Practice Changing Trials in Advanced Non-Small Cell Lung Cancer - Episode 14

New Standard of Care for ALK-Rearranged NSCLC


Benjamin P. Levy, MD: Let’s move on to our last section, another genotype where we’ve witnessed practice-changing data over the past 1 to 2 years with ALK-rearranged lung cancer. ALK rearrangements occur in roughly 3% to 5% of the patient population. Interestingly in one study, if you look at the patients under the age of 40, that prevalence goes up quite high. But we’ve, again, seen some practice-changing data coming out. Obviously, the ALEX trial has altered the way that we treat these patients. Suresh, do you want to walk us through the ALEX trial, what it showed and how you view the data?

Suresh S. Ramalingam, MD: Sure. Let me start by saying that as you introduced the topic, seeing how quickly the landscape has moved has been fascinating. This is a small subset of lung cancer. It was not even known until the year 2007 that it existed. Now we have 4 approved therapies for this patient population. Crizotinib was the first drug to get into this space. We know that it has a median PFS of about 10 months. Response rate is about 70%, and patients often end up progressing in the brain when you give them crizotinib therapy.

Now, we have a new frontline therapy approach, alectinib, which is a second-generation, more potent ALK inhibitor that also has a better activity in the brain. There have been 2 randomized clinical trials. One is the J-ALEX conducted in Japan. And then the ALEX was just conducted in the rest of the world. And the ALEX trial is a more recent one, but it’s fair to say that both trials showed very similar results.

Head-to-head comparison, first-line treatment, alectinib versus crizotinib, showed that the median PFS was substantially better; hazard ratio was 0.47. For the controlled arm, it was 10 months, exactly what you would have predicted for crizotinib. In the J-ALEX trial, the median PFS was over 25 months with alectinib. In the ALEX trial, the median PFS number has not been reached as of the publication, but we know now that that number is around 25 months. What was even more impressive is the brain control rate in the ALEX trial, where they had formal planned brain MRIs done on a regular basis. They showed that the hazard ratio for brain progression was 0.16 favoring alectinib. So, 85% reduction in risk of brain progression.

In a disease where nearly 65% of the patients will develop brain metastases at some point during the course of the disease, I think it’s truly impressive. Alectinib also had better tolerability in some ways compared to crizotinib. So, all of these put together now have moved alectinib to the frontline space for ALK-positive disease. And this, I think, is a major change in the landscape of this condition.

Benjamin P. Levy, MD: Yes, I would agree. I think recapitulating the J-ALEX into ALEX really cemented this as a first-line therapy for our patients. Patients who are ALK-rearranged who go on to alectinib, unfortunately, progression is universal in these patients at some point. What are the options and do we understand mechanisms of resistance? I would say that we have a better understanding of a neat little pie-graph for EGFR resistance with a T790M in small-cell. We don’t really have that graph for resistant mechanisms for ALK. Can you talk a little bit about that and the clinical implications of testing for that?

Suresh S. Ramalingam, MD: Sure. So, we have a good understanding of what happens when you give crizotinib first. If you look at proper assistance mechanisms, one-third of them will have ALK-dependent resistance, one-third of them will have non-ALK—dependent resistance, and the other one-third don’t have a defined mechanism of resistance. Among the gatekeeper mutations, which is one-third of the patients who have ALK with dependent disease, often the gatekeeper mutation is very similar to the T790M EGFR mutation. And the majority of these tend to be sensitive to the second-generation ALK inhibitors, except perhaps the G1202 mutation, which tends to be more refractory to treat.

We’re now also learning about the importance of the ALK fusion variant itself, variant 1 versus variant 3. Now the FISH test will not tell you which variant it is. The RT-PCR you will know, and it seems like the variant 3 is more prone to develop the G1202 mutation. So, even within ALK patients, there is heterogeneity. The most important clinical question now though is, what happens when you give first-line alectinib? What are the resistance mechanisms, and how are we going to treat them? And that’s an area where we don’t have a lot of information on. People are just beginning to report on this. So, at this point, I would say that’s an open question.

Benjamin P. Levy, MD: I think what may not work is immunotherapy in these patients, although down the line, that may be one of the options. But I think we’re trying to understand how to sequence these ALK-directed therapies.

Suresh S. Ramalingam, MD: I would qualify that a little further by saying we don’t know what immunotherapy does well in this space because there’s not a lot of information.

Benjamin P. Levy, MD: That’s true.

Suresh S. Ramalingam, MD: Anecdotally, people have noticed responses, so I don’t think you want to take immunotherapy completely off the table, but that would not be the immediate next treatment I would give the patients.

Benjamin P. Levy, MD: This goes back to the osimertinib data with EGFR and kind of combining it with the ALEX trial. When a patient is on one of these great genotype-directed therapies, management of oligometastatic disease, are we more vigilant with that now, given how well these drugs work in terms of even in the brain, or are we riding out these drugs as long as possible, is that the message?

Suresh S. Ramalingam, MD: I think Roy mentioned it earlier about how our willingness to tolerate minor progression is far more with the genotype-driven oncogenic tumors.

Roy S. Herbst, MD, PhD: And if there’s one site that seems to be growing and all others are stable—and this would have to be watched over a long period of time, I’m talking 6 to 12 months—we’ll pluck one out every once in a while, and really with a good surgeon. We do some radiation, but only in very selected cases, really on a case-by-case basis, and it’s got to be really one area that seems to be resistant whereas the others are all responding.

Hossein Borghaei, DO, MS: That’s what we’ve done.

Transcript Edited for Clarity