Lorlatinib for Metastatic ALK-Positive Non-Small Cell Lung Cancer: Todd Bauer, MD

Todd Bauer, MD.

Recently, the FDA granted approval to lorlatinib (Lorbrena®, Pfizer, Inc.) for the treatment of patients with anaplastic lymphoma kinase (ALK)–positive non-small cell lung cancer. This subset of lung cancers defined by their chromosomal rearrangements of the ALK gene are highly sensitive to small-molecule ALK tyrosine kinase inhibitors (TKIs). Lorlatinib is a novel third-generation small-molecule ALK TKI that was designed to cross the blood-brain barrier in an effort to better treat patients whose disease has progressed to the central nervous system (CNS). In this interview, Todd Bauer, MD, Associate Director of the Drug Development Program at Sarah Cannon Cancer Institute and principal investigator for the phase 3 CROWN trial (NCT03052608), on which the approval was based, speaks with Oncology Data Advisor about the challenges of treating patients with advanced ALK-positive lung cancer and lorlatinib’s potential as a treatment option.

With the recent approval of lorlatinib, how do you see the treatment of metastatic ALK-positive non-small cell lung cancer evolving?

Todd Bauer, MD: That’s a really good question. The approval of lorlatinib adds yet another very good drug to the first-line treatment options for patients with ALK-positive lung cancer. The evolution of that space over just the last five years has come at an incredibly rapid pace. Right now, we don’t have all the answers that we’d like to have about how to sequence these drugs and which ones truly belong up front. As far as trying to compare alectinib, brigatinib, and lorlatinib together, we don’t have any studies that look at that. So it’s all cross-trial comparison, which is a statistically terrible idea because each of these have been compared against crizotinib in the frontline. It’s clear that in the United States, crizotinib probably should not be utilized for ALK-positive lung cancer patients, given these approvals. Once you get down into the other three drugs, including lorlatinib, it really comes down to whether they have brain metastases already, their current comorbidities, and their tolerances for different side effect profiles, because the drugs do act differently from the side effects standpoint.

In the study you published last year in Targeted Oncology, you thought that there was more durable activity in the central nervous system with lorlatinib and that it was possible that there might be fewer mutations in the lorlatinib-treated CNS lesions, since this might be the first time that they were being treated with a TKI. Have you gotten any further data?

Todd Bauer, MD: We’re still watching that data evolve. I assure you that all of us who have an interest in ALK-positive lung cancer are keen to learn how to pick the right drug for the right patient. I don’t think there’s any drug out there that’s clearly the absolute best choice for every patient. But we really need to personalize a bit more and try to sort out who’s going to benefit from which of the three agents in the first-line setting.

You mentioned that side effect profiles are an important consideration for treatment choice. What adverse events are a concern with lorlatinib, and how are they best managed?

Dr. Bauer: It’s interesting how lorlatinib has grown out of some early phase 1 studies, and there’s kind of a reputation out there about it amongst the ALK-positive community, which is a very strong patient advocacy group, which I think is tremendous. Of the couple of things that have really emerged from lorlatinib, the most common side effect that we see is hypercholesterolemia. It is very easily managed just by starting patients on a few select statins. Now there’s a little bit of a challenge in there because due to CYP3A4 interactions, not all statins are okay to use in combination with lorlatinib. However, rosuvastatin is safe to use with lorlatinib and manages the hypercholesterolemia very well. There can also be some hypertriglyceridemia, and if that isn’t controlled by the rosuvastatin, institution of fenofibrate works well for that.

That’s the most common thing we see. I often think about that, like we think about treating hypothyroidism with checkpoint inhibitors. Nobody bats an eye at starting a patient on some levothyroxine when their thyroid stimulating hormone (TSH) starts to climb because of an autoimmune thyroiditis. In much the same way, I don’t really ever get bothered about hypercholesterolemia in patients on treatment of lorlatinib because I know I can control it so easily.

There are a couple of other things. We also do see some peripheral edema or swelling in the legs that can be bothersome. Sometimes we do have to use furosemide and dose adjust the lorlatinib for that. It’s not entirely clear why, but some patients do develop some significant weight gain as well, where it can be 10% to 15% of the body weight. So that’s something to watch out for.

The most concerning side effect, and where this reputation for lorlatinib comes from, has been the concern about CNS toxicity. Throughout all the studies that we’ve done, most notably in the early phase 1 studies in patients who had been heavily pretreated and a number who had had radiation to their brain, there was a trend towards some CNS toxicity that looked different in different patients. In some patients, we saw some mild confusion. We saw some slowed speech. We did see some hallucinations, and we saw some depression. The etiology of this is not clear, but I guess sometimes the strength, or also the weakness, is we know that lorlatinib gets across the blood-brain barrier very well. So there’s certainly some activity that it has in the brain that’s causing these things. Now the reassuring thing about this is that even in the most severe CNS toxicities that I have had the misfortune of having to care for so far, simply holding the drug and dose reducing it does resolve the side effects in almost all cases.

Those can certainly be scary if you take somebody who is a high functioning executive or a certified public accountant (CPA), and all of a sudden they’re a little too fuzzy to do their job. But typically, we’re able to manage that very well simply through dose reduction and/or dose hold. Interestingly, in the phase 3 CROWN data, which earned lorlatinib its first-line approval, when you really compared the side effect profile and dose discontinuation rates compared to those of the other first-line agents— again, trial comparison, and even for crizotinib—there wasn’t a significantly higher number of patients. In fact, it was a lower number of patients that had to come off of lorlatinib compared with the other agents.

It’s reassuring that even though there’s sort of this stigma about it and this reputation about it, it is a medicine with side effects that can be managed, and patients can stay on for quite some time.

The incidence of brain metastasis with non-small cell lung cancer is quite significant, correct?

Dr. Bauer: That’s correct. Even more so than that, the ALK-positive population has a strong propensity to have brain metastases either at the time of diagnosis or as a first sign of progression. So that’s why the ability of lorlatinib to treat those patients and/or prevent those patients from developing metastases, it seems, is pretty incredible.

Do you have any words of advice for patients with metastatic non-small cell lung cancer? How would you counsel them?

Dr. Bauer: Well, I think the most important thing that I can offer to all patients across the board, whether it be non-small cell lung cancer or breast cancer or colon cancer, is that every patient with metastatic disease needs to have broad-based molecular profiling done to better understand their tumor. Though the incidence of ALK is only about 3% to 5%, when we look at our lung cancer population, when you add up EGFR and ALK and ROS1 and MET and HER2 and BRAF, we really start to see those numbers where it’s not just a 3% or 5%; probably about half of patients with non-small cell lung cancer have an identifiable genetic alteration that can guide their therapy. If we aren’t finding those in our patients, they aren’t going to get the best treatment out there for them. So that’s a lot of words to say every patient deserves to have broad-based molecular profiling of their tumor done to look for driver alterations.

About Dr. Bauer

Todd Bauer, MD, MBBS, MRCP, is the Associate Director of the Drug Development Program at Sarah Cannon Cancer Institute and an oncologist at Tennessee Oncology. Dr. Bauer specializes in providing personalized medicine for his oncology and hematology patients, and he leads a spectrum of phase 1 clinical trials focused on the treatment of patients with pancreatic cancer, lung cancer, ovarian cancer, and other advanced malignancies.

For More Information

Bauer TM, Shaw AT, Johnson ML, et al (2020). Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer. Target Oncol, 15(1):55-65. DOI:10.1007/s11523-020-00702-4

Shaw AT, Bauer TM, de Marinis F et al (2020). First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Eng J Med, 383 (21):2018-2029. DOI: 10.1056/NEJMoa2027187

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 

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