Sequencing Therapies in ALK-Rearranged NSCLC

Transcript:Benjamin P. Levy, MD: We’re going to do a thought experiment and some crosstrial comparisons, which we’re taught not to do. The updated ALEX trial was presented this year at the ASCO [American Society of Clinical Oncology] meeting. I think the PFS [progression-free survival] updated with more mature data. The hazard ratio is 0.43.

Solange Peters, MD, PhD: The median has not been reached, and we now know it’s 35-something. That means it’s going to be difficult to displace or replace or fight against alectinib for the time being. The hazard ratio for brain progression is 0.16 and so on and so forth. But like you say, it’s about maturity of data. It’s about the timeframe. If you have something in the data, we need some more time to accumulate. I think those drugs might both have a very good safety profile and very good efficacy, maybe even equivalent at the end with a longer follow-up. But they have slightly different toxicities.

I had this patient on alectinib in the ALEX trial with muscle pain that was really limiting, and you will have this problem of dyspnea, which might sometimes prevent some patients from having benefit. There’s the fever of this drug. There will be different drugs, I hope. It will be good for the patient if they have the same magnitude of benefit. But still, alectinib has some meters of advantage or some achievements that make it the standard. But that may be bias here.

Sanjay Popat, PhD, FRCP: Of course. I think the alectinib data are more mature. Because they’re more mature, we understand the toxicity is better and we understand the efficacy better. The one thing that the brigatinib data have shown is that we have no new safety concerns with brigatinib. In fact, the early pulmonary events are at a much lesser rate in the frontline setting when you see postcrizotinib data. They are very different in terms of their toxicity profile. I think both are potentially reasonable options to use in that setting, and the real key issue here is, how does the maturity of the data with ALTA-1L affect what see as we move forward?

Benjamin P. Levy, MD: Let’s say we do have mature data, the data hold up and are similar to ALEX, and we look at the crizotinib-refractory cross-trial comparison, and those data look fairly comparable, perhaps favoring brigatinib in terms of its PFS. Let’s say it all holds up and is similar. Does the difference in pill administration make a difference? One pill a day versus 8, is that something that you think matters? I don’t think there’s a right answer here, but would that potentially change what patients would want, if they’re deciding between 4 and 4 with the alectinib versus just 1 or 2? I don’t know how brigatinib is dosed. I haven’t used it yet. Does once-a-day dosing with brigatinib make a difference for a practitioner?

Suresh S. Ramalingam, MD: What will make a difference, Ben, as we understand the resistance mechanisms for these 2 drugs, is what resistance pathways are activated. Are they different between these 2 drugs? For instance, we know that the G1202 mutation tends to be a very resistant mutation to treat. If we see a difference in how frequently we see that between one drug versus the other, that might guide how we use them. My one view of this whole field is that alectinib clearly has the pole position in Formula 1 line.

The question was, is there space for anything else? The ALTA-1L trial clearly shows that brigatinib probably belongs in that space. It’s a bit too soon, because with more follow-up, we’ll have more information. But clearly this opens the space up for us to have these conversations. It’s a good position to be in when you have more than 1 drug, and we’ll figure out what the best one is for our patients. I find that the ALTA-1L results are exciting. They do add to the existing landscape, and we will be learning more about this regarding resistance mechanisms particularly. I’m looking forward to that.

David Planchard, MD, PhD: It will also be challenging for the Asian population, the Japanese population, for which with alectinib there is also a specific trial with J-ALEX. There are data of efficiency in the ALK-positive Asian population. That’s why I don’t know if we are seeing this type of benefit in the Asian population with brigatinib and the same magnitude of benefit. That’s probably something that should be considered for Asian countries and Asian populations.

Sanjay Popat, PhD, FRCP: Absolutely. The brigatinib trial was a global trial. It recruited patients from all around the world, including Asian patients, and we have not seen any challenges with efficacy or safety in that population. I would suggest that we have similar benefits and no deterioration in toxicity for that Asian population.

Solange Peters, MD, PhD: We had a specific trial presented at the ASCO meeting for the Asian population with alectinib. It’s called ALESIA. I agree with you: If the drugs perform the same, we will have to look at potential practical parameters: accessibility and cost will be one, the pricing of the drugs, maybe the pharmacology at the brain level will be one, just taken by PFS at that level. But we might have to look at details to differentiate. All these data are very nice. We have too many options. But all these data will help us choose over time. Resistance is very important. How much you can take action after these drugs to be successful for your patients will be a very important problem, too.

David Planchard, MD, PhD: What is probably the most impressive for me with alectinib is the prevention of the brain metastases again. It will be something important to look at for the behavior of alectinib, if we have these types of data and magnitude benefit on the brain. I do not have to treat the brain metastases but can instead prevent the brain metastases. I think this is something that matters.

Sanjay Popat, PhD, FRCP: In ALTA-1L, we’ve looked at the complete risk analysis for both intracranial events and extracranial events. In a similar manner, brigatinib is highly effective at reducing the rate of new CNS [central nervous system] metastases developing. We’ll hopefully have a much more robustly detailed CNS efficacy dataset presented at the ESMO [European Society for Medical Oncology] meeting.

Benjamin P. Levy, MD: If we think alectinib—for now, at the World Conference on Lung Cancer in Toronto in 2018—is still the preferred first-line drug, until we see more mature data, how do we sequence these drugs? Alectinib comes first. It’s a similar theme with osimertinib. What comes next? What comes after alectinib? Is it brigatinib? I don’t think we have a lot of data with that, although brigatinib, to my knowledge, does target D1202. Is it lorlatinib or is it chemotherapy? How do we do this?

Solange Peters, MD, PhD: It’s interesting. What we know is that we have this algorithm for preclinical or in vitro kinase activity that maybe helps in choosing for every single mutation. But the G1242R mutation, which is more and more encountered the more you accumulate TKIs and the more you go to next-generation agents, is a challenging mutation. Theoretically in the in vitro model, kinase enzymatic activity might work, but there are very few reports on it. I had 2 case reports in JTO [Journal of Thoracic Oncology]. We really need to have more data. Lorlatinib has shown a bit more data here. You have a nice protocol telling you that at the brain level, at the systemic level, this just might be the next option.

Lorlatinib is probably also a challenger in terms of frontline options. It has some toxicities, right? What I would say for lorlatinib is that it’s a good opportunity for this specific mutation of resistance. After alectinib, I would tend to try to get a molecular assessment, but sometimes it’s difficult. But if you can get it, I would do that. I would try lorlatinib because we had very good responses with this third-generation TKI in this type of patient. I would probably not go to another second-generation agent but move to lorlatinib.

Benjamin P. Levy, MD: Don’t forget pemetrexed. It’s a wonderful drug in the absence of chemotherapy and can certainly be active in the ALK-positive patients.

Solange Peters, MD, PhD: Absolutely.

David Planchard, MD, PhD: I completely agree. I think one of the issues with lorlatinib—and we’ll await the ongoing phase III trial comparing it to crizotinib—is the tolerability and the toxicity. I think it will be an issue in first-line treatment with lorlatinib, particularly if we are comparing directly to brigatinib and alectinib where we saw nice tolerability. I think this is something important. For lorlatinib, it will be an issue. I’m quite confident of the efficiency of lorlatinib beyond progression on alectinib and brigatinib, particularly if you develop these mutations of resistance that have been well demonstrated. It’s particularly important to be efficient even if the patient progresses in the brain area with lorlatinib after alectinib.

I’m quite happy to have lorlatinib in the second line of treatment for this population. After, perhaps use chemotherapy beyond that, particularly with pemetrexed. The last question is, why not try to make a combination of chemotherapy and an ALK TKI. We are coming to this combination in the EGFR space. We might also look at it perhaps for this ALK population.

Transcript Edited for Clarity