced NSCLC - Episode 6

Updates in the Treatment of ALK+ and ROS1+ NSCLC

Transcript: Benjamin P. Levy, MD: So, let’s move on, for the sake of time, to the next segment which is ALK-rearranged lung cancer. ALK rearrangements are in roughly 3[%] to 5% of all non—small cell adenocarcinoma. It’s a crowded space. We have a lot of drugs that have made their way. We of course have started out with crizotinib from the PROFILE trials showing a benefit over chemotherapy. And we have other drugs, of course, that have now come in—ceritinib, alectinib, brigatinib [Alunbrig], lorlatinib (PF-6463922). We’ll talk about these. Shirish, you want to start out with the alectinib data, and also mention the ceritinib data with ASCEND-4?

Shirish M. Gadgeel, MD: Sure. So, the alectinib data that was presented at ASCO was an update of the ALEX study that was presented at last year’s ASCO [American Society of Clinical Oncology Annual Meeting] and was published in the New England Journal of Medicine. This was a global study, which included patients that were found to be ALK-positive or had ALK-positive tumor based on a centrally tested IHC [immunohistochemistry] test. So that’s how the patients were selected, and they were randomized to alectinib at the standard dose of 600 mg bid versus crizotinib at the standard dose of 250 mg bid. At last year’s ASCO, the median follow-up was about 17 to 18 months, and that showed an improvement in progression-free survival with a hazard ratio of 0.47. That translated into a median progression-free survival of about 11 months with crizotinib, but it had not been reached in patients with alectinib.

At this year’s ASCO, there was a further follow-up of about 27 months—so about 10 extra months of follow-up. And the hazard ratio for progression-free survival actually was a little better now with a hazard ratio of 0.43, and almost a 35-month median progression-free survival in the patients treated with alectinib. So, an impressive almost 3-year median progression-free survival in alectinib patients with the median progression-free survival in crizotinib patients of about 10.9 months.

What was also seen—and again confirmation of the results presented at last year’s ASCO—that patients both with and without CNS [central nervous system] metastasis at baseline had benefit with alectinib or had improved progression-free survival with alectinib. There were no other sort of safety signals. Overall, the patients who received alectinib had somewhat of a better tolerability as compared [with] crizotinib. And so, this not only confirmed the results that were presented and published at last year’s ASCO and then published in the New England Journal of Medicine, but with the longer follow-up now, we basically have a suggestion that the benefit may be even better than what was perceived from last year’s results. We also have another drug that is approved. By the way, based on the ALEX results, alectinib now has been approved in the United States; actually November of last year, for frontline treatment of ALK-positive advanced stage non—small cell lung cancer.

So, another next-generation ALK inhibitor that is being evaluated in the frontline setting was in the ASCEND-4 study. This was actually compared with chemotherapy and like in ALEX study where it was compared with crizotinib, patients with ALK-positive disease were randomized to ceritinib at a standard dose of 750 mg versus chemotherapy—either pemetrexed with either cisplatin or carboplatin. And the primary endpoint was again progression-free survival. It did show an improvement in progression-free survival with a hazard ratio of about 0.55 that translated into median progression-free survival of about 16.6 months with ceritinib and about 10 months with crizotinib.

What was interesting is when data was analyzed based on whether the patients had brain metastases at baseline or not, there was not much difference in the median progression-free survivals between the 2 arms in patients who had baseline CNS metastases. So, it appears that even though ceritinib may provide a better outcome—at least as compared to chemotherapy—that it may not address effectively patients who have baseline CNS metastases. Not to mention the fact that the drug does have some tolerability issues, particularly when it comes to gastrointestinal toxicities. Now, there have been subsequent studies that have shown that if the drug is taken at a lower dose of 450 mg after a meal, that it may be better tolerated. Nonetheless, at the present time, based on the ALEX results, the preference has been for alectinib. And I don’t think ceritinib as yet has officially received approval for frontline treatment.

Benjamin P. Levy, MD: Yes, it’s unfortunate. I think it’s a great drug, ceritinib. The toxicity again seems to be prohibitive. In the context of really good drugs, really effective drugs, they don’t have that same toxicity.

Shirish M. Gadgeel, MD: Correct.

Benjamin P. Levy, MD: Anyone use ceritinib on the panel and have experience with it?

Anne S. Tsao, MD: I don’t use it frontline [therapy].

Benjamin P. Levy, MD: Yes, but have used it.

Anne S. Tsao, MD: I have certainly used it.

Anne S. Tsao, MD: Yes. So, either they do well with it or they don’t. I have had some patients that I’ve started off with the dose of 750 mg. They have done okay, and then I’ve had other patients that I had to dose de-escalate to 600 mg and then to 450 mg with food. But the whole point is that we are sequencing these ALK inhibitors.

Mohammad Jahanzeb, MD, FACP: I’m going to make a little philosophic point that this old drug development paradigm of maximum tolerated dose, has done patients a lot of disservice in this era of targeted therapies. So, they are tested the same way, and this dose of 750 mg was totally unnecessary. Because long before they did the study in 40 patients with food or 3 pills, we know food does promote absorption of TKI, which was not a recently learned fact; that has been known for more than a decade. There is even an editorial in the Journal of Clinical Oncology with Mark Ratain[,MD,] and Ezra Cohen[,MD,] called “[The] Value Meal[: How to Save $1,700 Per Month or More on Lapatinib].” They showed the exact same study with lapatinib [Tyverb] in breast cancer—3 pills with food, Big Mac, fries. That’s why they call it “real value meal.” Then they gave 5 pills to other women on an empty stomach, and the gastrointestinal toxicity is a night and day difference. So, since I started doing that on my own, 3-plus years ago, I have patients on this drug, ceritinib, without any problems.

Benjamin P. Levy, MD: So, you have a fair amount of experience with the reduced dose?

Mohammad Jahanzeb, MD, FACP: Yes.

Anne S. Tsao, MD: And it can be tolerated. I mean, you can create a situation because we have to, right? Because, in time, everybody begins developing resistance to whatever TKI [tyrosine kinase inhibitor] they’re on. And we’re going to have to circulate all of them through all of our patients to get them through.

Shirish M. Gadgeel, MD: I think the practical aspect is though that ALEX was comparing a TKI [with] a TKI, whereas ASCEND-4 was comparing TKI to chemotherapy. And though one suspects that if ceritinib had been compared [with] crizotinib, maybe the efficacy would have been different, but when you have data that shows one TKI being better, I’m not sure that people would necessarily switch away from it.

Transcript Edited for Clarity