Updates Informing the Management of ALK-rearranged mNSCLC

Lyudmila A. Bazhenova, MD: NCCN [National Comprehensive Cancer Network] guidelines list 4 agents appropriate in first-line ALK-mutated non–small cell lung cancer. Two of them are crizotinib and sorafenib, gaining their approval based on the trials that compared ALK tyrosine kinase inhibitors to chemotherapy. The other 2, brigatinib and alectinib, were approved based on randomized head-to-head comparisons to crizotinib. Both brigatinib and alectinib improved progression-free survival [PFS] over crizotinib. Both have CNS [central nervous system] efficacy, so I prefer to go with either brigatinib or alectinib when I treat my patients with ALK-rearranged metastatic non–small cell lung cancer.

Jonathan W. Riess, MD: There have been some great updates in clinical trial data that show the fantastic activity of next-generation ALK inhibitors in ALK-rearranged non–small cell lung cancer. Updates to the ALEX trial, which randomized patients to receive alectinib versus crizotinib, show progression-free survival was about 3 years, and overall survival in the alectinib arm was not reached compared to median overall survival at 57.4 months with crizotinib.

Even with crizotinib, the median overall survival was over 5 years, which is amazing, but not even reached for alectinib. With the median progression-free survival of about 3 years, with all these other ALK inhibitors in development, it's really exciting that we’re able to bring some fantastic treatments to these patients, to meaningfully improve their lives and clinical outcomes. Five-year overall survival was 62.4% with alectinib compared to 45.5% with crizotinib, so well over half the patients are alive after 5 years.

If you look a few years ago, the SEER [Surveillance, Epidemiology, and End Results] database of 5-year survival for stage IV non–small cell lung cancer was 5%. Now, were looking at these ALK subsets where the majority, over 60%, are alive after5 years. We need to do better. We need to work on curing patients, but this is fantastic. On top of that, the J-ALEX trial, which was conducted in Japan, had comparable PFS, up to 34.1 months median with alectinib, compared with crizotinib at 10.2 months.

The median overall survival was not reached with alectinib versus 43.7 months for crizotinib. This was backed up by the ALESIA study, which was done with the East Asian population, with a hazard ratio of 0.374 for progression-free survival. So there is an amazing benefit from alectinib in terms of PFS and OS [overall survival] compared with crizotinib. The ALTA-1L study median PFS was 24 months with brigatinib versus 11 months for alectinib, with a hazard ratio of 0.49 and reduced disease progression or death by 51%. There are some fantastic updates and pivotal advances in the treatment of ALK-rearranged non–small cell lung cancer.

Balazs Halmos, MD: The management of ALK translocation-positive lung cancers has exploded in the last couple of years. It was 10 years ago or so that the disease was identified and the first patient with an ALK translocation was diagnosed. Since that time, we’ve seen the development of multiple generations of agents, and we now have the luxury to have a number of frontline agents to pick from. The one that was first developed, crizotinib, has fallen to the wayside because it does not have good CNS penetration, which is a major deficiency in the management of this particular patient subset, with a very high frequency of brain metastases, up to 40% to 50% in different series. Every drug that you want to use in the front line, we want to make sure there’s good CNS penetration and appropriate control of CNS disease. Luckily, a series of drugs that includes alectinib, brigatinib, and now lorlatinib and ensartinib, are joining the crew and have that defining feature. Each of them surpass crizotinib dramatically, doubling or more than doubling the progression-free survival. That includes CNS disease control as well.

Just last week, we heard that lorlatinib came out with a positive study, the CROWN study, as compared with crizotinib. A few days ago at the World Conference on Lung Cancer, we heard positive results with ensartinib, so the list grows regarding the number of agents that we can choose from. How do we choose for each patient? At the moment, alectinib is in the lead because it was the first drug that showed positive results compared with crizotinib. It doesn’t seem to have any glaring weaknesses. It has great CNS activity, and it has a favorable adverse event profile. We have to continue to watch the data; maybe we’ll see some studies comparing these outstanding molecules. Lorlatinib, brigatinib, and ensartinib have great data as well, but there might be some slight weaknesses. Lorlatinib has a bit more of a problematic adverse effect profile. Brigatinib tends to be well tolerated, but it does have an early pulmonary toxicity that some physicians are a bit worried about, but most patients are able to get through fine.

Ensartinib seems to have a favorable adverse event profile, but it’s coming a bit too late to the market. Alectinib will remain in the lead for the time being, but it’s nice to have a number of different treatment choices because not every patient will tolerate a drug as well as the average. Having alternatives is nice, and some of these drugs can also be used at the time of resistance. For example, lorlatinib seems to have great efficacy, even in patients who have developed resistance to one of the earlier-generation ALK inhibitors.

There are some differentiators in terms of adverse event profiles. Alectinib is very favorable, nothing outstanding regarding major adverse events or of significant concern for the average patient. With brigatinib, the sore point is that early pulmonary toxicity, but we’ve learned how to deal with it. We have dose uptitration. It really seems to be a transient issue and not a serious one. Lorlatinib is a bit trickier to use because it has some longer-term management issues regarding lipid profile changes—high cholesterol, hypertriglyceridemia—which many times needs to be comanaged. There’s also some potential for mood disorders, which also need to be comanaged. Many clinicians view lorlatinib as a great drug in the second-line setting but a bit challenging for first-line use.

Ensartinib is a new molecule that I don’t have a lot of experience with, but it does seem, based on reported data, to have a fairly favorable adverse event profile similar to alectinib without a whole lot of major issues that stand out.

Transcript Edited for Clarity