In this segment I’ll be talking about ALK rearrangements in non-small cell lung cancer. I think what we know now is that ALK rearrangements do occur at a frequency of around 3% to 5% of all advanced non-small cell lung cancer adenocarcinoma patients.

I think that 3% to 5% is a little misleading, however. I think that in some studies that number is higher, for instance, there’s a study that suggests that never smokers in which their EGFR is negative, the incidence of ALK goes up to about 30%. And other studies—the Young Lung study—suggest that, in patients under the age of 40, the incidence and detection of ALK is much higher than that 3% to 5%, and that really makes the argument that every patient that walks through the door with an advanced adenocarcinoma of the lung should be tested for ALK, given that we have many therapies available.

And the story of ALK rearrangements in lung cancer is so emblematic of the pace of genomic discoveries and drug development for this disease. ALK rearrangements were identified in 2007, and the first drug was published in 2011, crizotinib. It took 4 years, which is a very short time, given that many drugs are developed only 20 to 25 years after the mutation is discovered. So, quite a remarkable story, and so symbolic of where we’re heading with all of targeted therapies for lung cancer.

When we look at ALK-directed therapies, it is certainly a crowded space for a mutational niche that’s a little bit less common in EGFR. Currently the only approved ALK-directed therapy upfront is crizotinib. That may change soon and I’ll talk about that at the end of the segment, but crizotinib remains the standard for patients with advanced adenocarcinoma of the lung that are ALK-rearranged. We know that crizotinib, when compared to chemotherapy—either first-line or second-line—improves response rates, improves progression-free survival, and improves quality of life, but of course doesn’t improve overall survival, due to the high rate of crossover.

I think things have changed dramatically about what to do with patients who progress on crizotinib. I think before what we were doing is, for patients receiving crizotinib that were doing well that eventually developed progression, we were defaulting to chemotherapy, and one of the more active chemotherapies is pemetrexed. I think what we now know is that there are 2 new ALK-directed therapies that are approved. One is ceritinib, and the other is alectinib.

There are some considerations that I want to mention here about these 2 drugs. One is that they are structurally different and more potent than crizotinib, and that allows these drugs to overcome crizotinib resistance, and this is been seen in the studies. If you look at most of the studies that have looked at these 2 agents for crizotinib-refractory patients, these drugs elicit response rates on the order of 50% to 60%, which is quite remarkable when we were having to default before to chemotherapy. We now have ALK-directed therapies that we can give patients who progress on crizotinib.

The second interesting thing about these drugs is that they have the proclivity and the chance to cross the blood brain barrier, which is quite important in this type of lung cancer. We now know for that patients were on crizotinib who develop resistance to crizotinib, in the studies, 40% to 50% of those patients develop brain metastases, and giving these drugs will not only controlled the disease below the neck, but they may control the disease in the brain. 

So as before when a patient was on crizotinib and that patient was progressing in the brain, we would often have to refer the patient to radiation oncology, and that patient would have to get whole brain radiation followed by chemotherapy. Now these 2 drugs, if given, can not only control the disease below the neck, but may circumvent the need to give whole brain radiation, because these drugs penetrate the blood-brain barrier. It’s a win for our patients and it’s a win for physicians.

So I think we have 2 very good drugs. I will say that, in my experience, alectinib is much better tolerated than ceritinib, and because of that, it’s been my go-to drug for patients that are crizotinib-refractory. I think we’re going to have—or do have data currently—to suggest that many of these drugs, specifically alectinib, may be better than crizotinib upfront in the first-line.

There were data at our most recent ASCO meeting—the J-ALEX study—that compared alectinib to crizotinib in ALK-therapy naive and ALK-positive patients, showing a huge PFS advantage for those patients that got alectinib vs crizotinib. There will be a global ALEX study that hopefully confirms this, but if the data holds up, alectinib may be the first-line gold standard, and we’ll just have to wait and see.

Moving forward, where are we heading with this, in terms of the  ALK therapies in the ALK space? We’ve got 2 more drugs are coming down the pike: brigatinib and lorlatinib. These drugs, again, are very active, and are little bit better ALK inhibitors than crizotinib, but with all these drugs there are a lot of answered questions. I think number one is, how do we sequence these drugs? We have now or soon maybe 5 ALK-directed therapies for ALK-mutated lung cancer. How do we sequence—or what’s the optimal sequence—and what’s going to get patients living longer?

And then the other issue with ALK disease is that we don’t have the sophisticated understanding of resistance to crizotinib or other ALK-directed therapies like we do for the EGFR TKIs. I think we know for the EGFR-space patients who progress on erlotinib, afatinib, or gefitinib, two-thirds of those patients will develop a gatekeeper mutation called T790M. I think for ALK there are just so many different mutations that can happen—amplifications, bypassing link pathways—so there are a lot of unanswered questions and I think that really highlights the need that we’re going to either need to do re-biopsies on patients through tissue or plasma. I hope, in the next few years, we’re going to make significant gains with this disease.