Posted: August 14, 2019
Lorlatinib, a smallmolecule inhibitor of ALK and ROS1, was granted accelerated U.S. Food and Drug Administration approval in November 2018 for patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease. Todd M. Bauer, MD, a medical oncologist and senior investigator at Sarah Cannon Research Institute/Tennessee Oncology, PLLC, in Nashville, has been very involved with the development of lorlatinib since the beginning. In the following interview, Dr. Bauer discusses some of lorlatinib’s unique toxicities, as well as his first-hand experiences with the drug.
Q: Lorlatinib’s toxicities, including CNS effects and secondary elevations of cholesterol and triglycerides, are unique. To what extent do these side effects influence tolerability, and what are the best tips for managing toxicities?
A: I have one of the longest-running patients in the world. He was amongst the first patients ever treated when he started dosing in April of 2014, and has tolerated it quite well for over 5 years. He has had a near-complete response, with just a few 5- or 6-mm spots from prior CNS metastases that were irradiated, which I view as mostly just scar tissue and not a sign of active disease.
The CNS effects that we’ve seen with lorlatinib are interesting— they are a little tough to put a finger on. When we first started using lorlatinib and were escalating the doses, we had some reports of sluggish thought. Patients would indicate that they just couldn’t quite connect the dots—almost what you might think “chemo brain” would be like. This is something we had not seen previously with the ALK TKIs, so it became a point of focus. There are also some effects regarding mood (patients reporting depression and generally feeling poorly) and others regarding speech. For the vast majority of patients, we were able to stop therapy, and then the symptoms would resolve. We would then reduce the dose as necessary, and patients were able to continue on without problems.
Regarding cholesterol and triglycerides, most of the patients are very compliant with a statin and a fibrate as necessary. I had one patient who did not want to pursue pharmacologic therapy; he just wanted to manage it through diet. Finally when his cholesterol rose to the 500s, he relented and let me start him on a statin. People do well with the statins, which control cholesterol without any major problems. So the correlation between lorlatinib and elevated cholesterol is there, it’s very real—I can’t tell you why it happens, but it is very controllable using a statin and/or a fibrate as necessary.
Q: What are your best-practice tips for this fairly new drug?
A: The key to lorlatinib is that it is a very different TKI from crizotinib, for example, which caused a lot of edema and other significant issues for patients. It’s really a matter of watching the labs closely and talking to the patient to ensure that his/her thought processes are okay, and that there are not any mood changes. It is important to incorporate the family and caregivers into that discussion as well because they can sometimes identify subtle shifts that patients have trouble identifying themselves.
It’s amazing the number of times, especially on a clinical trial, that a patient will “shush” their loved one and tell them not to bring something up because the patient is worried that he/she will be taken off the drug. Caregivers are the key to really understanding some toxicities that the patients sometimes minimize or do not want to acknowledge.
Q: How does lorlatinib compare to alectinib or brigatinib?
A: I think it compares very well to those drugs. We don’t have any direct head-to-head comparison but certainly the intracranial control rate that we see with lorlatinib, even after failure of alectinib or brigatinib, is hopeful; it can re-establish control of disease that has progressed with those two drugs. Those are great drugs; I just think that, if you look at the basic science, lorlatinib targets the resistance mutations within ALK a bit more strongly than either alectinib or brigatinib. So lorlatinib can be a salvage medication for patients whose disease progresses on those therapies.
Q: What is in the pipeline for lorlatinib?
A: I think that there will continue to be studies looking at how to best sequence these drugs. We truly don’t know that answer right now. I think it is safe to say that crizotinib has fallen out of use after the presentation of the ALEX data, with alectinib now being the first-line drug. Second line gets a little fuzzy, so trials will be important. It’s an exciting time for patients with ALK fusion–positive lung cancer. The drugs available now are incredible, but we always encourage—in the appropriate setting—participation in clinical trials to help better define patient care. ✦
For further reading: Solomon B, Besse B, Bauer T, et al. Lorlatinib in Patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet. 2018;19(12):P1654-1667.
1. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. J Clin Oncol 36, 2018 (suppl; abstr 9043).