Transcript:
Dr. Helen Ross: I'm Dr. Helen Ross. I direct the Thoracic Malignancies Program at Mayo Clinic in Arizona. I'd like to talk about the role of ALK and ROS1 rearrangements in non-small-cell lung cancer. These are the secondary mutations behind EGFR in terms of frequency of the targetable driver.
ALK and ROS1 are similar mutations in that they are fusions rather than point mutations in genes. They're identified in about five percent and about two percent of non-small-cell lung cancer, respectively. They both were responsive to crizotinib as first-line therapy.
Crizotinib is a better MET inhibitor than an ALK inhibitor but came into the fore with the PROFILE 1014 trial which showed superiority of crizotinib over chemotherapy in patients who had ALK gene rearrangements. Also, showed significant response rates with durable response in ROS1-rearranged lung cancer. This was the first-line therapy for some time.
One of the quirks of these driver mutations is that patients who have ALK and ROS1 rearrangements have a high chance of progression in the brain. If you look over time with patients who were treated with crizotinib, after about a year, up to 40 percent of those patients will have progressed in the brain.
Second-line agents are now available for both crizotinib-resistant ALK rearrangements, as well as crizotinib-resistant ROS1 rearrangements. Some of those second-line therapies have now made it into first-line treatment.
For example, in the United Sttates, the most common first-line treatment for ALK-rearranged non-small-cell lung cancer is alectinib, based on the results of the ALEX trial which showed superiority of alectinib over crizotinib, both in systemic disease control as well as in progression in the brain.
For example, with alectinib versus crizotinib, there is about a 9 percent incidence of brain metastases after a year with alectinib compared to about a 41 percent incidence of brain metastases with crizotinib. This is obviously of great benefit to patients.
There is also equivalent disease control with alectinib, whether patients have brain metastases at diagnosis or not. This is not the case with the older first-generation agents, such as crizotinib.
There are now a number of newer agents which can be used and have been compared to crizotinib. We don't have FDA approval of these agents in the first-line yet, but some of those will be coming, we think, in the next 6 to 12 months.
Just today at ESMO Asia, the updated results of the ALTA-1L trial were presented with brigatinib versus crizotinib, which confirms the ongoing improvement of progression-free survival, as well as progression-free survival in the brain with brigatinib over crizotinib. The Takeda company is likely to be looking for FDA approval of this agent in the early part of 2020.
In addition, a number of other agents including lorlatinib are in use. Lorlatinib is a third-line agent, and is particularly useful against the G1202R mutation, which is a significant cause of progression in patients who have ALK gene rearrangement and is really the only of the currently available agents that works well against this particular mutation.
ALK fusions are predominantly with EML4, but there are several different variants of ALK fusion with EML4. It seems that the variant 1 fusion, which is responsible for about half of EML4 ALK fusions, has a better overall response rate and a better overall survival than the other variants. This may be something that is looked at in ongoing clinical trials.
In addition, the lorlatinib also penetrates the brain very well. There are first-line trials which are going on now, comparing lorlatinib to crizotinib. We may see an additional first-line indication, depending on the results of those trials which are still ongoing.
ROS1 rearrangements are an even smaller proportion of the pie, being responsible for one to two percent of non-small-cell lung cancer patients. Again, mostly in younger patients and mostly in patients who have never smoked, crizotinib works extremely well in ROS1 rearrangements. There are many patients who are still on crizotinib from the early days of its use against ROS1.
Lorlatinib is also useful in ROS1-rearranged patients and gets into the brain better than crizotinib. It's a good choice for those patients. The recently approved entrectinib, which is an NTRK-targeted agent, also has significant activity against ROS1 and gets into the brain.
It's really important to identify these patients with ALK and ROS1-rearranged lung cancer because when they are treated with the appropriate targeted agents, they have an extremely long survival in the setting of metastatic disease.
We are seeing median survivals in patients that are treated with the appropriate targeted therapy in the eight or nine-year range. Knowing that these mutations are present is crucial in order to get good outcomes for these patients.
