Ibrutinib in Mantle Cell Lymphoma Yields 'Unprecedented' Response Rates 


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The investigational agent ibrutinib demonstrated “unprecedented” single-agent activity in relapsed or refractory mantle cell lymphoma, according to the lead author of an international phase II study reported at the Annual Meeting of the American Society of Hematology (ASH).1

Durable Responses

“The responses have been durable and the median duration of response has not been reached,” reported Michael Wang, MD, Associate Professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, Houston. “The response improved with longer follow-up, demonstrating the phenomenon of ‘incremental response.’”

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase, which is a critical kinase for lymphoma cell survival and proliferation. Bruton’s tyrosine kinase inhibitors block signaling and induce apoptosis.

“Ibrutinib produced the highest response rate ever observed with a single drug in the history of relapsed mantle cell lymphoma,” Dr. Wang told attendees. “Patients with all characteristics benefited across the board.”

Study Details

The PCYC-1104-CA study is an ongoing international multicenter open-label phase II single-agent trial of ibrutinib in patients with relapsed or refractory mantle cell lymphoma. Patients are being treated orally with ibrutinib at 560 mg per day until disease progression.

At data cutoff in September 2012, the study population included 115 patients (110 evaluable) with mantle cell lymphoma (cyclin D1–positive or t[11;14]), 65 of whom were of whom were either totally naive to bortezomib (Velcade) or had received fewer than two cycles of bortezomib (“bortezomib-naive”), and 50 of whom had received at least two cycles of the agent. Subjects were allowed to have received up to five prior lines of treatment.

The overall response rate to single-agent ibrutinib was 68% for the total study population, 65% among bortezomib-naive patients, and 72% for patients exposed to at least two cycles of bortezomib. The complete response rates in these cohorts were 21%, 23%, and 22%, respectively, Dr. Wang reported.

By patient characteristics, all subgroups benefited. Response rates were 64% for patients with bulky disease, 65% for patients with refractory disease, 70% for those not disease-refractory, 66% for patients with at least three prior regimens, 76% for patients with prior lenalidomide (Revlimid), and 74% for those with a high-risk score.

Longer Follow-up

Longer follow-up on the initial 51 patients demonstrated that responses increased over time. The increase in response and complete response rates, respectively, from the earlier analysis at 3.7 months to a median of 14.7 months, was as follows: in all patients, 69% and 16%initially, and now 75% and 39%; in bortezomib-naive patients, 71% and 16% initially, and now 77% and 40%; in bortezomib-exposed patients, 65% and 15% initially and now 71% and 38%.

“We saw the overall complete response rate increase to 39%, which we have termed the ‘phenomenon of incremental response,’” Dr. Wang said. “We saw this in bortezomib-exposed and bortezomib-naive patients. This is higher than the complete response rates we see in other subtypes of lymphoma, including [historically] in mantle cell lymphoma. It is an unprecedented single-agent response rate.”

He added that the time to response was “very fast, after two cycles usually,” though the average time to achieve a complete response was 5.5 months (ranging from 1.7 to 16.4 months).

Median progression-free survival was 13.9 months for the whole population; for responders, it has not been reached, whereas the average nonresponder showed disease progression in less than 7 months. Similarly, the median duration of response has not been reached and responses have been dramatic in some patients, he noted.

Ibrutinib is well tolerated. Treatment-emergent adverse events were consistent with the safety data previously reported for this investigational agent. Grade 3 and 4 events occurred in fewer than 5% of patients. Approximately 10% of patients experienced grade 1 or 2 confusion, epistaxis, petechiae, and ecchymosis.

In conclusion, Dr. Wang let his enthusiasm for this agent be known. “I look forward to the future with excitement, caution, and confidence,” he said. ■

Disclosure: Dr. Wang reported no potential conflicts of interest.

Reference

1. Wang M, Rule S, Martin P, et al: Interim results of an international, multicenter, phase 2 study of Bruton’s tyrosine kinase inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma. 2012 ASH Annual Meeting. Abstract 904. Presented December 11, 2012.


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