Targeted Therapies in Advanced NSCLC - Episode 4

Crizotinib for ALK-Rearranged NSCLC


Mark A. Socinski, MD: ALK translocations in adenocarcinoma of the lung were initially described in 2007, so it’s been less than 10 years that we’ve understood this population. This population has a different demographic. These patients tend to be younger. Most of the studies show the median age of these patients to be in the mid-50s. There is almost a 1:1 distribution between men and women, whereas EGFR mutations are more common in women. Like EGFR mutations, ALK translocations are more common in adenocarcinoma, as well as never-smokers, so it follows that paradigm of never-smoking lung cancer in slightly younger patients.

Interestingly, about four years ago, we had the approval of crizotinib for this setting. Crizotinib was not initially felt to be the best ALK inhibitor, but there was activity seen. And, so this drug was rapidly developed in the ALK population and it was highly effective, with response rates well above 50%, and with progression-free times in the range of 10 plus or minus a couple of months in this population of patients.

We also know that both in the second-line setting, as well as the first-line setting, if you take ALK-positive adenocarcinoma patients and you randomize them to crizotinib or standard chemotherapy, that crizotinib is associated with higher response rates and better progression-free survival, which was the primary endpoint of those trials. We don’t yet have survival data. However, I think the ability to take a well-tolerated oral agent that’s targeted at your oncogenic driver yields better response in progression-free survival outcomes. It’s a huge advance and really has changed the standard of care in the ALK-positive population.

Alice T. Shaw, MD, PhD: Crizotinib is a really interesting sort of drug development story. Crizotinib was first developed to inhibit a different tyrosine kinase, c-MET, but was subsequently found to inhibit ALK and ROS1 and, now is an approved agent for ALK and, hopefully, soon for ROS1. And its activity in MET is still being investigated. We do use crizotinib as the standard first-line agent for patients who have metastatic ALK-rearranged lung cancer, also as a first-line agent for metastatic ROS1-positive lung cancer. And overall, it’s a very well-tolerated drug.

And, of course, we know efficacy is very high based on all of the studies—they’re called profile studies. These are global, multi-center studies establishing the efficacy of crizotinib. So it’s an excellent drug, but it does have some limitations.

I would say overall, the safety of crizotinib has been excellent in the studies. It’s a very well-tolerated drug. The side effects are generally quite mild. So I would say safety is not really a limitation generally with crizotinib. But, probably the main limitation with crizotinib is two-fold.

One is that patients often will relapse in the brain—the central nervous system, and that’s primarily due to inadequate penetration of the drug into the central nervous system. So it’s really a pharmacokinetic failure leading to CNS relapses. And we do see that quite commonly on crizotinib where a patient may be doing well with no evidence of systemic relapse at all, but they now have asymptomatic or symptomatic CNS disease.

We see that CNS relapses do occur in many patients. This was actually studied recently by Dr. Daniel Costa and colleagues, where he showed that the CNS was the most common site of relapse in our patients on crizotinib. Because of this, we do monitor the CNS quite proactively. Even in patients without any symptoms and who are showing sustained systemic responses, I do recommend surveillance brain MRIs every six to nine months. We do this routinely, and we do commonly pick up small asymptomatic brain metastases that we can then treat using local radiation therapy or, if there’s multifocal disease, we can then switch to a more brain penetrable inhibitor.

The other limitation with crizotinib is that most patients, if not all patients, will develop resistance at some point. This is different than CNS relapses, where we believe it’s a pharmacokinetic failure of the drug to reach adequate levels in the brain. Here, I’m talking about relapses systemically that are due to acquired resistance to the drug. So the body’s been fully exposed to therapeutic levels of the drug, and the cancer manages to develop ways to bypass the drug.

In about a third of patients who relapse on crizotinib, we identify a resistance mutation in the ALK gene itself. Typically, it’s in the tyrosine kinase domain of ALK, where the drug binds, and it prevents drug binding. That’s its mechanism of resistance. We can also see amplification or too many copies of the ALK fusion gene. And then in about two-thirds of cases, there’s no change in ALK itself, but, it’s likely activation of alternative signaling pathways that allow the cancer to grow in the face of crizotinib.

Gregory J. Riely, MD: In patients with ALK-positive lung cancer, we have a great opportunity for use of crizotinib as our first-line therapy. It has excellent efficacy and a relatively tolerable side-effect profile. But unfortunately, patients often develop resistance and we have to think about how we can best extend the use of crizotinib to prolong the time until we need to move to a second- or a third-line ALK inhibitor. For instance, one of the problems we often see with patients who are treated with crizotinib is development of brain metastases. When we identify patients who have brain metastases, one of the key things we can consider for them is simply treating the brain metastases with radiation therapy, but continuing crizotinib, and continuing to see how well a patient does.

There are published data that suggest that, that sort of approach can extend the time on an ALK inhibitor by about five or six months. And that would extend the time until we need to pick that second-line drug, and extend the time the patient might be alive. So, I think this is the strategy I’d like to use for those patients I have on crizotinib who develop a relatively localized progression.

Transcript Edited for Clarity