Yesterday, the FDA approved the oral second generation ALK inhibitor LDK378, also known as ceritinib and newly christened Zykadia, for ALK-positive NSCLC who have progressed on or are intolerant of XALKORI (crizotinib). It is a treatment option that represents a major step for the 4-5% of NSCLC patients in the US who test positive for an ALK rearrangement, to be sure, but there are several implications for people outside of this narrow population as well.

The approval is based on the extremely favorable results with Zykadia in a phase I trial published in the New England Journal of Medicine earlier this year by Dr. Alice Shaw and colleagues, in which a total of 130 patients were treated with the agent, which is 20-fold more potent in inhibiting ALK than XALKORI. An initial 59 were part of the dose escalation phase, which ended when the dose of 750 mg was selected as the maximum tolerated dose. Beyond that point, an additional 71 patients were enrolled in an expansion phase and received the dose now approved as a starting dose.  The objective response rate was 58% for the 114 patients who received a dose of at least 400 mg daily: encouragingly, this was nearly identical in the 80 patients who had received and become refractory to XALKORI vs. the 34 patients among the 114 who were XALKORI-naïve (56% vs. 62%, respectively).  Below you can see a "waterfall plot" in which each patient's response is represented by a downward line  on the right (for tumor shrinkage) or upward line (on the left), with the length of the lines proportional to the degree of change; the "waterfall" transition being so far toward the left illustrates that most patients are experiencing tumor shrinkage, and you can see from the long lines on the right that many are experiencing a lot of shrinkage.  The bottom portion of the figure shows a "before vs. after" PET scan, with most of the disease now no longer visible.

Notably, most of the patients who didn't achieve a response that qualified as a significant one still had some tumor shrinkage or disease stability, so the "disease control rate" was approximately 80%.  The median duration of response was approximately 7 months, though there are several patients who remain without progression for a few years and ongoing.

An additional important benefit of this agent, as well as several other second generation ALK inhibitors such as alectinib and AP26113, is that patients with brain metastases demonstrated responses.  While XALKORI does not penetrate into the central nervous system (CNS), which is a "sanctuary site" in which we often see new disease appear in patients on XALKORI, Zykadia may be far better at preventing new disease from appearing in the CNS and can potentially treat pre-existing disease there. 

Toxicity is a potential challenge, more so than with XALKORI, especially gastrointestinal issues. Nausea was noted in 82%, diarrhea in 75%, vomiting in 65%, fatigue in 47%, and liver function tests were noted to be abnormally elevated in 35%.  These issues were dose-related, and many of the researchers with the greatest experience with this agent have conveyed that the dose of 750 mg daily may be too high for many people, but that they have often had a more successful balance of efficacy and tolerability after reducing the dose to 600 mg or sometimes 450 mg per day (4 or 3 tablets, respectively).

Obviously, this is a significant treatment opportunity for the 4-5% of patients with an ALK rearrangement, whether they have progressed on XALKORI or not. For those who have progressed and don't have good access to a trial with Zykadia or another promising agent, this approval now enables them to avail themselves of a treatment with responses seen in nearly 2/3 of patients and disease control in about 4 out of 5, and with responses that typically last for many months or sometimes a year or years.  It can also be an attractive option for others, such as my patient with a brain metastasis in his midbrain, a location where there is greater risk in doing a stereotactic radiosurgery approach (Gamma Knife) -- perhaps Zykadia will provide a response within the brain after he has demonstrated progression of the lesion on XALKORI.  

Though some will probably be inclined to use it as a first line treatment for ALK-positive NSCLC, I think there are several practical and theoretical reasons not to do so. Practically speaking, if it costs $10,000 per month (I don't know the cost yet, but I'm going to just make the leap that it will be painfully expensive), use will almost always be limited by whether an insurer covers it, and the approval is specifically for post-XALKORI treatment. Beyond that, we know that many patients do very well on XALKORI for a very long time, and this still leaves Zykadia as a great backup plan.  In contrast, by starting with Zykadia, even if it's somwhat more longitudinally effective as initial treatment than for ZALKORI-refractory disease, you wouldn't expect that XALKORI, 20 times less potent as an ALK inhibitor, will provide any benefit, so you'll have no great backup plan. There also isn't any real evidence yet that other second generation ALK inhibitors work after Zykadia.

The approval is significant in other ways as well. It's the first approval and proven effective therapy for "acquired resistance" to a targeted therapy in lung cancer, the progression we see after an initial great response to an ALK or EGFR inhibitor in patients with the right driver mutation.  While it's wonderful for patients with one of these mutations to respond well, the question of what to do when progression sets in remains a vexing issue. For the first time, we have a way to get the genie back into the bottle.  As new agents are being tested in acquired resistance for EGFR and ALK, we've broken the impasse and have shown that it's possible to do good trials on narrow populations with an uncommon target and who have developed acquired resistance.  Patients will find their way to these studies, in droves.

It's also important that the drug was approved relatively quickly by the FDA, just a few years after the first patient received the drug. Given the high response rate, the FDA didn't require a randomized trial with hundreds of patients -- it is now getting the drug into the hands of oncologists and patients in a very timely way, pretty much as soon as the safety and efficacy could be clearly established.  This bodes well for future targets that may be found in only 1-5% of the broader lung cancer population.  I suspect that pharmaceutical companies are reassured that it is worth developing agents for these patients.

Finally, it's encouraging for the 1% of NSCLC patients with a ROS1 rearrangement, who have a very high probability of responding well to XALKORI but who don't have many other target-specific options available, including in clinical trials.  We will likely see ROS1-positive patients trying Zykadia soon, if they can get it.

More to come. These are exciting times.