Precision Medicine in Advanced Non-Small Cell Lung Cancer - Episode 9

Alectinib in ALK-Mutated NSCLC


Benjamin P. Levy, MD: For the sake of time, I think we’re going to shift gears into the ALK space, and, potentially, the ROS space, if we have some time. ALK is a rearrangement that was discovered in 2007 (I believe), in lung cancer, with the first drug approved in 2011. It took 4 years, which is really emblematic of the pace of genomic discovery and the development of drugs wedded to those particular genomes that they work for. We’ve had a lot of movement in the ALK space. Alex, maybe you can talk about the ALEX trial, and other frontline data?

Alexander Drilon, MD: I think it’s fantastic. Even though we’re switching gears from EGFR to ALK, we’re seeing a very similar theme. In the ALK-rearranged space, you had a first-generation drug like crizotinib, followed by second-generation agents alectinib and ceritinib that have broader activity against a wide range of ALK alterations and have improved CNS coverage—again, harking back to that osimertinib story. In the ASCEND trial for ceritinib versus chemotherapy in patients who are treatment naive, we’re clearly seeing that ALK-directed therapy is superior in terms of overall response and progression-free survival. This is very similar to the data that we saw earlier on with crizotinib in the first-line setting. The big difference is that ceritinib, compared with alectinib, has a very different safety profile. We saw diarrhea, nausea, and vomiting that were greater than 60%. Obviously, when you want to dose a drug chronically, it can be very prohibitive.

Thankfully, we have the ALEX study, which is a better comparison. You have a head-to-head study of crizotinib, a first-generation drug, and alectinib, a later-generation agent. Clearly, as we’ve seen with the FLAURA data, alectinib was superior. You had a median progression-free survival of 35 months versus 11 months, and you’re seeing much more durable disease control plus improved control in the CNS. Even if you broke out patients by those who have CNS metastases, those patients still did very well on alectinib. So, a similar theme to what we’ve already discussed.

Benjamin P. Levy, MD: And what about toxicity concerns? You’ve used a lot of alectinib. Are there any issues that you’re experiencing in the clinic that mirror the data? This is 4 pills given twice a day. Is there anything that you’re having to do in everyday practice? Is there a message? Is there anything to watch out for if using alectinib?

Alexander Drilon, MD: For the vast majority of patients, it’s a pretty tolerable drug. It was striking that when you compare the toxicity side by side, alectinib still won over crizotinib, which we already think of as a tolerable drug. Obviously, we see certain class-type side effects like inflammation in the lungs, etc. You may also see gastrointestinal changes, or a rise in ALT or AST. But, by far, most patients actually tolerate the drug very well.

Benjamin P. Levy, MD: It’s hard to ignore. Similar to FLAURA, when you have a better drug, a better-tolerated drug with better penetrance in the CNS and median survival times that we have not witnessed before…

Zofia Piotrowska, MD: A progression-free survival of 35 months is really just unbelievable.

Benjamin P. Levy, MD: It’s unheard of.

Lyudmila A. Bazhenova, MD: It’s humbling. I’ve never imagined that I’d tell the patient who has just become diagnosed with stage 4 lung cancer, and these patients are usually young, that we won’t worry about them for at least 3 years.

Benjamin P. Levy, MD: Yes, it’s a remarkable story. People think that ALK is just a rare genotype, but it really isn’t in some patients. In the under-40 crowd, it’s quite high. When you have a great drug like this, it’s been a pleasure to witness the changes that have happened and the science that has affected patients immediately.

Transcript Edited for Clarity