Dr. Nathan Pennell, Cleveland Clinic, discusses acquired resistance to Xalkori in ALK-positive patients, and second generation inhibitors designed to overcome that resistance, such as Zykadia and alectinib.
I’d like to talk now about next-generation anaplastic lymphoma kinase, or ALK, inhibitors. So, we know for patients with ALK-positive non-small cell lung cancer, that targeted treatment with ALK inhibitors like Xalkori, or crizotinib, are now the standard of care for patients with advanced disease, based on head to head trials showing that they work better than chemotherapy in inducing major tumor responses and delaying the progression of the disease, and potentially even improving survival. While responses can sometimes last a long time with Xalkori, unfortunately a majority of patients will eventually go on to develop what is known as acquired resistance where the cancer begins to grow despite continued treatment with the drug that worked so well initially. Something has changed in the cancer that’s caused the drug to no longer work to inhibit it, and when we biopsy these cancers, we find that there are a lot of different changes.
So unlike epidermal growth factor receptor mutation-positive lung cancer, there is no one dominant mutation that’s leading to resistance in ALK- positive lung cancer. There are lots of different mechanisms, but fortunately there are a wide array of new ALK inhibitors out there which have shown to be effective in this setting.
The first one that was farthest along and, in fact, is already approved for patients in this setting, is called Zykadia, or ceritinib. This was approved last year based on a large trial in patients who had progressed on the Xalkori, and about 50-70% of patients will have a major response to the Zykadia, with a duration of disease control that’s, on average, probably in the eight to ten month range. This drug is a little bit tougher than the Xalkori, so many patients have some nausea or vomiting, diarrhea or upset stomach, but these are things that oncologists are used to dealing with and with dose reductions and management of side effects, patients can tolerate this and it can work quite well.
There are also a number of other ALK inhibitors that are still in clinical trials that are likely to be approved soon. Probably the one that’s farthest along is known as alectinib. So we’ve just recently seen trials, again, showing that between 50-70% of patients with acquired resistance to the Xalkori will respond to alectinib, and the vast majority will have disease control for a fairly good period of time — again, the average is somewhere in the eight to ten month range, but many patients longer than that, and at least in published results, alectinib may be easier to tolerate than the Zykadia.
So this is just the tip of the iceberg. At last count, I think there were six or seven other next-generation ALK inhibitors in development — I don’t have time to list all of them, and none of them have been compared to one another to know which one is best, but all of them, at least preliminarily, appear to be effective in the setting of acquired resistance to crizotinib.
What I would recommend in 2015 is, if patients develop an acquired resistance to the Xalkori, that they preferentially enroll on a clinical trial of one of the new next-generation ALK inhibitors because I think this is the only way we’ll ever learn which of them is best and which one works the longest. But, if you don’t have a clinical trial available to you, or you’re not eligible for a clinical trial, your doctor can prescribe Zykadia right now and we know that’s an effective treatment.
The other thing that’s nice about these drugs is that they all seem to have some activity in brain metastases. We know that ALK-positive patients develop brain metastases at an extremely high rate, and this can be a real problem, sometimes even while the rest of the cancer remains under control. Both alectinib and Zykadia have been shown to have efficacy in brain metastases, in addition to the rest of the body — so, good news for ALK-positive lung cancer patients.