ISSUE: NOVEMBER 2013 | VOLUME: 08:11 All signs point to the imminent FDA approval of ibrutinib, the once-daily oral Bruton tyrosine kinase (BTK) inhibitor with impressive efficacy in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). At press time, the FDA was reviewing a New Drug Application (NDA) submitted by the drug’s manufacturer, Pharmacyclics, Inc., on July 10, 2013.
The submission comes on the heels of findings published in The New England Journal of Medicine (NEJM) showing a 71% clinical response rate in difficult-to-treat CLL patients (2013;369:32-42).
The results have elicited nearly unanimous enthusiasm from the hematology/oncology community, including Nicole Lamanna, MD, an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Medical Center, in New York City.
“This is a huge kudos for the field,” said Dr. Lamanna, who was not involved in research on the drug. “There is little doubt in most of our minds that ibrutinib will be used in some fashion as first-line therapy for CLL, with the potential of sparing some patients a number of treatments that otherwise might be too toxic.”
Along with previously published findings, the NEJM results have impelled the FDA to also apply three Breakthrough Drug Designations to ibrutinib and to place it on a fast track for approval. In an email to Pharmacy Practice News, the FDA would not comment on the timing of the drug’s approval.
The NEJM data, initially presented at last year’s American Society of Hematology (ASH) annual meeting in Atlanta, included outcomes from 85 CLL patients with refractory or relapsed disease, who were randomized to receive 420 or 840 mg daily of the drug. The participants had undergone a median of four prior therapies. Of the patients, 33% had 17p deletions and 36% had 11p deletions; both deletions predict poor treatment response. Patients were a median 66 years of age and were followed for a median of 21 months.
Led by John Byrd, MD, from the Division of Hematology in the Department of Internal Medicine at Ohio State University in Columbus, the researchers reported that 71% of patients in either group experienced a clinical response. Since most had some evidence of continuing disease, their response was considered partial. The estimated progression-free survival and overall survival rates were 75% and 83%, respectively, over 26 months, and the likelihood of response was independent of clinical and patient characteristics.
The investigators found that 78% of the partial responders experienced transient lymphocytosis in the early part of treatment. However, an additional 20% in the low-dose group and 15% in the higher-dose group had persistent lymphocytosis despite significant reductions in tumor size, and therefore were classified as nodal partial responders.
What Can Pharmacists Expect?
Informing physicians of the potential for transient lymphocytosis early in the course of treatment will be a key role for pharmacists, said Lindsay Hladnik, PharmD, BCOP, a clinical pharmacist for Hematologic Malignancies/Stem Cell Transplantation at Barnes-Jewish Hospital in St. Louis, Mo. “It will be important for them to know that this is likely due to the drug’s mechanism of action and not to disease progression,” said Dr. Hladnik, who was not involved in the research.
According to the NEJM study, the most common adverse events (AEs) were grade 1-2 diarrhea (47% of both groups), grade 1-2 fatigue (28%) and grade 1-2 upper respiratory tract infections (33%). Grade 3-4 AEs included pneumonia (12%), dehydration (6%), neutropenia (15%), pyrexia (5%), hypertension (5%) and sinusitis (5%). Most infections occurred early in the course of treatment.
Two patients in the 420 mg group and four patients in the 840 mg group discontinued treatment because of AEs, the investigators reported.
Robert C. Wolf, PharmD, the hematology/oncology pharmacotherapy coordinator and program director of the Pharmacy Practice Residency in Oncology at Mayo Clinic College of Medicine in Rochester, Minn., said ibrutinib’s “specific role and place in therapy will be better defined over the ensuing months to years as clinical trial results evolve.” Pharmacists can expect to provide the usual range of care to patients receiving ibrutinib, said Dr. Wolf, who has not been involved in research on the drug.
“While not necessarily unique to ibrutinib, issues of access, adherence, follow-up for efficacy and safety, drug interactions and affordability will need to be addressed,” he said.
Potential Accessibility Implications of Long-Term Treatment
Dr. Hladnik added that having knowledge of the available patient access programs for ibrutinib and being able to direct physicians to these resources will be critical, “especially since patients will take ibrutinib continuously until disease progression or unacceptable toxicity."
“This could potentially be a very expensive treatment and patient access could become a real issue,” Dr. Hladnik added. “Hopefully, there will be good patient access programs in place.”
For her part, Dr. Lamanna said, “I wonder about the long-term unexpected toxicity with ibrutinib, as this will likely be prolonged therapy. Also, will ibrutinib need to be used indefinitely—as it is currently administered in clinical trials—if patients who respond eventually achieve complete responses or MRD [minimal residual disease] negativity?” she asked.
At press time, Dr. Hladnik said she was not aware of any information on any ibrutinib dosing adjustments, drug–drug and drug–food interactions and adverse-event monitoring. However, she said ibrutinib appeared to be straightforward to administer and manage.
“The once-daily oral dosing will definitely help with patient compliance, although we could play a key role in verifying patient compliance and evaluating and managing any adverse events, like diarrhea, so that patients can stay on the medication,” she noted.
Dr. Hladnik echoed the enthusiasm shared by the broader hematology/oncology community regarding the drug’s efficacy and safety, but noted that findings to date have been from Phase 1 or 2 studies, including the Phase 1b-2 NEJM study. “When it comes to oncology drugs, you can get an agent approved based on Phase 2 studies if there is an unmet clinical need, but outcomes can be different once it’s studied in Phase 3 studies,” she cautioned.
At press time, seven of the 31 registered clinical trials of ibrutinib were Phase 3 studies. A number of the head-to-head trials among these studies are examining use of ibrutinib in combination with other established treatments and for a range of B-cell leukemias.
Dr. Lamanna said she hopes findings on combination treatment with ibrutinib will reveal a further increase beyond the already impressive clinical response rates. She is awaiting updated findings slated for presentation at this year’s ASH annual meeting and at the International Workshop on CLL in Germany, where she expects favorable results on the durability of CLL clinical response with ibrutinib.
“As more data on this drug from ongoing clinical investigation emerges,” Dr. Lamanna said, “lots of exciting new questions in terms of how best to use the drug will, hopefully, be answered.”
Sentiment: Strong Buy
Looks like the author of this thread changed it to November from Sept. See below
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Juggernaut CLL/MCL Drug, Ibrutinib, En Route to FDA Approval