FDA approval of Crizotinib (Xalkori) and background information

This page is for people to discuss and post links to research about the ALK inhibitor called Crizotinib also known as Xalkori (formerly PF-02341066).

This entry was posted in crizotinib - Xalkori from Pfizer, Lung cancer, Potential Treatments, Regulatory applications & approvals, Research and tagged . Bookmark the permalink.

22 Responses to FDA approval of Crizotinib (Xalkori) and background information

  1. admin says:

    Below are links to 2 part of the FDA approval of Crizotinib which have a lot of detailed scientific data,

    Summary: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000SumR.pdf


    I was surprised to see that 35% of 19 ALK negative patients had their tumors shrink or stabilize when treated with Crizotinib. The FDA speculates that this could be caused by the test for ALK status being set too high (false negatives) or that the drug may be effecting other kinds of lung cancers. Pfizer is required to check these two ideas as part of the follow up testing.

    This document also indicates that the absorption of Crizotinib is related to the stomach’s acidity. Decreased absorption happens with higher PH levels. The FDA has required Pfizer to research the affect of antacids (which increase PH levels) as part of ongoing research.

    The FDA also requires Pfizer to do studies of both CYP3A inhibitors and inducers because of an apparent drug interaction with them.

  2. admin says:

    Here are links to two podcasts about Crizotinib. The first one mostly talks about the biology of the ALK fusion mutation and the most current data from the Crizotinib trial by Pfizer. http://cancergrace.org/lung/2011/10/31/ben-solomon-alk-inhib-podcast/

    The second podcast talks about screening issues and possible 2nd generation drugs for treating ALK+ patients who have become resistant to Crizotinib (all of which are mentioned on this website).

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  5. admin says:

    Insight Genetics has won a contract to develop a test to identify multiple mutations of the ALK gene. This will help in mapping which future drugs work against different mutations of ALK that confer resistance. For more details see this link http://finance.alphatrade.com/story/2011-10-05/MRW/201110051404MRKTWIREUSPR____0806150.html

  6. admin says:

    There was an interesting article in the Economist magazine on Sept. 24, 2011 about a potential way to overcome resistance to Crizotinib. Rene Bernards of the Netherlands made a presentation to AACR in San Francisco on Sept. 18 on the use of a TGF Beta inhibitor to overcome some forms of resistance. A posting on Inspire.com has said that the name of at least one TGF Beta inhibitor is Lucanix.

    See here for the Economist article: http://www.economist.com/node/21530080

  7. admin says:

    Pfizer announced that the FDA has approved Crizotinib (now known as Xalkori).

    Here is a Reuters article on it: http://www.reuters.com/article/2011/08/26/idUS227732+26-Aug-2011+BW20110826

    I believe this is the first time they mentioned a second study. The median response duration was 42 weeks for the first study and 48 weeks for the second study.

    The Phase III study is still ongoing.

  8. admin says:

    A 2011 ASCO presentation showed that for 82 patients treated with Crizotinib the overall survival rate at 1 year was 77% and at 2 years was 64%. By comparison for 37 patients who were ALK + but were not treated with Crizotinib the 1 year survival rate was 73% and 2 year rate was 33%.

    2 to 3 articles quoted survival rates for the “control” group as being 46% at 1 year and 9% at 2 years. It appears that this is a comparison of only patients who received 2nd or 3rd line treatments so it may be more accurate.

  9. admin says:

    As of January 19th Pfizer and Abbott are simultaneously filing submissions to the US Food and Drug Administration for a drug (Crizotinib) and diagnostic test (for the ALK mutation) combination. They received fast-track status, which will allow them to submit data on a rolling basis. The hope is that they will recieve approval by the end of 2011.

    See these articles for more details:
    http://www.genomeweb.com/dxpgx/pfizer-abbott-plan-parallel-filing-fda-approval-nsclc-drug-crizotinib-fish-test )

  10. admin says:

    Here is another abstract (http://www.ncbi.nlm.nih.gov/pubmed/21030459 ) that identifies a secondary mutation (F1174L) that allows ALK + cancer to develop resistance to Crizotinib (in neuroblastoma). The good news is that two drugs (TAE684 and the HSP90 inhibitor 17-AAG) were still effective against this mutation.

    This mutation appears to be similar to but not exactly the same as one of the mutations (F1174C) identified in Ariad’s test tube mutation analysis of Crizotinib that was done in April 2010. Ariad’s drug was effective against that mutation. It is likely but not certain that it would be effective against this mutation as well.

  11. admin says:

    The New England Journal of Medicine published several articles on October 28, 2010 summarizing research results on Crizotinib.

    From the abstract, it appears that the results in the first article are very similar to those presented at ASCO in June 2010. See http://www.nejm.org/doi/full/10.1056/NEJMoa1006448 for the abstract.

    From a second abstract it appears that researchers have identified two mutations that cause the cancer to develop resistance to Crizotinib. See http://www.nejm.org/doi/full/10.1056/NEJMoa1007478 Of particular interest the abstract labels the two mutations as “C1156y” and L1196M”. As a point of comparison Ariad’s mutation analysis labeled two of the sixteen mutations they discovered as being “C1156” and “L1196”. Thus it appears that the two studies are talking about the same mutations and that Ariad’s drug probably will overcome the resistance of both mutations.

    From a third abstract it appears that researchers have treated one patient with ALK positive Inflammatory Myofibroblastic cancer and that patient had a partial response. See http://www.nejm.org/doi/full/10.1056/NEJMoa1007056

  12. admin says:

    This graph shows the maximum average shrinkage of tumors by 113 patients taking Crizotinib in the Phase I trial. The shrinkage is based on the RECIST criteria (and thus measures the tumor only by its longest dimension and does not measure the volume shrinkage). In other words, a 30% RECIST shrinkage translates into aproximatly a 66% volume shrinkage and a 50% RECIST shrinkage translates into roughly a 87.5% shrinkage by volume. This is from Oct 2010.

  13. admin says:

    Here is a link to a chart that shows 15 patients who continued to take Crizotinib after their cancer progressed. In several cases they continued treatment for over 6 months. This chart is from Oct 2010. You may have to zoom in on the chart to get an easy to read version.


  14. admin says:

    Here is a chart that shows the Progression Free Survival of 113 patients taking Crizotinib in the Phase 1 trial is around 9 months. This is from Oct. 2010.


  15. admin says:

    Here is a second interview at the October 2010 Esmo Conference. This interview focuses more on the process for developing drugs like Crizotinib. The interview is with Dr. Jamey Skillings.


  16. admin says:

    Here is a video interview Dr. Camidge at the October 2010 ESMO conference with an update to the Crizotinib data. As he points out there is exciting data that indicates that patients can continue to benefit from Crizotinib even after initial progression.


  17. admin says:

    Here is a link to some of the preclinical research done by Pfizer (in 2007) that was the basis for it getting the phase I trial approved. Of interest the research was done using ALK + lymphoma cells. Given the subsequent success of the phase I trial with lung cancer it does suggest that Crizotinib should work on ALK + cancers wherever they are found.


  18. admin says:

    The graph below shows the maximum average shrinkage of tumors by 82 patients taking Crizotinib in the Phase I trial. The shrinkage is based on the RECIST criteria (and thus measures the tumor only by its longest dimension and does not measure the volume shrinkage). This is from June 2010.


  19. admin says:

    Here is a link to a graph that shows how long patients in the Phase I trial have stayed on Crizotinib. This is from the June ASCO presentation. Please note that some of the tumors in the patients may have started growing again, but that some of those patients have stayed on the drug.


  20. Kirkwood says:

    Here is a link to the powerpoint slides that were presented at ASCO in June 2010.


    The presentation is based on a Phase I trial with 82 patients (so far) with ALK induced lung cancer. There was an overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%.

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