ALK-Positive Lung Cancer

Transcript:Mark A. Socinski, MD: Let’s transition to ALK disease, the second most common. Interestingly, this was initially described in lung adenocarcinoma, in 2007, so we’re less than 10 years into this. As we alluded to early on, we have a new standard, crizotinib, that’s been compared in the first- and second-line to standard chemotherapy, and is better. How do we make crizotinib better?

Gregory J. Riely, MD, PhD: I think one thing that we have to remember is that this is a tremendous story, where you go from identification of ALK gene rearrangements in lung adenocarcinoma, in 2007, to an approval for a drug in 2011. What kind of gets skipped over along the way, is that crizotinib happened to have a little bit of ALK activity, but was being developed as a MET inhibitor. So, people have to acknowledge that it wasn’t the best ALK inhibitor out there. We’ve seen crizotinib as an extraordinarily useful drug and we’ve seen progression-free survivals on the order of what we see for any targeted therapy. So, it’s been great. But the way we move forward for ALK, and what we’ve seen approved in the second-line for patients with ALK-positive disease, is simply better ALK inhibitors. It’s not necessarily a spectrum of activity or targeting particular mutations. It’s just better ALK inhibitors, and those have made dramatic strides for us in the second-line.

Mark A. Socinski, MD: Jared, walk us through. We now have two true ALK inhibitors, a so-called second-line. Maybe they’re the first-generation ALK inhibitor. But we have two. We have ceritinib and alectinib. Give us your perspective on these two agents.

Jared Weiss, MD: Sure. So, it’s a lot the same as what we saw with the next-line EGFR story. We have agents with very high response rates on the order of about two-thirds of patients meeting RECIST criteria for response. We have nice durable progression-free survivals. I think what we don’t know is how to sequence these agents. We see that these two agents, as well as, some of the later generation inhibitors being studied in clinical trials for ALK, have somewhat different spectrums of activity against particular resistance changes. And I think as we move forward, a more sophisticated understanding of exactly which resistance change is present might help us to drive a little bit better which agent might be best for a particular patient, particularly as we get a few more of these approved.

Mark A. Socinski, MD: With these two agents, we really have no guidance yet in terms of which one should be first and which one should be second. The other perspective I’d like to get, maybe I’ll ask Tom about this, is about the ALK population; it has a propensity—ALK disease does—to involve the CNS. And we see many of these patients doing that. These drugs have activity in the CNS, and so I think that’s an advantage. Your thoughts about that?

Thomas E. Stinchcombe, MD: I think on a second-line trial, about 40% of the patients had brain metastases, and so this is a huge portion of our patient population. And I think in some ways—and certainly some of my patients, that’s become the life-limiting disease—they get these recurrent brain metastases, and then in the worst case scenario, they get leptomeningeal disease. So, I think the blood-brain penetration of both alectinib and ceritinib are huge advantages at this point. And I think you’re going to see more of our trials really monitor the CNS recurrence, and progression, and response.

Mark A. Socinski, MD: And I think in several of my patients it’s allowed us to delay the use of whole brain radiotherapy. Remember the ALK population, the median age is early 50s. These are young people, often gainfully employed and productive and not wild about getting whole brain radiotherapy. So, if you can extend that time period to when they need whole brain radiotherapy, and get them used to taking a well-tolerated pill... Ben, let me ask you your thoughts about toxicity profiles between the two agents.

Benjamin P. Levy, MD: Very different, and that perhaps may drive treatment decisions for our patients. As somebody who’s used both of these agents, ceritinib has a higher rate of nausea, and vomiting, and certainly diarrhea. LFT abnormalities are also there. And with alectinib, we don’t see those signals as high a frequency as we do with ceritinib. In my experience, and patients have told me this who have been on ceritinib, and then gone on to receive alectinib, is that alectinib—even though it’s more pills a day—seems to be better tolerated. We’re not seeing those rates of nausea and vomiting, certainly not the diarrhea, even though it’s 8 pills a day. I believe that’s the dosing—4 in the morning, 4 in the evening. This drug seems to be, has been, a welcome change from at least the ceritinib story thus far.

Mark A. Socinski, MD: If I remember correctly—and panel members, please correct me if I’m not remembering this correctly—there are very few drugs that I’m aware of that when you take them orally, they have the same plasma and CSF concentration, right? And this is one of them that comes close to that. So, I think that’s a huge advantage for alectinib in terms of the brain stuff. I don’t know the data on ceritinib, but I’m just saying that that’s a huge advantage for all of these second-generation. Tough question. We’ve talked a lot about T790M, and that occurs in 50% to 60%. We say re-biopsy is the standard of care. You have an ALK patient presenting. We know that ALK resistance is a little murkier in terms of what to do. Secondary mutations or amplifications are in the minority of patients, not the 50% to60% that we see with it. Greg, I’m going to pick on you, should we be re-biopsying ALK patients to look for these things, or what do you do with these?

Gregory J. Riely, MD, PhD: I certainly think we need to learn a lot more about these patients, and I think understanding this from a research perspective is a rational approach. I think we’ve learned the value of re-biopsy just in terms of understanding patients’ tumors, and we learned a lot from this. It’s hard to say that this is a standard of care in any way, shape, or form to re-biopsy at this point. And partially what drives that is with the initial report on ceritinib’s efficacy, it was phase I trial reported in the New England Journal of Medicine, there’s a waterfall plot that specifically looks at patients whose mechanism of resistance was identified. And there are a variety of mutations. There’s amplifications, there’s losses. It’s all there, and they all responded about the same.

Mark A. Socinski, MD: And there’s no mutations. They can’t document an ALK alteration and they still respond.

Gregory J. Riely, MD, PhD: That’s right. And, I think while T790M is a clear dominant mechanism of resistance for EGFR, there’s no dominant mechanism in ALK. It’s a lot less clear as to whether that biopsy is a clinically relevant one.

Mark A. Socinski, MD: So, talk to us, and tie up this section. We hear about drugs coming down the line, brigatinib, lorlatinib, and others that are coming around. How many of these drugs do we need?

Gregory J. Riely, MD, PhD: That’s a really fair question. I think there are at least another 3 drugs that are nearing FDA approval in this space, and I think a lot is going to depend on what we find is the right first-line drug. I think we’ve seen a recent press release for a trial that compared alectinib to crizotinib as a first-line treatment in Japan, so, a very different patient population. But, that suggested that there was a prolongation of progression-free survival. We need to know how big that difference in progression-free survival is, so we need to figure out what the right first-line ALK inhibitor is, and then we’re going to figure out the second-line. The real paucity of data for us now is, how does a patient who’s progressed on ceritinib do with alectinib, and how does a patient who’s progressed on alectinib do on ceritinib? Where does brigatinib work in all these? We really need to understand this, but this is a patient population of 4% or 5% with lung adenocarcinoma. There’s not an infinite number of trials that we can do, and there’s not a lot of incentive to compare various sequences by the sponsors of these drugs. So, I think the NCI had hoped to look at this. I’m not sure where that project stands right now, but it’s an important question that we’re going to have to understand clinically the results.

Transcript Edited for Clarity