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ALK inhibitor XALKORI (Crizotinib) FDA-Approved: New Era, with New Challenges

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Yesterday afternoon, the FDA approved the ALK inhibitor crizotinib, newly christened as XALKORI, for patients with locally advanced or metastatic NSCLC who have an ALK rearrangement as identified by a particular central lab (test co-developed by Abbott and Pfizer, the makers of XALKORI). We’ve discussed the significant efficacy of XALKORI for this subset of NSCLC patients, with the frequency of an ALK rearrangement being somewhere in the range of 4-5%, and about 2/3 of ALK-positive patients showing significant tumor shrinkage on XALKORI, and more than 90% showing stable disease or tumor shrinkage. Moreover, these responses are of a duration typical of those we see with targeted EGFR-based therapies for patients with an EGFR mutation — in the range of a year, in contrast with more typical chemotherapy-based responses for advanced NSCLC, which more commonly last for several months, at most. The fact that XALKORI is an orally available anti-cancer treatment with very mild side effects also adds to the appeal.

The biggest limitation, of course, is that 4-5% frequency of an ALK rearrangement, far more commonly seen in patients with an adenocarcinoma, little or no smoking history, and also apparently more prevalent in younger patients, men a little more commonly than women, and especially seen in patients with the unusual (and often more aggressive) NSCLC subtype of signet cell adenocarcinoma.

Dr. Ross Camidge, lung cancer expert at the University of Colorado and friend of GRACE (and me), has been working with crizotinib from its earliest clinical trials in patients. Click to get to his excellent presentation from early 2010 that describes the early development of this agent, and also a post with information he provided as an update. In addition, my TEDxOverlake talk from a couple of months ago discussed broader themes of the benefits of self-educated patients, centered around the impact of XALKORI for one remarkable patient.

The approval of XALKORI is one more important landmark in the development of “molecular oncology”, as cancer care becomes defined by specific genetic alterations that can increasingly be treated by targeted therapies. Though we sometimes see efficacy of targeted therapies given to broad populations, we have seen a new category of efficacy when we give targeted therapies to targeted populations, such as an oral EGFR inhibitor to patients with an EGFR inhibitor, an antibody against HER2/neu for the subset of breast cancer patients with HER2 overexpression, and now ALK inhibitor therapy to the subset of patients with an ALK rearrangement.

The clinical trials testing XALKORI required testing of a wide range of patients to enroll a much smaller number. It was important to demonstrate that it’s possible to develop new agents and conduct clinical trials for small subsets of patients, geographically dispersed all over. In many cases, patients were the drivers of their molecular testing, and they often needed to travel significant distances to participate in the research opportunities. But while so many other new treatment approaches aspired to only a small incremental benefit wouldn’t have produced enough incentive to leave a patient’s home state, the promise of a targeted therapy for a precisely targeted population is enough to get people flying to get access to such an agent.

Of course, that kind of activity comes at a price, and for XALKORI, it’s $9600/month, which makes Tarceva seem like quite a bargain at $5000/month. The higher price point of XALKORI is presumably based on the following considerations:

1) XALKORI is likely to be far more effective for ALK-positive patients than Tarceva will be for the patients who don’t have an EGFR mutation (about 85-90% of patients with advanced NSCLC in North America are EGFR wild type, meaning no mutation)

2) The market for XALKORI, limited by the FDA to the 4-5% of NSCLC patients with an ALK rearrangements, is only a small fraction of the market for Tarceva (pretty close to all patients with advanced NSCLC).

Thankfully, Pfizer is offering a patient assistance program for uninsured or underinsured patients, and a co-pay assistance program for patients who would be required to pay more than $100/month.

You can learn a few more details about availability and other practical issues from the FAQ (produced by Pfizer) below:

xalkori-faq

Finally, we’ll be having our next webinar, likely in the last week of September, with Dr. Camidge and Dr. Ben Solomon from Melbourne, Australia, providing an overview of the development of XALKORI, the trials that led to its approval, how it will be used, and some future directions for the field. Details coming soon.


7 Responses to ALK inhibitor XALKORI (Crizotinib) FDA-Approved: New Era, with New Challenges

  • certain spring says:

    What fantastic news for anyone with the ALK rearrangement.

  • FaithAndHope79 says:

    Wonderful news!!!

  • JimC says:

    Thank you for the update on crizotinib (XALKORI). Since the FDA approval is limited to patients with verified ALK rearrangements and the price of the drug is beyond high, I assume that no insurer will pay for it outside the approved context. For ALK-negative patients who want to use it as a MET inhibitor and who can’t/don’t want to pay for it out-of-pocket, do you have any sense as to whether the phase I crizotinib trial (which doesn’t require ALK-positive status) will continue?

    Jim

  • Dr West says:

    I believe that now that XALKORI is commercially available, Pfizer and the lung cancer community will be prioritizing testing its efficacy in a much broader lung cancer population, in lung cancer and other cancer settings.

    -Dr. West

  • Laya D. says:

    YAHOOOOOO!!!!

    Laya

  • Ken_B says:

    Typically do drugmakers at this point generally keep existing trials going, just to continue to collect statistics on the population they started with, or is there just as likely to be a sudden shut down of such trials? I know you can’t speak to this specific set of trials.

  • Dr West says:

    Sorry for the delay in answering. I think it really depends on individual circumstances. The big international trial of giving XALKORI to ALK-positive patients is closing to new enrollment, since commercial drug should be available as an alternative. Patients on the trial now can continue to participate on it.

    There are other (smaller) trials with XALKORI, which should not be affected, and I expect that the company will expand new trial opportunities now that Pfizer can channel their research efforts on something beyond the initial FDA approval.

    -Dr. West

  • marissk says:

    I’m a newly diagnosed NSCLC patient with ALK mutation. My cancer appears to be very aggressive since there was no sign of it whatsoever in August 2010 when I underwent a battery of tests for hospital-acquited pneumonia. In August 2011, what was diagnosed as pneumonia that would not resolve, a CT scan showed lung cancer, and the PET showed mets to my hip. Stage 4 in a year. I started the usual cisplatin/pemetrexed protocol for 4 cycles, then pemetrexed alone and responded very well. However after cycle 6, a CT scan showed that while 2 tumors had resolved, a new tumor that was not in the previous CT scan showed up on the right bronchostem. That was removed by bronchoscopy 2 days later (December 28). The tumor board is surprised that while the primary tumor is stable and two previously detected tumors had resolved, why did I grow a new tumor? Is pemetrexed single agent? I’ve got another CT scan scheduled for 1/31 and the decision will be made as to whether we move me immediately to XALKORI or continue with Alimta, which will happen only if there is no sign whatsoever of progression.

    It’s all moving so fast!

  • Dr West says:

    Alimta (pemetrexed) is very appropriate as a single agent as maintenance therapy after 4-6 cycles of treatment with a two drug platinum-based combination, but we do typically see some progression at some point after that, even though it’s a very fine treatment.

    I think it sounds very sensible to continue on the current therapy if control is still very good overall. We also have some evidence that Alimta is often unusually helpful for people with an ALK rearrangement. But it’s always good to know that you have a compelling ace in the hole with XALKORI available as a next choice at some point when the progression is convincing enough to merit a new strategy.

    Good luck.

    -Dr. West

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