Targeted Therapy for ALK+ NSCLC

Mark A. Socinksi, MD:One of the things that came out early in the development, before we get to targeted therapy, that I think is important for clinicians to remember is that there is some literature that would suggest that they have greater sensitivity to pemetrexed-based chemotherapy. That was an early observation made by, I think, Dr Ross Camidge of the Colorado group.

Thomas E. Stinchcombe, MD:With a rush toward targeted therapy, you bring up a good point. Platinum pemetrexed is what I most often use, and it’s generally well tolerated. You can control the disease for about 8 or 12 months, on average, with that. And I sometimes talk to patients like, “All right, we’ve run out of targeted therapies. We need to do what I describe as a holding therapy, maybe until we can get you on to the next trial.” I don’t think we should dismiss the role of chemotherapy in this disease.

Mark A. Socinksi, MD:We’ll get to talking about ALK inhibitors. But at some point, you may exhaust your options from an ALK inhibitor. So don’t forget that chemotherapy does play a role in these patients.

Thomas E. Stinchcombe, MD:You know, many of these patients live 4, 5, 6 years, and we’re really talking about a sequence of therapies rather than just 1.

Mark A. Socinksi, MD:You mentioned briefly the 2 PROFILE trials, so we did have evidence. It’s interesting that crizotinib became the standard of care. Crizotinib, not being necessarily the best ALK inhibitor, really came into clinical trials as a MET inhibitor. But early observations showed responses inALK. We had the 2 PROFILE trials—second-line, first-line—that were clearly better than chemotherapy, so it changed the standard of care. I think crizotinib was approved in 2011, so just 4 years after the original observation. It was actually quite dramatic, the benefit, at least in PFS [progression-free survival].

Thomas E. Stinchcombe, MD:It was quite dramatic, and I think the frontline trial sticks more in my mind, where the response rate was 75% and the PFS was around 11 months. That was a very good trial in terms of defining what the benefit is. And also, we haven’t touched on this, but the toxicity was better than what chemotherapy offered.

Mark A. Socinksi, MD:If you go back to crizotinib being the standard, then we had the influx of a number of true ALK inhibitors or second-generation ALK inhibitors. The first one I wanted to discuss is alectinib because the first trial we saw was the J-ALEX trial at ASCO [the American Society of Clinical Oncology] several years ago, followed, again, by the ALEX trial, that really supplanted crizotinib as the first-line therapy. Give me, just briefly, the top line results of the J-ALEX and ALEX trials.

Thomas E. Stinchcombe, MD:I think importantly, alectinib was really designed to have a narrow focus. More potent ALK inhibition but to reduce some of the adverse effects of it. And also, it was more active and it penetrated the blood-brain barrier. What we saw in both of these trials was a dramatic improvement in progression-free survival. If we look at the hazard ratio of crizotinib versus carboplatin and pemetrexed, it was 0.5, whereas alectinib versus crizotinib is approximately 0.5. And so, we’re really improving the progression-free survival. The response rates were slightly higher with alectinib, but it’s really the progression-free survival and the lower toxicities that drove the adoption of this therapy.

And then, in the ALEX trial they looked at the patients who developed brain metastases. There was a dramatic reduction in the development of brain metastases on the alectinib arm compared to the crizotinib arm. And clinically, we really like this idea of preventing brain metastases rather than treating brain metastases.

Mark A. Socinksi, MD:Yes, so obviously getting to the issue of: Can we protect the brain? In those patients who don’t have brain metastases at the time of diagnosis, do these agents have a protective effect? I think there is some suggestive evidence to say that’s the case.

Thomas E. Stinchcombe, MD:I think, yes, they have a preventive effect. And I think interestingly, now we’re seeing more studies looking at small asymptomatic brain metastases and using these therapies as a primary treatment for brain metastases, and then maybe avoiding or delaying the role of radiation therapy.

Mark A. Socinksi, MD:Would you agree that based on the J-ALEX and ALEX studies that alectinib became the standard of care in the first-line?

Thomas E. Stinchcombe, MD:I think it’s unambiguously the standard of care in the first-line setting.

Mark A. Socinksi, MD:The next drug that I wanted to get your thoughts on is ceritinib. We had the ASCEND-4 data that compared it in the first-line to chemotherapy. Give me your thoughts about that trial.

Thomas E. Stinchcombe, MD:I think ceritinib showed a lot of promise in the second-line setting, but it was dosed at 750 mg.

Mark A. Socinksi, MD:It got off to a bad start.

Thomas E. Stinchcombe, MD:That might have been a higher dose than what was necessary and convenient.

Mark A. Socinksi, MD:A lot of GI [gastrointestinal] toxicity.

Thomas E. Stinchcombe, MD:And so, I think that was one of the problems. But ceritinib versus chemotherapy showed an improvement in progression-free survival. I think the median was about 16 or 17 months on the ceritinib arm, which was impressive. It clearly had more potency and activity. They tried to adjust the dose. The new dose is 450 mg with food to mitigate some of the GI toxicities.

Mark A. Socinksi, MD:I agree with that. But part of the problem that I’ve always had with the ASCEND-4 trial is that the target isn’t better than chemotherapy. I think crizotinib established that with the PROFILE trials. The question is, is it better than other ALK inhibitors?

Thomas E. Stinchcombe, MD:I think they did a trial that was sufficient for regulatory approval but not clinical adoption, and that’s what I think held the drug back. I’m sure there are complex reasons for that, but I think alectinib versus crizotinib was a much more clinically relevant comparison for us.

Mark A. Socinksi, MD:And then, most recently we have the data with brigatinib. Walk us through the early data we have—the trial comparable to the ALEX trials comparing brigatinib to crizotinib. Your thoughts?

Thomas E. Stinchcombe, MD:I think brigatinib had shown a promising response rate of around 50%, 60% in the second-line, and a median progression-free survival on the FDA-approved dose of around 16 months. So it looked like a very active drug. Then it was compared to crizotinib in the frontline setting, in treatment-naїve patients, at least ALK TKI [tyrosine kinase inhibitor] treatment-naїve patients. It showed a similar improvement in progression-free survival on the first interim analysis. The hazard ratio was around 0.5, and it clearly improved on crizotinib. In the patients with baseline brain metastases, this benefit was a hazard ratio of around 0.2 or 0.3, showing that a similar pattern of the CNS [central nervous system] activity is really critical in this patient population.

Mark A. Socinksi, MD:So brigatinib has this unique toxicity, the pulmonary syndrome, that occurs early on. Can you walk us through that and explain what the observation is?

Thomas E. Stinchcombe, MD:I think this is unique to this ALK TKI, and I think it happened on the frontline trial about 3% of the time. These are calledearly onset pulmonary events, and they can show up with some dyspnea, some shortness of breath, and occasionally some hypoxia. This is what initiated the dose escalation, where you do 90 mg and then escalate up to 180 mg after a week because the patient may develop tolerance to the brigatinib. Then you’re less likely to see it in the dose escalation. Clinically, I see these patients back a week after I start the brigatinib just to make sure that I’m assessing the symptoms and watching them.

Mark A. Socinksi, MD:Does your staff call them during the day? Because it’s usually day 2, 3, 4, or in that range.

Thomas E. Stinchcombe, MD:We counsel the patients and then sometimes call them. The pharmacy has a system of calling to make sure there are not any unexpected adverse effects.

Mark A. Socinksi, MD:And the mechanism of action of why this happens is elusive, correct?

Thomas E. Stinchcombe, MD:Yes. I’ve actually asked some prominent people who could explain this to me, and I’ve not really gotten an answer. Brigatinib also hits the EGFR receptor slightly, and that was part of the drug development. We know that pneumonitis is seen with all of these tyrosine kinases. It just seems to be slightly higher with this group, so it’s a unique toxicity.

Transcript edited for clarity.