Sequencing of Therapies in ALK+ NSCLC

David Spigel, MD: One big area of importance in clinical research is understanding the value of taking a next-generation ALK inhibitor and moving it to the first-line setting. Right now, we have crizotinib, and then we have these next-generation drugs approved. So, crizotinib is a fantastic drug. If a patient progresses, they can get ceritinib or alectinib at progression and do well. Still, what we want to know is, can you take those great drugs and move them into the first-line setting? Can a patient do even better, when you add it all up, than if they had gotten 2 sequences of therapy? Because one of the concerns is what you do when someone progresses on the best first-line drug you have. You’re not going to give them an inferior ALK inhibitor after, but I think people will do that, and ultimately it will need to be studied.

Really, you’re looking at chemotherapy until a next-generation ALK inhibitor gets approved. That is one of the concerns: What is the value of taking an effective drug in the second-line setting and moving it into the first-line setting? Are you helping the patient overall? I think we tend to believe that giving the better drug first is the way to do that. But, really, I think more time will be needed to sort out the true benefits in terms of absolute overall survival.

The ALK inhibitors that have been approved include crizotinib, ceritinib, and alectinib. There’s a shift in the line of therapy that those drugs are effective in now—all moving into the first-line setting. There are other agents in development. One of them in particular, brigatinib, was recently FDA approved to be used in the second-line setting. There are other agents behind that. One is called lorlatinib, an agent that looks to be very effective as well. The pivotal trials of lorlatinib are just getting under way, so comparing how that drug does versus standard therapy like crizotinib will help define whether or not that drug can move into the first-line setting. And there are at least 2 other agents in development that look promising as well. When you add it all up, we have 7 ALK inhibitors: 4 of these are already approved, 3 are on the horizon, and there are probably others in the future.

The hope would be that we have drugs to be used in sequence. So, if someone is on a great drug and they progress, they can get another great drug. I think more research will have to be performed to understand the sequencing of these drugs, and these trials are in progress to look at that sequencing issue.

It’s hard to predict the future. For right now, it has been to just design a better drug, to take your best treatment and see if you can tinker with it a little bit and find a way of making it more effective. That has been a good strategy, not just in ALK inhibitor drug development but also in the CML andEGFRsettings. But it’s hard to ultimately keep doing that, and you may reach a point where you have the best inhibitor on the market, and you may not be able to fine-tune that much more. So, the big question is, can you develop other drugs for alternate escape pathways or resistant pathways?

There have already been data, and the Massachusetts General Hospital group has shown that you can treat somebody with a drug, they can develop resistance, you can treat with another drug, they can develop another resistance, and you can come back to the first drug. So, it may be that if you just have a toolbox filled with agents—and you really understood what kinds ofALK-rearrangements and mutations they were effective against and which ones they don’t work against—in theory, you could test a patient at progression and decide that they get drug A this time, drug B this time, and maybe drug A later. That may be a direction we’re headed in, where blood-based testing can solve that sequencing. Or, it may be that we decide that adding immunotherapy to these agents, or some other novel combination, makes more sense. The best example I can think of is inBRAF-mutated lung cancer, where we know BRAF inhibitors are very effective, but when you add a MEK inhibitor, you can enhance that efficacy and improve safety. There might be strategies like that in the future of ALK inhibitor drug development, but for right now, we have multiple agents—single agents—that are in development.

Transcript edited for clarity.

• A 62-year-old female never-smoker presented with dyspnea, cough and fatigue.
• Patient has a performance status of 1 due to the decrease in her daily activities.
• Chest X-ray showed multiple bilateral lung nodules.
• PET/CT showed left adrenal metastases.
• Brain MRI was negative.
• Bronchoscopy was performed with a fine needle aspirate biopsy.
• Pathology results showed moderately differentiated adenocarcinoma.
• Molecular testing showed ALK-rearrangement.
• Patient was started on ceritinib.