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PCI-32765 associated with 70% response rate in CLL
53rd ASH Annual Meeting
Six-month PFS was greater than 90% in patients with chronic lymphocytic leukemia assigned to the novel experimental agent PCI-32765, according to updated results from a phase 1b/2 study.
PCI-32765 is an orally-administered irreversible inhibitor of Bruton’s tyrosine kinase, a central mediator of B-cell receptor signaling that is essential for normal B-cell development. The drug induces apoptosis, and it inhibits cellular migration and adhesion in malignant B cells.
“In the 15 years I’ve been practicing as a CLL-specific specialist, this is by far the most phenomenally active drug for refractory CLL patients in terms of response and durability and tolerability,” said John C. Byrd, MD, director of the hematologic malignancies program at the Ohio State University Comprehensive Cancer Center and one of the study’s co-authors.
“Eighty-six percent of people receiving this drug are progression free at 1 year. Given the durability and the potential that patients can stay on therapy for an extended period of time without adverse events, it’s likely this is going a paradigm-shifting drug.”
Susan M. O’Brien, MD, professor in the Department of Leukemia at MD Anderson Cancer Center, presented the results at ASH during a session Dec. 13.
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Patients aged 65 years or older with relapsed or refractory disease were assigned to 420 mg daily PCI-32765 (n=27) or 840 mg daily PCI-32765 (n=34) in 28-day cycles until progression.
Patients in the 420 mg cohort had a median number of three prior treatment regimens; the median number was five in the 840 mg cohort, and 72% of patients had at least one poor-risk molecular feature. Median follow-up time was 10.2 months for the 420 mg cohort and 6.5 months for the 840 mg cohort.
Objective response rate (ORR) in the 420 mg group increased from 48% in the initial reporting to 70% in this analysis. ORR=44% in the 840 mg cohort.
ORR appears to be independent of molecular risk features, Byrd added.
Six-month PFS was 92% in the 420 mg cohort and 90% in the 840 mg cohort.
“In a disease like chronic lymphocytic leukemia, which is very often measured in years or even decades, an overall survival benefit will be hard to demonstrate,” said Jeff Sharman, MD, vice chair of the US Oncology Hematologic Malignancies Research Committee and a study co-author. “On the other hand, the regulatory agencies have approved drugs in CLL on the basis of PFS, and I wouldn’t be surprised if we saw similar registration strategies in this family of drugs.”
Two patients discontinued treatment due to adverse events, and six patients have required dose reductions.
Researchers observed serious adverse events in 38% of patients. Serious adverse events potentially related to PCI-32765 have occurred in 10% of patients.
Sharman added that he expected that a phase-3 study to confirm these results would begin early next year. – by Jason Harris
Disclosure: Drs. Byrd and Sharman both report receiving research funding from Pharmacyclics. Additionally, Dr. Byrd is an unpaid consultant for Pharmacyclics and serves as a member of the company’s scientific advisory board. Dr. Sharman serves on the scientific advisory board for Celgene.
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It’s early data but the good news is that, scientifically, the concepts are sound and it’s a good group of investigators. In the responders, almost all patients are still responding. Fewer than 10% of the people who received the drug relapsed. But the follow-up is short — less than one year. It would be nice to see some biological correlates to see if the drug is actually doing what we think it’s doing, but it’s good data. I’m optimistic about it. We have a lot of drugs to treat CLL but, at the end of the day, most patients will still have major problems with their disease at some point. A new class of drugs that looks to be very promising is terrific. The other aspect I found interesting was that the researchers observed an increase in peripheral lymphoid cells for the first two months that later resolves. That is something we do not see in most therapies, which is intriguing in terms of mechanism of action.
Brian Bolwell, MD
Chairman of Taussig Cancer
Institute at Cleveland Clinic
Disclosure: Dr. Bolwell reported no relevant financial disclosures.
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