Ponatinib Withdrawal Update

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Amice Sutton
6 years ago
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1 Hello. This is Dr. Stuart Goldberg from the Leukemia Division at the John Theurer Cancer Center at Hackensack University Medical Center in Hackensack, New Jersey. I am speaking on behalf of ManagingCML.com to provide you with an update on the recent events surrounding ponatinib. MediCom Worldwide, Inc. 1

2 As all of you know, ponatinib is a potent oral tyrosine kinase inhibitor of BCR ABL, the driving force of chronic myeloid leukemia. This agent is a so called third generation TKI and was specifically developed to help treat the most difficult cases, those patients who had developed mutations that were insensitive to other TKIs such as the T315I mutation, as well as to treat those patients who were already resistant or intolerant to secondgeneration agents such as dasatinib or nilotinib. The results of the phase I study were very encouraging, and this lead to a large international phase II study known as the PACE Trial, which was reported by Dr. Cortez and colleagues in The New England Journal of Medicine very recently. 1 In the phase II trial, patients achieved a complete cytogenetic response who had failed other therapies, approximately 40% of patients who were either resistant or intolerant to dasatinib or nilotinib could enter back into cytogenetic remission. In addition, 66% of patients who had developed a gatekeeper T315I mutation, a mutation typically insensitive to all the other TKIs, entered remission. Unfortunately, the agent was also associated with significant toxicities which lead the sponsor as well as the FDA in cooperation, to withdraw the agent from the market on October 31, References: 1. Cortes JE, Kim DW, Pinilla Ibarz J, et al. PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome positive leukemias. N Engl J Med. 2013;369(19): U.S. FDA. FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales 11/5/ MediCom Worldwide, Inc. 2

3 The basis for the withdrawal comes from the review of both the phase I and phase II trials with ponatinib. 1 In these studies it was noted that there was a risk of serious adverse vascular events, which included both fatal and non fatal myocardial infarctions, cerebral vascular actions strokes, as well as significant arterial clotting episodes requiring sometimes emergency surgery. In the phase I studies, for patients who were followed for approximately 2.7 years, 48% of the patients developed these cardiovascular events. And in the recent PACE study, 24% of patients who were treated for a median 1.3 years developed these episodes. In addition, the vascular thrombotic episodes were identifiedin in patients who did not have any prior risk features, and in the FDA analyses, no dose dependency, that is they could not find a safe dose. The vascular events also occurred soon after initiation of therapy, but also could occur delayed. Additionally, 67% of the patients developed or worsened hypertension, and 8% of the patients developed congestive heart failure. Thus, because of these cardiovascular events, the medication was voluntarily withdrawn from the market in October Reference: 1. U.S. FDA. FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales 11/5/ MediCom Worldwide, Inc. 3

4 So what are our options for treating patients with refractory or intolerant CML? Well, for the patient who is responding to ponatinib and tolerating the medication, we can consider continuing the medication as part of the Investigational New Drug (IND) process, and I will describe this in a future slide. 2 We also can however consider switching the patient to an alternate second generation TKI such as dasatinib, nilotinib or bosutinib. 1 In several phase II studies it was noted that a patient who fails one agent has approximately 25% chance of responding to the second agent. Now this is lower than we were seeing with ponatinib, but it still means that some patients can be salvaged. For those patients who have failed multiple TKI therapies or for those patients who however have a high risk for T315I mutation we could also consider using omacetaxine. 2 8 This is a synthetic version of an older medication known as homoharringtonine. Omacetaxine is given by subcutaneous injections twice a day for two weeks, and then given one week per month as a maintenance. In the registration trials approximately 18% of the patients had a major response. 3 5 And finally for the younger patient who has failing TKI therapies, we should not forget allogeneic transplantation still can be curative It was not that long ago that every patient with CML was offered transplantation if they were young and healthy and we have sort of abandoned this because of the safer TKIs, but in a patient who is not responding, we may want to reconsider this older and curative therapy though. MediCom Worldwide, Inc. 4

5 References: 1. U.S. FDA. FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales 11/5/ National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia Version (release date: 11/01/2013). 3. Cortes J, Digumarti R, Parikh PM, et al. Omacetaxine 203 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol. 2013;88(5): Cortes JE, Nicolini FE, Wetzler M, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk. 2013;13(5): Cortes J, Lipton JH, Rea D, et al. Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic phase CML with T315I mutation. Blood. 2012;120(13): Visani G, Isidori A. Resistant chronic myeloid leukemia beyond tyrosine kinase inhibitor therapy: which role for omacetaxine? Expert Opin Pharmacother Oct 23. [Epub ahead of print] PubMed PMID: Nazha A, Kantarjian H, Cortes J, Quintás Cardama A. Omacetaxine mepesuccinate (synribo) newly launched in chronic myeloid leukemia. Expert Opin Pharmacother. 2013;14(14): Nicolini FE, Chomel JC, Roy L, et al. The durable clearance of the T315I BCR ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallenge. Clin Lymphoma Myeloma Leuk. 2010;10(5): Pavlu J, Szydlo RM, Goldman JM, Apperley JF. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood. 2011;117(3): Saussele S, Lauseker M, Gratwohl A, et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood. 2010;115: Jabbour E, Cortes J, Santos FPS, et al. Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR ABL1 kinase domain mutations. Blood. 2011;117: Nicolini FE, Basak GW, Soverini S, et al. Allogeneic stem cell transplantation for patients harboring T315I BCR ABL mutated leukemias. Blood. 2011;118(20): MediCom Worldwide, Inc. 5

6 What about the patient you feel is doing well on ponatinib and is tolerating it? Well, the FDA has developed a system in concert with ARIAD Pharmaceuticals, the medication s manufacturer, to allow us to continue using the medication. 1 We should decrease to the lowest effective dose, such as 15 mg per patient in complete remission, however, the cardiovascular events were not dose dependent, according to the FDA review, and we do not know that reducing to 15 mg per day will be any safer for our patients. A second option may be to also add an antithrombotic agent such as aspirin 81 mg per day. Again, this has not been studied and is therefore of unproven benefit. And finally, one of the options that I have been considering for my patients is to add an anti lipid agent such as atorvastatin 20 mg per day, however, again, this is of unproven benefit and actually may increase ponatinib levels as we know that atorvastatin and the other anti lipid agents work through the P450 system and therefore we could predict that the ponatinib levels would go up. 2 Whether this will be beneficial or harmful to our patients needs to be shown in future clinical trials. References: 1. U.S. FDA. FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales 11/5/ LIPITOR (atorvastatin calcium) Tablets for oral administration. Highlights of prescribing information. Pfizer. LAB October Accessed at on November 13, MediCom Worldwide, Inc. 6

7 Well, in order for our patients to continue to receive ponatinib, the physician must act as an investigator as this will now become a non marketed agent. So first we need to contact the FDA to receive an emergency IND number for our patients. 1 The number shown on the screen is the daytime number for the FDA. We have already been doing this at our center and we have noted that the FDA has been very quick in turning around our requests, often within one to two days. Once we receive the IND number we then contact ARIAD Pharmaceuticals to obtain a shipment of ponatinib for our patients. ARIAD has promised that the medications will be at the doctor s office within several days so the patients can continue to receive their medications on a timely basis as their current prescriptions are running out. We then need to receive, also from ARIAD, a packet that details other information that must be sent to the FDA within 15 days to complete the IND process. As we are now investigators, we are charged with following our patients and reporting the outcomes of our patients both to the study sponsor, ARIAD, as well as to the FDA. In addition, you will need to contact your own hospital s IRB to see what other requirements they may have so that you can continue to use this now experimental medication. I know this has been a difficult time for some of your patients who have been on ponatinib as they have heard news reports about these episodes, and we need to counsel our patients about the risks and benefits of continuing ponatinib, to talk about the unknowns, as well as the other options that our patients may have. Hopefully this short update will give you a starting point in counseling your patients. I am sure that we will be hearing more from the FDA and more from the study s sponsor over the next several weeks. Best wishes in taking care of your patients. For more information about CML and more updates on ponatinib please check out the website ManagingCML.com. Thank you. Reference: 1. U.S. FDA. FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales 11/5/

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