Suresh S. Ramalingam, MD: We also have seen 2 randomized trials, Giorgio, comparing alectinib to crizotinib in the frontline setting. Talk to us about the ALEX trial, and give us your thoughts on whether or not alectinib is poised to be a new frontline option.

Giorgio Scagliotti, MD, PhD: We initially saw the study done in Japan, and that was called the J-ALEX trial. The study was using, compared to the ALEX study that has been presented more recently, a lower dose of alectinib in comparison with the standard dose of crizotinib among the Japanese population. So, the first study, the Japanese study, showed an outstanding superiority for alectinib compared to crizotinib. But considering the ethnic differences between Asiatic patients and Caucasian patients, a second study was needed, and the second study was the ALEX study.

As Benjamin said before, alectinib showed a striking superiority compared to crizotinib in the second study. When you are also considering the activity of alectinib, the minimum toxicity that you are generating with this agent in the patients with ALK translocated disease, I truly believe that alectinib should be a preferred agent.

But, again, I truly believe that in the patients with ALK mutations, as well as for the patients with EGFR mutations, the most important message that should be communicated is that, independently from which kind of treatment you are choosing in the frontline setting, it is critical to perform a rebiopsy at the time of the progression. Why am I saying that? I’m saying that because as you said in your introduction to this session, and as Benjamin said before, we are dealing with multiple agents. These multiple agents at this time—only in cell lines, not in human beings—showed a differential activity based on the type of resistant mutation that is being observed. So, it could be that in the near future we are able to tailor treatment. It’s not just a matter of sequencing. Sequencing by chance means you will start with crizotinib, you will move to alectinib, then to brigatinib, and then to lorlatinib. That is what, at least in my center, we are doing these days.

But it could be that increasing the sensitivity of the diagnostic techniques, increasing the amount of rebiopsies that—not only from us, but also outside of the academic centers—the patients will receive. We’d be able to frame our sequence of treatments in a different way, based on and guided by the type of resistance mutation we see in the tumors. I know that it’s just a dream, but I need to be a dreamer. Consequently, I truly believe that even more importantly that, in the context of the EGFR mutations—where there is 1 resistance mutation that is overarching all the others, because we were talking about how T790 is 60% versus all the others—we probably need to learn a little bit more about how to sequence all of these agents.

It’s a matter of fact that any decision we make in the clinical practice is always a trade-off between the activity of the drug and the toxicity. We learned over time how to manage the toxicity of crizotinib. It’s not an issue anymore. At the beginning, we were fearing a lot of short-term and long-term consequences, including the interference with the endocrine system. But this is something that is not really relevant because across a learning process, we started managing all these kinds of toxicity. Considering, as I said, that we are making therapeutic decisions based on this trade-off, I truly believe that alectinib may be a good frontline agent for our translocated patients.

Suresh S. Ramalingam, MD: That was an excellent summary of the critical issues that we face about testing and sequencing. I want to bring up the issue of brain metastases. In ALK-positive patients, we know that the disease has a high predilection for brain metastases, and we’ve seen activity with crizotinib in the brain. We’ve seen activity with ceritinib and alectinib. But the second-generation drugs seem to have more activity in the brain. So, Marina, if you have a patient with brain metastases who has ALK-positive disease, how do you approach the treatment?

Marina Garassino, MD: We have to consider that ALK-translocated patients have more brain metastases compared with other actionable mutations. So, in this kind of patient, this is really a huge problem. We know that crizotinib, which is a wonderful drug, is not the best drug to be active in the center in our system. We have results from all of the second-generation drugs, because they are almost all active on the central nervous system. But I totally agree with Giorgio that we have to create a balance between toxicity and activity, and alectinib proved several times to have high activity on brain metastases with very good tolerability. And I can tell you the story of a young lady who underwent a CT scan after just 20 days of starting alectinib—she was full of brain metastases—and just after 20 days she was cleaned. So, the activity is very strong, it’s very quick, and the safety is wonderful. Compared with ceritinib, I would prefer, again, alectinib for the treatment of brain metastases.

And then, for the sequence of the drugs, I totally agree with Benjamin on the problem of the sequence. But I think that we have to also consider that we are far from the EGFR mutation study because in ALK inhibitors, we have several types of mutations, and they represent just one-third of the mechanism of resistance to ALK inhibitors. There’s a wonderful piece of paper by Gainor suggesting that every drug has a specific mechanism of resistance with the mutations. So, I totally agree that we have to personalize therapy accordingly with the mutation, but also with the other pathways activated after the first-generation ALK inhibitor. But, for sure, with the brain metastases, I think that the first line can now be alectinib.

Transcript Edited for Clarity