Richard Pazdur, MD
Acting ahead of schedule, the FDA has granted an accelerated approval to ibrutinib (Imbruvica) as a treatment for patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, based on a single-arm clinical trial demonstrating a durable improvement in overall response rates (ORR).
In the phase II trial, labeled PCYC-1104, the oral first-in-class Bruton's tyrosine kinase (BTK) inhibitor ibrutinib demonstrated an ORR of 68%, including a complete response rate of 21%. Moreover, the median duration of response was 17.5 months. Based on these data, the FDA granted ibrutinib a Breakthrough Therapy designation and the eventual approval.
“Imbruvica’s approval demonstrates the FDA’s commitment to making treatments available to patients with rare diseases,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The agency worked cooperatively with the companies to expedite the drug’s development, review and approval, reflecting the promise of the Breakthrough Therapy Designation program.”
The PCYC-1104 trial enrolled 111 previously treated patients with relapsed or refractory MCL. The median age of patients was 68 years. According to clinical prognostic factors, 86% of patients had intermediate or high-risk MCL. In general, patients had received a median of three prior therapies, including bortezomib. Tumor response was assessed every two cycles according to the revised International Working Group for NHL criteria.
In the study, ibrutinib was administered orally at a 560 mg dose. The analysis of the trial was divided into two cohorts, based on previous exposure to bortezomib. However, as data from the trial accrued, prior treatment with bortezomib was found to have no effect on response to ibrutinib.
According to results published in The New England Journal of Medicine
, an ORR of 68% was observed in patients treated with ibrutinib (complete response rate = 21%; partial response rate = 47%). The estimated median duration of response was 17.5 months and the median progression-free survival was 13.9 months. At a median follow up of 15.3 months, the data for overall survival (OS) was not yet mature. However, the estimated rate of OS at 18 months was 58%.
"This is a meaningful day for previously treated mantle cell lymphoma patients, who are in need of new treatment options," said Michael Wang, MD, an associate professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center, and lead investigator for the pivotal registration trial PCYC-1104. "With Imbruvica, we now have an important new medicine that is a once-daily oral therapy with a favorable risk–benefit profile."
The most common ibrutinib-related adverse events in the PCYC-1104 trial were mild or moderate diarrhea, fatigue, and nausea. In total, grade 3 or higher hematologic events were infrequent and included neutropenia (16%), thrombocytopenia (11%), and anemia (10%).
"We continue to explore Imbruvica's potential to treat cancer patients in need. Presently we are in the midst of investigating this medicine in numerous additional B-cell malignancies with 37 clinical studies ongoing," said Bob Duggan, CEO and Chairman of the Board of Pharmacyclics, the company developing the agent. "Today we celebrate the first approval of Imbruvica. I would like to thank the patients and physicians for their trust and participation in our clinical trials.”
Ibrutinib is an irreversible small-molecule inhibitor of BTK activity. The agent works by blocking B-cell activation and signaling, which prevents the growth of malignant B cells that overexpress BTK. In general, BTK overexpression is abundant in B-cell malignancies, making this agent an effective treatment for many types of blood cancer.
The FDA is also considering ibrutinib as a treatment for patients with chronic lymphocytic leukemia (CLL), based on the same new drug application that resulted in the MCL approval. Since the beginning of the year, ibrutinib has received a Breakthrough Therapy designation as a treatment for CLL, MCL, and Waldenström macroglobulinemia.
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516.