乌鸦传媒

In 5-year follow-up data from the phase III CROWN trial of ALK-positive advanced non-small cell lung cancer (NSCLC), patients receiving lorlatinib (Lorbrena) had the longest progression-free survival (PFS) ever reported in this setting. The findings were presented at the American Society of Clinical Oncology (ASCO) annual meeting.

乌鸦传媒 brought together three expert leaders in the field for a roundtable discussion: Moderator Roy Herbst, MD, PhD, is joined by Anne Chiang, MD, PhD, and Sarah Goldberg, MD, MPH, all of Yale Cancer Center in New Haven, Connecticut. This second of four exclusive episodes focuses on the 5-year update from the CROWN study.

Click here to watch the other videos from this ASCO roundtable series.

Following is a transcript of their remarks:

Herbst: Next, why don't we talk about ALK. Now, we had a 5-year update of the CROWN study.

Goldberg: Unbelievable.

Herbst: So Sarah, why don't you start us out on that one.

Goldberg: So this I think maybe was, I don't know the most, definitely one of the most exciting studies at ASCO or maybe this year. It's really incredible what we're seeing. We've known that that study was positive for a while now. So that trial again is patients with metastatic ALK-positive lung cancer who are randomized to either lorlatinib, the next generation ALK inhibitor, or crizotinib. So again, we've known that that study was positive for a few years, it's now approved not just in later lines for ALK, but it's also now approved for first line ALK-positive lung cancer.

But what this study showed, which is just so incredible, is that at 5 years, well more than half of the patients continue to respond. It's unprecedented. It's not just even in the ALK-positive space. It's like any subset of lung cancer, any patients with metastatic disease that's ever been studied. This is the longest progression-free survival that we've seen. So these patients are doing incredibly well.

Herbst: It was good at 3 years though too, right?

Goldberg: It was good at 3 years. I think that's around the time it got approved. It was good last year at 4 years and now it's at 5 years. It's continuing, that curve is just practically flat in terms of progression-free survival. So these patients have an ongoing response at 5 years. It's incredible.

Herbst: And how many years will you say they're cured?

Goldberg: I think actually that question, basically that question got asked at the panel, can you stop the drug? Can we think about stopping it? We do that with immune therapy after a few years, and those patients can continue going. I don't know that we're there yet with ALK. I think lorlatinib is an incredible drug, but I have concerns with stopping it. So I think those patients probably will keep getting drug.

The other thing that was shown in that presentation at ASCO this year is that the brain metastasis response was so durable as well. So this trial didn't require radiation to brain metastases [mets], unlike the one we were just talking about with small cell. This trial allowed it, but didn't require it. So most patients actually did not get radiation to their brain mets. And so even patients who had brain mets who didn't get well, most of whom didn't get radiation, they had an ongoing response at 5 years, the majority of them did. There were some patients who progressed, so MRI surveillance is still important, but most of those progressions were pretty early. And then after, I think it was about 2 years, that curve also flattens out where there's no intracranial progression beyond, I think it's 2 years.

So even patients with brain mets, I know it's unbelievable. And patients without brain mets really don't have brain progression, so very exciting.

Herbst: So you're very bullish on the data. What about...

Goldberg: I'll keep going.

Herbst: What about side effects, lorlatinib versus other drugs? Any unique side effects with lorlatinib?

Chiang: It's a hard drug to give. I mean, that's the flip side of it. You can have some confusion, you can have some depression. It's a little bit difficult and sometimes you have to do dose reductions, but that 92% intracranial progression-free percentage is really impressive.

Herbst: OK, so now the big question for the two of you. It was compared in this trial to crizotinib, but nowadays I would think most of us in the United States, maybe in the world, use alectinib [Alecensa]. So I'll ask each of you in turn. They're both approved so we don't have to wait for the FDA here. What are you going to use front-line when you see a patient Monday morning?

Goldberg: My opinion has changed over the last, really the last year since we've seen the 3- and 4-year data, but now even more with the 5-year. I think it's weighted now more towards lorlatinib. I think that data is just so compelling. I agree with Anne about the concern for side effects. It probably is a tougher drug, but what I tell patients is, these things may happen and lowering the dose helps.

I think if you tell them that upfront, it's not as much of an issue. And typically what I have found in my experience is lowering the dose really removes the side effects or makes them much more tolerable. Weight gain is the other thing that I think I've seen in a lot of cases with lorlatinib that can be difficult, significant weight gain, but that also can improve with dose reduction.

So I think if you're open with that discussion with patients at first, and there's pros and cons, but I think it really is getting to be pretty compelling that lorlatinib looks really, really good. And if the side effects are discussed and dealt with, I think it can be a well-tolerated drug as long as you're aggressive with that management.

Herbst: Excellent. Anne? Switch, stay the same? What are you going to do?

Chiang: I think we got to switch, yeah. I think the question would be do you start off at a little lower dose and then ramp up, or do you start at the higher dose and ramp down?

Goldberg: I think that's a great point. I think for patients, maybe you're particularly concerned about maybe some frail or older patients you could probably think about a lower dose. But maybe that's something that hopefully we'll learn in the future is about the right dose, not necessarily the approved dose.

Herbst: I'm not so sure you switch, we don't have the trial that really we need between alectinib, there is more toxicity. My sense is that probably about half the physicians might switch and the other half might wane, and maybe of that group, half of them are unsure. But it might be what this old shared decision making, where you talk with a patient and you discuss the pros and cons, but it'll be interesting to see. Do we see a lot of ALK patients each year? How frequent is that?

Goldberg: ALK is rare. So it's 3-5% of lung cancer, but we see them and they tend to be young. And so I think we want to give people -- obviously want to give anybody as much time as possible -- but these young patients, I think the risk of side effects is there. But again, I agree with you, it's shared decision-making, talking about the possible side effects. If they have side effects, you can lower the dose or switch then.

So I felt the same way where I was on the fence. It's pros and cons, but I'm really feeling like lorlatinib has this, what looks coherent cross trials, to be a better disease-free survival. And we don't have [overall survival] data. And after alectinib, some patients do respond to lorlatinib. So it's like this old question of, is it better to reserve your best drug until later or use it upfront. We don't really know. Like you said, it hasn't been compared head-to-head, but I'm leaning more towards lorlatinib these days.

Chiang: I don't think I'll switch it if I have a patient on alectinib that's doing well...

Herbst: Oh, of course.

Goldberg: Oh, I agree.

Chiang: I don't think that there's a need to switch then.

Herbst: But I definitely think in oncology you want to use your best drug first. This is going to require some post-ASCO discussion, but sounds like you two are pretty bullish on it.

Goldberg: Yep.

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