Carfilzomib Approval Ready -- or Not?

Bruce D. Cheson, MD


July 02, 2012

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Hello again and welcome to Medscape Hematology. I am Bruce Cheson from Georgetown University Hospital, the Lombardi Comprehensive Cancer Center.

Over the years, a number of drugs have been approved for hematologic malignancies, and I am fortunate to have been involved in the clinical research that led to the approval of some of these drugs. In particular, new drugs for lymphoma and chronic lymphocytic leukemia (CLL) seem to be popping up regularly -- novel, effective drugs. This is unlike some of the other hematologic malignancies, such as acute myeloid leukemia, for which we are still using 7 + 3 (cytarabine and daunorubicin) like we did when I was a fellow, and multiple myeloma, which is sort of in the middle. Several new drugs approved over the last few years (bortezomib, thalidomide, and lenalidomide) have had a major impact on the treatment of patients with multiple myeloma and clearly improved outcomes, but we need to do better. Unlike the lymphomas and CLL, for which we have several monoclonal antibodies, drug antibody conjugates, and new small molecules, we are taking shorter steps in myeloma.

Recently the Oncologic Drug Advisory Committee (ODAC) of the US Food and Drug Administration (FDA)[1] unanimously voted to approve carfilzomib. This is a next-generation proteasome inhibitor and most likely will receive accelerated approved, given the ODAC decision and the data that supported this application. (I will leave it to you to decide on the strength of the data.) This was a study of 226 patients with relapsed-refractory disease. Nearly all patients received bortezomib, more than 90% received lenalidomide, and about three fourths received thalidomide as well. Of importance, 87% of patients were considered intolerant (or unresponsive) to bortezomib and lenalidomide; 56% were unresponsive to thalidomide, and many patients were unresponsive to other drugs, including melphalan, cyclophosphamide, and anthracyclines.

The primary endpoint was overall response rate. At the end of the study, the overall response rate for the various subpopulations was 22.9%. The duration of response, by the company's analysis, was 7.8 months; by the FDA's analysis, it was 6.5 months. The progression-free survival was 3 months and the overall survival about 15 months. There were some toxicities (cardiac, hepatic, and pulmonary), but carfilzomib seems to be significantly less neurotoxic than bortezomib. The drug was given (at least in this study) on days 1, 2, 8, 9, 15, and 16 of every 28-day cycle.

What will happen if carfilzomib is approved? Will it be used, and how will it be used? That remains to be seen. Will it be moved up front because it has less neurotoxicity than bortezomib? I don't know. We do need active drugs with less toxicity. I have given you the numbers and you can decide on your own level of enthusiasm for carfilzomib. It is a potentially important drug. Now that bortezomib has been approved for subcutaneous administration, how will the community, and the patients, take to an intravenous drug on the strength of these data?

This is a recent event of interest to the hematology community. It is likely that carfilzomib will be officially approved in an accelerated manner, and how we use this drug will depend on your impressions of the data.

Thank you for tuning in today. This is Bruce Cheson, signing off for Medscape Hematology.


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