Suresh S. Ramalingam, MD: My views on the alectinib data are that the median progression-free survival is over 2 years, it has good activity in the brain, and, as mentioned, it has a very good tolerability profile. So, I understand the importance of the sequencing issue, but I think that the ability to have a patient on a well-tolerated drug for over 2 years is very appealing to me when considering moving alectinib to the frontline setting. I do think that alectinib is likely to get approved in the frontline setting based on the 2 ALEX trials, at least in the United States, which means we’ll have 3 options in the frontline space for ALK: crizotinib, alectinib, and ceritinib. People are going to have to make decisions on which is best suited for their patients based on many of the factors that we discussed. What I want to talk about is the fourth drug in this space, brigatinib, which is now approved for second-line therapy in ALK-positive disease. Marina, I know you’ve been part of some of these trials. Share with us the data of brigatinib and how it fits into the landscape.

Marina Garassino, MD: Brigatinib is another very interesting drug because the results coming from the ALTA trial suggest that there is a very long progression-free survival in advanced lines. The drug was developed with 2 dosages, so you have to start with 90 mg and then move to 180 mg, and the drug is very well tolerated. However, you must be very careful, because there is a particular toxicity appearing just in the first 3 to 5 days of the drug, which is pulmonary toxicity. I can tell you that I did a chest x-ray for a patient after 2 days, and she had pneumonitis from this drug. So, if you can manage the first few days and you do not have toxicity, then the drug is well tolerated and you can give it continuously for a longer period. I don’t know which is the right place to put brigatinib now in the marathon of ALK inhibitors, but for certain, it is an active drug with very good progression-free survival.

Suresh S. Ramalingam, MD: Thank you for bringing up that pulmonary issue. While it is problematic when it occurs, the incidence is fairly low, less than 5%. Obviously, that’s a reason to start the drug at a 90-mg dose for the first week. Once you get through that period where the patients are at risk, you can go up to the 180 mg. The median PFS reported with brigatinib in the second-line space is close to 13 months, which is a number we’ve not seen with some of the other ALK inhibitors in that space, and to me that makes this a valuable drug in this situation. Obviously, understanding the mechanism of resistance and using the right drug to treat the mechanism is an ideal situation, but we’re not there yet. Benjamin?

Benjamin Besse, MD, PhD: You are referring to a very nice second-line PFS, but it’s from second-line brigatinib after crizotinib, and you are promoting alectinib as start-off care, first-line. So, what will be the activity of brigatinib plus alectinib? This is really the question. In the paper on resistance mechanisms, it’s really striking to see that post-crizotinib, you have 10% of aggressive resistance mutations. When you are post-brigatinib, it’s up to almost 70%. That’s why when we talk about sequence, we have to take into account that when you give a strong drug up front, you probably select a more aggressive disease at progression. That’s why overall survival data will be important. If you are treating staphylococcus, for example, that is wild-type, you don’t choose the last-generation antibiotics. You use the first-generation drugs, and when it recurs, you do the antibiogram and you adapt.

I think that it’s still a good strategy, and I don’t promote crizotinib as a first-line therapy. But in the ALEX trial, there is a figure in the superiority material that is really, really striking. It shows that if you take out the brain metastases, the activity on all the other sites is exactly similar between both drugs. And, in ALEX, an MRI was done every 2 months. I would like to know if the audience really thinks that this is a standard of care, to perform a brain MRI [magnetic resonance imaging] every 2 months. So, it’s easy to say that a drug has a long PFS and that the competitor is weak because I’ve obsessively looked at new brain metastases. When there is a new brain metastasis, it’s an event. It’s a 5-mm brain metastasis, asymptomatic, but it’s an event. That’s why the ALK inhibitors are very, very nice, but I think sometimes we rush into new strategies without a good knowledge of which is really the best sequence for these patients who live, again, for a very, very long time.

Suresh S. Ramalingam, MD: Thank you. Now, let’s talk about some of the promising upcoming drugs for some of the rare mutations. I want to wrap up this ALK discussion talking about lorlatinib, which is not approved but has shown activity in some of the rare mutations. Giorgio, what are your thoughts on what you’ve seen with lorlatinib so far?

Giorgio Scagliotti, MD, PhD: We got an original presentation a few months ago that was presented, if I remember correctly, at ASCO about this new treatment opportunity. The study has been presented in patients who were heavily pretreated. In the waterfall plot that they showed in the context of refractory disease, it was quite exciting for a clinician. At this meeting [ESMO 2017], there is, I believe, a poster discussion about the activity of lorlatinib in ROS1-translocated patients. Personally, I have only a few patients who have been treated with lorlatinib, so it’s mainly based on the gut feeling on the systematical assessment of its activity.

Consequently, I made my judgment based on what I saw at the presentation. It’s an active agent with a toxicity profile that is not so relevant or important. The agent has the possibility to move to early phases, but again, I share the opinion of Benjamin. We need to be careful in the way that we are moving all these agents to the front line or to the early lines of treatment. The primary aim, as I said before, is to make this type of disease a chronic disease. In addition to that, I see biological differences between the ALK-translocated non—small cell lung cancer and the EGFR-mutated non—small cell lung cancer. When the disease is becoming truly refractory to the currently available targeted therapies, it’s a rapidly progressive disease and it’s a rapidly metastasizing disease.

Consequently, regarding the rational use of sequencing, I can agree that 1 year from now we can meet for this kind of activity and all of us will agree that alectinib is the best choice based on the growing evidence and the maturity of the data and so on. But using the right sequence of the drugs in a pure clinical way, a pure empirical way, or through the guidance of rebiopsies—if we want to make this disease a chronic disease, we need to use this kind of approach.

Transcript Edited for Clarity