Therapy Options at Progression in ALK+ NSCLC

David Spigel, MD: Knowing when ceritinib is not working anymore can be challenging. Often, you can have patients who are feeling and doing well, but their scans show that there has been growth or a new lesion. This is actually a challenge limited to not just theALKsetting. This happens in other targeted populations, like patients withEGFRorBRAFmutations. Even with our more traditional therapies like chemotherapy, and now with immunotherapy, knowing when you should stop a drug is not always easy. In general, when somebody has florid progression on imaging, and that correlates with clinical decline. It’s a pretty easy thing to sort out.

The most complicated scenario is somebody who’s doing really well physically, clinically—they feel well, and they’re doing well—but they have a new lesion in the brain. What do you do then? Often, we will keep the systemic therapy going—ceritinib in this example—and address the brain lesions, if they’re symptomatic, with something like radiation therapy. Radiation to the limited spot or spots can be an effective strategy. When you have a lot of new lesions, though, and somebody is feeling well, it’s hard to keep that therapy going. So, for example, finding multiple new liver lesions, new lung lesions, new brain lesions—even in somebody who is feeling very well—is the time to make a change in care. In my view, that’s not a patient who’s just going to stay well forever. That’s a patient who, in time, is going to start to feel the effects of that progressive disease. And so, making a decision about whether or not to go on to a next-generation ALK inhibitor as part of a clinical trial, or moving on to chemotherapy, is something that needs to be decided relatively quickly to make the best treatment plan for the patient.

Following patients on oral therapy forALK-rearranged lung cancer is very much like following anybody on treatment for any cancer. This is one area, though, where there are a couple of caveats worth mentioning. So, one is brain imaging. In addition to standard body imaging, physical exams, and evaluating patients in your clinic, imaging the brain periodically is a must, in my opinion. Our third-party payers and guidelines don’t always endorse that, but a common area for progression is the brain. And adequate studies—contrasted imaging, ideally MRIs—are the best way to identify that. But if you’re not doing it, then you’ll never know, and a lot of times patients will miss the opportunity to have isolated lesions addressed with radiation therapy, and it gets discovered only when they have florid, widespread progression.

The other caveat I’ll mention—and this is a relatively new thing—is that blood-based testing is available. There are some physicians who are asking or wondering if they can do serial monitoring or blood testing to try to identify progression earlier than a scan will show. Simply said, the answer would be no, that we’re not quite there. I think we can get there, where you can use blood-based testing to help you understand, are you losing that control? Are you developing a resistant mutation? I think there’s value there, but right now I don’t think it’s there in terms of routine clinical practice. I just don’t know how far away we are from that being standard of care. It’s just not quite there yet.

When you’re on a good drug like crizotinib, ceritinib, or alectinib, you really want to stretch that out as long as you can, but when it’s time to make a change, you need to make that change. So, when you have clear evidence of progression—these are scenarios where patients have obvious growth on their scans or new lesions in the brain that are symptomatic—this is the time to begin thinking about making a change in care. Ideally, it’s a clinical trial, and ideally, it’s getting access to a next-generation ALK inhibitor.

Sometimes, you can even identify the resistant mutation and steer your care to an agent that addresses that mutation, but sometimes it just means moving on to chemotherapy. A lot of these patients have never received chemotherapy. The oral agent has been their first and only therapy. And so, you still have the benefits of platinum doublet chemotherapy, and for a lot of patients, that will be carboplatin and pemetrexed-based treatment. That would be the regimen they move on to next. My only little tip when a patient moves on in that transition is that it happens relatively quickly. Sometimes that gap between stopping their oral agent and deciding what to do next can lead to rapid progression of the cancer and clinical decline. So, bridging the patient from their oral therapy to chemotherapy as quickly as possible is really the ideal strategy.

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.