Future Directions for Precision Medicine in Advanced NSCLC - Episode 7

Practice-Changing Frontline Treatment of ALK+ NSCLC

Transcript: Benjamin P. Levy, MD: So, I think we can all agree that alectinib [Alecensa], for now, is our treatment of choice for treatment-naïve, ALK-rearranged adenocarcinoma. But we have some emerging data with another next-generation ALK tyrosine kinase inhibitor [TKI], brigatinib. We’ll have some data presented here at World Lung 2018 in Toronto. Lyudmila, do you want to talk to us about this potentially practice-changing data that we’re going to be seeing soon?

Lyudmila A. Bazhenova, MD: Sure. First a little background on brigatinib. So brigatinib is an ALK tyrosine kinase inhibitor that was first approved for patients who have failed crizotinib. And that was based on a study called ALTA. The ALTA study was a randomized study, which compared 2 doses of brigatinib, 90 mg continued versus 90 mg for 1 week, followed by dose escalation to 180 mg. The reason for dose escalation in that study was that 180 mg had a better CNS [central nervous system] penetration, and we were hoping to see improvement in progression-free survival [PFS] systemically, as well as improvement in CNS control. The ALTA study was presented in 2017, and it showed the response rate in 90-mg lead-in dose followed by 180 mg was 55% compared [with] 46% in just 90 mg dose. The updated progression-free survival for post-crizotinib patients is about 15.6 months. This is the longest reported progression-free survival across all other ALK inhibitors used in the same setting. The CNS response rate was 67%, so we know the drug definitely has a good CNS penetration, and then progression-free survival in a CNS was 18.4 months.

Based on our experience with brigatinib, in the phase I dose escalation study where 8 patients were crizotinib-naïve were treated with brigatinib which showed [a] response rate of 100% and progression-free survival, which is a pretty mature data set—to this point is slightly over 30 months. So that led to the design of the ALTA-1L trial which is a head-to-head comparison—very similar to what we just discussed, the ALEX trial—of patients randomized to crizotinib versus brigatinib. We have some early data on the study. We do not have median progression-free survival yet. Certainly, the study data set is not as mature as the ALEX data set, but it did show that at 1 year, the response rates were very similar—71% with brigatinib and 60% with crizotinib. The 12-month progression-free survival with brigatinib was 67% and with crizotinib it was 43%. So at least based on the progression-free survival, brigatinib appears to be better than crizotinib.

When you go and compare, again, with the ALEX trial, we do have the median PFS already reported. With brigatinib with the ALTA-1L trial, we don’t. But, if you do the cross-trial comparison, if you look at the mark on the ALEX trial which at 12 months—again just looking at the Kaplan-Meier curves—appears to be very similar; about 67[%] to 70%. So, I think this could emerge as a potential alternative strategy or additional strategy for patients who are newly diagnosed ALK-mutant non—small cell lung cancer, similar to what we have just heard about alectinib.

Shirish M. Gadgeel, MD: I think I would just also like to highlight a couple of other points including the study entry criteria. This study did allow if a patient had received chemotherapy, to go on. Because, yes, as we know, especially in the past, there were some patients who were started on chemotherapy and only after that, you realized that the patient had ALK-positive disease. And this was locally tested, so this was not centrally confirmed. Actually I view that as the strength of the study because I think it reflects real-world settings, maybe a little more closely than the ALEX trial did, where it was an essentially tested ALK test. And so probably the cleaner dataset, but nonetheless, maybe a little more practical, I think, in the ALTA-1L study.

Anne S. Tsao, MD: I actually am a big fan of brigatinib, because preclinically it looks like it targets many of the resistant mutations that we’re beginning to see from alectinib failure, crizotinib failure, ceritinib failure. And so, although this was a frontline trial, again, it’s not compared [with] another ALK TKI [tyrosine kinase inhibitor]. I can see a lot of patients who are on alectinib now that will go on to brigatinib. I see that very clearly in clinical practice.

Shirish M. Gadgeel, MD: But I would also say, at least for me—and yes, the median follow-up is much shorter here than ALEX—based on these results, I don’t feel that one has to necessarily switch now to brigatinib. It becomes another option. It is possible that with longer follow-up, the efficacy in patients receiving brigatinib may be even better. But at the present time it looks like these results are very similar to ALEX.

Benjamin P. Levy, MD: Okay, so we’ve talked about not doing cross-trial comparisons, but we do them because we don’t view this data in silos. We have the frontline data, as you’ve gone over, suggesting that the outcomes may be similar. We need longer follow-up, as we saw in ALEX. And we’ve seen in the crizotinib-refractory setting, that brigatinib has one of the longest progression-free survivals that we’ve seen. Does this cement brigatinib as a bona fide first-line [treatment] for patients with treatment-naïve ALK-rearranged lung cancer?

Lyudmila A. Bazhenova, MD: I think it is one of the options, assuming an FDA approval. If you look at, again, the cross-trial comparisons, the numbers of alectinib and brigatinib are very similar in 12-month PFS, and in hazard ratio. Toxicities are slightly different. So, we’ve talked about the fact that we have ceritinib, we have alectinib, and hopefully in the future, we might have brigatinib. Ceritinib has all the gastrointestinal toxicities as we just described. Alectinib is well-tolerated. Brigatinib isn’t generally well-tolerated. You do have to be aware of acute onset pulmonary events which happens within the first couple of days after you start the drug. They are usually very minor, and they’re reversible with drug holds and you can re-challenge the patient if acute onset pulmonary event was not severe.

I think based on the preclinical data, what Anne just mentioned, that it does cover the 1202R, which is one of the resistant mutations post crizotinib. And there’s the longest PFS on a cross-trial comparison. It might emerge in a cross-trial comparison as a better option than alectinib, but I think we need to see that. Right now, to me those 2 drugs I would consider as one of the 2 options. And it’s, what you have experience with. I’ve had all the experiences with the drug brigatinib. I’m very comfortable with the drug.

Anne S. Tsao, MD: So, I do agree that it’s a viable choice. For right now in my practice I’m going to be giving alectinib and saving brigatinib because of what we know right now about resistance mechanisms. And it’s dirty with the resistance mechanisms. We don’t have a lot of data about it. And so, this could very well change as we get more data on brigatinib resistance and how these patients do.

I do want to put a quick plug in for the ALK master protocol, which is designed to specifically address this sequencing issue about ALK TKIs. The ALK master protocol should hopefully be opening soon nationwide.

Transcript Edited for Clarity