ALK-Positive NSCLC

Transcript:Benjamin P. Levy, MD: ALK mutations are the second most common driver mutation or rearrangements identified in lung adenocarcinoma. The story of ALK is emblematic of precision medicine. We identified ALK mutations. It only took 4 years to develop crizotinib. The pace of just drug discovery is really quite rapid these days. We, of course, have first-generation drugs. Crizotinib is now approved for a first-line indication—that may change. But, we have next-generation ALK inhibitors that are structurally different, a little more potent. They’re able to overcome crizotinib resistance, which has led to more ALK inhibitors—a crowded space. We have now several drugs at our disposal, with more coming down the pike. Mark, give the highlights of where we are with crizotinib and ROS-1, which is another rare mutation. But, then talk about where we’re heading with the ALK-directed therapies—ceritinib, alectinib—their potential to cross the blood-brain barrier, and some of the data we may see tomorrow with brigatinib.

Mark G. Kris, MD: So, in many ways, I think everybody looks at it as analogous to the EGFR experience. But, it is different in a few ways. I asked Sarah’s colleague, Katie Politi, is there any difference in the laboratory from one of the first-generation EGFR TKIs, and even second generation? And, she said, no. However, these drugs are different. Their potency against the target is quite different. And I believe there’s a manifestation of that; the patterns of resistance are different. There is not a common gatekeeper mutation in 60% of patients that have an acquired resistance to crizotinib; it’s a different story. And you’ll say it’s a complicated pattern of acquired resistance, and yes, there are some gatekeeper mutations. But, it’s a very, very different story. A lot here has to do with potency in the drugs. And I think all of them are very potent.

The second thing is the ability of the drug to treat an established brain metastasis. And I’ll make the broad statement—as good as a drug is in the chest, it’s as good in the brain—every single drug. Yet, yes, theoretically, there may be some differences. But, if a drug works in the chest, it’s going to work in the brain. And it’s clearly uncertain that any of these things, for an existing brain metastases, works better. But, somebody getting ceritinib or alectinib gets a very good response after failure on crizotinib, and it’s probably because they’re more potent. How do we sequence these drugs? We just have no idea. However, just like in renal cell cancer, now, where there are a lot of kinase inhibitors—and they’re starting to look at what’s the best one—we’re starting to do that now, and with the ALK inhibitors, as well. Already there’s been a press release of a trial comparing crizotinib to alectinib. And the press release says there’s an improvement in progression-free survival. There will be a presentation at the American Society of Clinical Oncology meeting that details that, as well.

So, there are differences in toxicity; there are differences in potency. And, right now, I guess, if you believe that press release, the better PFS would be with alectinib. The tolerability of alectinib is excellent. If you treated patients with both alectinib and crizotinib, by and large, they tell you the alectinib is easier for them. And I have a feeling that alectinib is quickly going to move up to the first spot. But, it is a slightly different situation. I’m happy we have all these choices. I think there are differences in toxicity. Obviously, I think we’ve all seen that hepatic toxicity with one often is not repeated with another. And that’s a nice thing with those patients that have hepatic toxicity, or edema. But, it’s somewhat different, and it’s something we’re gonna have to work out.

Benjamin P. Levy, MD: You mentioned brain metastases. The ability of alectinib and ceritinib to cross the blood-brain barrier to elicit responses in the brain, and also parallel to being able to elicit responses in crizotinib-refractory patients. In the trials, at least, up to 50% to 60% of all crizotinib-refractory patients do develop brain metastases at some point. My question is do we need to surveil patients with routine brain MRI? Is this a special population where we need to routinely be doing brain MRIs every 6 months, every 9 months, every 12 months to pick this up earlier?

Mark G. Kris, MD: That’s a tough question because this is a very common problem in all lung cancers. And many feel that with longer survival, that this becomes more common. And, who do we have with the longest survival, it’s ALK and EGFR, it’s ROS-1. So, by the nature of those illnesses, we are going to be seeing more brain metastases. And they’re a huge problem.

With surveillance, I’ll take my experience in small-cell lung cancers. Ultimately, most of the tumors we’ve found on surveilled patients happened between the scans. And, my guess is, if we started doing that, we’d probably get the same thing. So, I’d probably be wary of doing surveillance on patients, and be, of course, very quick, if they were symptomatic to jump on that. And, by the way, these drugs are very effective when you have a brain metastasis just like they’re effective in the chest. And I have to throw in a word for chemotherapy. There was a beautiful paper in Clinical Cancer Research, I guess about a year ago, now, from the French group giving paclitaxel, carboplatin and bevacizumab 63% response rate in the chest.

Benjamin P. Levy, MD: Right. So, there’s activity.

Mark G. Kris, MD: But, it’s exactly the same with ceritinib.

Benjamin P. Levy, MD: Right.

Mark G. Kris, MD: Or, alectinib, when you go into the reports of those drugs, as well.

Chandra P. Belani, MD: I think that these ALK patients are different.

Mark G. Kris, MD: Absolutely. They are different, yes.

Chandra P. Belani, MD: I think that to see 50% to 60% incidence of brain metastases, and then we are able to treat them with the second-generation and third-generation inhibitors, we should be looking for this so as to change the treatment in this group of patients.

Ramaswamy Govindan, MD: ALK is involved in neural development, too. So, we don’t understand what guides these things to a brain metastasis. The processes that guide these cells to grow well in the bone, you cannot escape the fact that the ALK is involved in the neural thing. And there, there’s a tropism in the brain, which is something we cannot forget.

Chandra P. Belani, MD: And with these longer survivals that we are seeing with these ALK+ patients, the question about sequencing, I think, is a big one here. Because, in alectinib, which is going to take the first-line position at this point in time is based on J-ALEX trial—which is being presented on Monday—that there is a significant improvement in overall progression-free survival against crizotinib. The question is what would be second, or what will work after alectinib? So, we really do not know what is going to work. As we said, we have now four or five drugs, and two or three others are also in development. I think it will be a big challenge how to sequence these ALK inhibitors in our practice.

Sarah B. Goldberg, MD, MPH: I think it’s the same with EGFR, though. Do you use your best drug first or do you use one that works first, and then another one that you know works second? We don’t know.

Chandra P. Belani, MD: Well, we just said that supposing osimertinib becomes the first-line, will any of the first- and second-generation inhibitors even work later?

Sarah B. Goldberg, MD, MPH: I think it’s the same story there.

Benjamin P. Levy, MD: Yes, I think there’s a lot of unanswered questions with these genotypes.

Chandra P. Belani, MD: But, it is impressive that alectinib has shown superiority. At least, it’s early. The phase III study, which is being conducted outside of Japan, has completed accrual, and I think we’ll get more data. Then, there is brigatinib.

Benjamin P. Levy, MD: We’ll have some information on that tomorrow.

Transcript Edited for Clarity