The Case for Lorlatinib in ALK-Positive NSCLC

At the Great Debates & Updates in Lung Cancer meeting in New York, New York, Misako Nagasaka, MD, PhD, University of California, Irvine, debated in favor of lorlatinib over alectinib when considering treatment options for patients with ALK-positive non-small cell lung cancer (NSCLC).

Transcript:

Hi, I'm Misako Nagasaka, Associate Clinical Professor at University of California, Irvine, I'm at Great Debates & Updates in Lung Cancer. Today, we had a debate regarding first-line ALK inhibitors. My role was to talk about the role of lorlatinib and my opponent was Dr Ticina Leal [MD, Winshop Cancer Institute, Atlanta, Georgia], and she had the alectinib side. Basically, it was a debate on alectinib versus lorlatinib for first-line ALK-positive patients. I had 3 points that I wanted to make regarding my talk– the 3 reasons why I would suggest lorlatinib for first-line treatment.

The first point would include the strong efficacy seen in [central nervous system] CNS data. The hazard ratio was fantastic. Intercranial time to progression, the hazard ratio was .08 which is something we've really never seen before. Patients without brain metastases, brain metastases being the progression at the 12-month mark, was 1%, and actually the 24-month mark was also 1%. That basically means that people were not really progressing in the brain and that's a big deal because, once you have brain metastases you have all these issues with headaches, nausea, vomiting, altered mental status, seizures, so we want to avoid those symptoms.

Second point that I made was that the total [progression-free survival] PFS is important. Right now, the lorlatinib data is based on CROWN study which they reported an interim analysis at the follow-up of 36.7 months and still the median was not met. That means that the median progression-free survival is going to be longer than 36.7 months because we haven't reached the 50% mark. If you think about it, if you use alectinib or brigatinib for first-line their [blinded independent central review] BICR assessed median progression-free survival was in the range of 24 to 25 months and if you add on second-line lorlatinib data, which after second-generation ALK inhibitors like alectinib or brigatinib, the range is several months. If you're going to add 7 or 8 months on top of 24 months, that only gets you to 30 to 33 months, and you see we’re already 3 months short on the lorlatinib first-line and we haven’t even talked about using other agents after lorlatinib use. So clearly, although it’s hard to embrace because we don’t have the median concrete number for the progression-free survival for lorlatinib, it is very likely that the median progression-free survival will not be met for another couple of years and that will show superiority of lorlatinib over alectinib.

The third point that I made was the fact that even though many of us are afraid to use lorlatinib because of its side effects, especially the CNS-related side effects, it is quite manageable. We know that when these things tend to occur, usually the hallucinations and wild dreams, they occur in the first 2 weeks and they go away on its own. Sometimes we have patients have impulse control issues or slowness in their speech or forgetfulness and that tends to happen a little later on. But by explaining these possibilities to patients and also alarming family members to watch out for these things, these things can be easily managed either with no intervention and just close monitoring, or dose interruption or dose reduction.

I did also make a point that alectinib might not all be that easy and in some patients significant weight gain has been reported.

With all these three points, I suggested that lorlatinib be considered as excellent choice for your first line treatment option for ALK-positive non-small cell lung cancer patients.

In the clinic, I really like to go over actually the 3 drugs that are listed on the NCCN guidelines which are alectinib, brigatinib, and lorlatinib. I try to summarize for my patients the efficacy data as well as their side effect profile and we have a shared decision making. I always want to make sure that I'm meeting the patient's goals, so I ask them about big goals like what they want to achieve: do they want to see their daughter get married, or is their son graduating? And I also ask them about their daily lives: do they want to go back to work or do they just want to have fun with their kids? Considering those social aspects as well, I try to come up with a program for my patients and it's been successful.

Source:

Nagasaka M. Debate: Alectinib vs lorlatinib in ALK positive - Lorlatinib. Presented at Great Debates & Updates in Lung Cancer; September 21-23; New York, NY.