February 12, 2014

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FDA approves Imbruvica for CLL

The FDA today granted accelerated approval to ibrutinib for use in patients with previously treated chronic lymphocytic leukemia.

Perspective from Jonathon B. Cohen, MD, MS; William G. Wierda, MD, PhD; Richard R. Furman, MD; John C. Byrd, MD; Mitchell R. Smith, MD, PhD; Jeffrey Jones, MD, MPH; Jennifer R. Brown, MD, PhD

Ibrutinib (Imbruvica, Pharmacyclics and Janssen), a Bruton’s tyrosine kinase inhibitor approved last year for patients with previously treated mantle cell lymphoma, targets the B-cell receptor signaling complex and blocks the enzyme that cancer cells need to multiply and spread.

“Today’s approval provides an important new treatment option for CLL patients whose cancer has progressed despite having undergone previous therapy,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release. “The FDA completed its review of Imbruvica’s new indication under the agency’s accelerated approval process, which played a vital role in rapidly making this new therapy available to those who need it most.”

Richard Pazdur

The accelerated approval process allows the FDA to approve a drug based on an intermediate or surrogate endpoint that suggests likely clinical benefit. Confirmatory trials typically are required to verify efficacy.

The FDA expanded ibrutinib’s indication to CLL based on results of a study that included 48 patients with previously treated disease. Patients had undergone a mean four prior therapies, and mean time between diagnosis and study entry was 6.7 years.

All patients received 420 mg oral ibrutinib daily until disease progression or unacceptable toxicity.

Researchers observed a 58% overall response rate, with duration of response ranging from 5.6 to 24.2 months. Researchers have not yet established improvements in survival or disease-related symptoms.

The most frequent adverse events observed in the study were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, fever, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis and dizziness, according to the FDA.

Perspective

Jonathon B. Cohen, MD, MS

Today's approval of ibrutinib represents a significant breakthrough for patients with CLL and the physicians who care for them. Although this does not represent a cure, ibrutinib is well tolerated over several months of administration, offers the convenience of oral dosing, and has demonstrated prolonged remission durations in the single-agent setting. Investigations of ibrutinib’s use in the front-line setting and in combination with other agents are ongoing, and I expect that this agent may quickly replace combination chemotherapy regimens for management of newly diagnosed patients.

Jonathon B. Cohen, MD, MS

Hematologist

Assistant professor in hematology and medical oncology

Winship Cancer Institute of Emory University

Emory University School of Medicine

Disclosures: Cohen reports no relevant financial disclosures.

Perspective

William G. Wierda, MD, PhD

I am very excited about the FDA approval of ibrutinib for treatment of relapsed patients with CLL and think it is a significant advance in treatment for all patients with CLL. This is a very well tolerated drug, which provides exceptional disease control with monotherapy. The patients who will benefit greatest initially are those with very high-risk features, like those who are relapsed with chromosome 17p deletion or fludarabine-refractory, for whom we have had no treatment that provided reasonable response rate with any durability. I expect it will be easiest to observe the improved survival with this drug in relapsed patients with 17p deletion CLL, then later in those with non-17p del relapsed disease. Our next challenge is to study other small-molecule inhibitors and integrate this and others of this type of drug into treatment strategies that eliminate chemotherapy, and develop treatments that are curative for our patients.

William G. Wierda, MD, PhD

Professor, department of leukemia

The University of Texas MD Anderson Cancer Center

Disclosures: Wierda reports advisory board, consultant and speaker roles with AbbVie, Celgene, Genentech, Gilead and Pharmacyclics.

Perspective

Richard R. Furman, MD

The approval of ibrutinib for CLL will go far to ensuring the availability of ibrutinib for all patients with CLL. My hope is that ibrutinib will start to gain use in previously untreated CLL patients as well, furthering the goal of eliminating chemotherapy from the treatment paradigm.

Given the dramatic results seen early on, ibrutinib has been studied in a large number of patients for a significant duration, helping to demonstrate its excellent tolerability, safety and efficacy.

With a medication like ibrutinib, we are closer to being able think of CLL in a manner similar to high blood pressure, where patients can control their disease indefinitely with an oral medication.

Richard R. Furman, MD

Associate professor of medicine

Weill Cornell Medical College

Disclosures: Furman reports research funding from and an advisory committee role with Gilead.

Perspective

John C. Byrd, MD

It is such a humbling feeling to have been part of such a wonderful team at OSU along with other investigators, Pharmacyclics, the FDA, and most importantly the patients who have participated in the ibrutinib trials. The great news today about the wide label of use for ibrutinib will hopefully contribute to our long-term goal of making treatment of CLL chemotherapy-free and patient friendly.

John C. Byrd, MD

Director, division of hematology

Ohio State University Comprehensive Cancer Center —

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Disclosures: Byrd serves as the lead investigator of a study evaluating ibrutinib in CLL. He also is an uncompensated consultant for Pharmacyclics.

Perspective

Mitchell R. Smith, MD, PhD

This is great news for several reasons. First and foremost, of course, we now can offer our patients a well-tolerated oral agent with a very high likelihood that their CLL will have a durable response. When imatinib (Gleevec, Novartis) was approved for chronic myeloid leukemia, many CLL patients came to the office wanting the “leukemia pill.” Now we have one for this disease. In particular, patients with deletion 17p —more frequent in relapsed CLL and usually resistant to our current treatments — respond as well. Second, this approval shows that scientific research into understanding disease biology — in this case the B-cell receptor — leads to treatment advances, and the time to translate new understanding into new treatments is being significantly reduced. Finally, this is only the beginning as we learn how to optimize use of ibrutinib and look forward to other novel agents in late-stage development.

Mitchell R. Smith, MD, PhD

Director of lymphoid malignancies

Cleveland Clinic’s Taussig Cancer Institute

Disclosures: Smith was a local lead investigator for a study of ibrutinib.

Perspective

Jeffrey Jones, MD, MPH

The approval of ibrutinib makes available one of the most effective and least toxic therapies yet developed for the disease.

For patients with relapsed deletion 17p disease, who are at highest risk of dying from CLL, ibrutinib represents a new standard of care.

The approval marks a new era in CLL medicine, one in which not only accepted therapies but also accepted paradigms of treating the disease will need to be revisited. The utility of early intervention and the role of hematopoietic stem cell transplant, particularly among the patients with genetically high-risk disease, are questions for which answers are already being sought. But most exciting is the new vigor with which we will once again undertake the search for potentially curative combination therapy.

Jeffrey Jones, MD, MPH

Assistant professor of internal medicine

Division of hematology

Ohio State University Wexner Medical Center

Disclosures: Jones reports advisory board roles with AbbVie, Gilead and Pharmacyclics.

Perspective

Jennifer R. Brown, MD, PhD

This is a great day for CLL patients! Ibrutinib is a well tolerated, highly effective oral therapy that is going to transform our treatment of patients with CLL. It is also the first of what will likely, ultimately be multiple targeted drugs for CLL. So stay tuned; this is the start of what promises to be great developments in CLL over the next several years.

Jennifer R. Brown, MD, PhD

Director of the Center for Chronic Lymphocytic Leukemia

Dana-Farber Cancer Institute

Disclosures: Brown has served as a consultant for Gilead, Pharmacyclics and Roche.