Benjamin Levy, MD: For the sake of time, we’re going to move on to gene fusions and MET exon 14 skipping mutations. The first gene fusion that’s relevant in lung cancer, right after EGFR, has been the ALK rearrangement, and we’ve made so much movement. Lyuda, you’ve been a part of the science of that and intimately involved in some of the studies. Do you want to talk about ALK rearrangements in lung cancer in general, and what the options are currently? We have some new first-line options, and maybe we can throw it to the panelists to discuss what to do at time of disease progression.
Lyudmila Bazhenova, MD: Sure. If you look overall at all comers, ALK rearrangement in lung cancer impacts about 5% of patients. The incidence increases if you select for nonsmoking patients or nonsmoking patients who are EGFR negative. We’ve had more drugs than patients, as the joke goes about ALK fusion. Currently, there are at least 5 drugs that have an FDA approval for different categories of patients without fusions, and a couple more in development. At ASCO [American Society of Clinical Oncology Annual Meeting], there is 1 abstract that gets my feel-good award, and this is a pat-on-the-back award. That is ALEX, whose investigators have presented their continuous update on survival data. Five-year overall survival [OS] with alectinib was 67%. When I started treating lung cancer 15 years ago, I could not have imagined in my wildest dreams that I would have a 5-year survival of 67%. The nice thing about ALEX is that this data is still immature. There is a 37% maturity, and the alectinib arm did OK—about 45%. [AC1] Still, the 5-year overall survival with alectinib is very impressive. We still have not reached median OS.
I was also asked to cover brigatinib. There was no efficacy update on brigatinib at ASCO. There was an efficacy update for brigatinib based on variance, as well as TP53 mutation, by Ross Camidge. Basically, it works. It’s better than crizotinib, regardless of your variant and presence or absence of TP53 mutation. The most recent first-line data that we have on brigatinib is based on the ALTA-1L trial that was presented at ESMO [European Society for Medical Oncology] Asia Congress in 2019. The ALTA-1L design is very similar but not identical to the design of the ALEX trial. Patients with ALK fusion lung cancer were randomized to brigatinib versus crizotinib. Prior chemotherapy was allowed on ALTA-1L, which is different from ALEX. Enrollment for ALTA-1L was also based on local testing, and ALEX was based on central testing. The primary end point in ALTA-1L was blinded independent review of PFS [progression-free survival]. In ALEX, it was investigator-determined PFS. The ALTA-1L trial was positive, showing improvement in PFS of brigatinib over crizotinib. It was a PFS of 24 versus 11 if you use blinded independent review, and 29 versus 9 if you use investigator-determined PFS. The activity seems to be present in patients with or without brain metastases. That is what we expect, knowing that brigatinib does have CNS [central nervous system] activity.
The main question that we have in the ALK space right now is, what is the right sequencing? I know you’re going to ask me that question, so I’m just going to say it out loud. For my next patient who has presented to me with ALK fusion, what is my drug of choice? Currently, if you look at FDA approvals, we have crizotinib, ceritinib, alectinib, and brigatinib. All 4 of them are approved in the first line. Currently, the true front-runners in that space are brigatinib and alectinib. I will put my name on the record. When ALTA-1L came out, I was using alectinib, and when the data came out and weren’t better than alectinib, I kept using alectinib. Now this is my drug of choice. Since I was involved with brigatinib for quite some time, that got my award for the most disappointing news of 2019, because I was definitely rooting for the drug. It is an approved agent, but right now I didn’t find a reason to switch. The question of sequencing still needs to be investigated. I strongly advise anyone to enroll in the NCI [National Cancer Institute]–NRG ALK Master Protocol, which answers the question of sequencing.
In my practice, I use brigatinib second line after alectinib, and I’ve seen responses. Those data regarding postalectinib response with brigatinib from both France and the United States showed a response rate of 30% to 50%. I’ve seen responses to brigatinib postalectinib.
Transcript Edited for Clarity