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BTK Inhibitor Ibrutinib Appears Effective Against Aggressive Lymphoma

LAINO, CHARLENE

doi: 10.1097/01.COT.0000414900.51438.a6
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CHICAGO—Preliminary results from an ongoing Phase II study suggest that the experimental oral BTK inhibitor ibrutinib can produce clinically significant responses in some patients with diffuse large B-cell lymphoma (DLBCL), including patients with chemotherapy-refractory disease. The data were reported here at the opening plenary session of the American Association for Cancer Research Annual Meeting.

While the results are early, many expressed excitement about the results and predicted the drug will be practice-changing.

In presenting the results, Louis M. Staudt, MD, PhD, Deputy Chief of the Metabolism Branch of the National Cancer Institute, noted that DLBCL accounts for about 40% of non-Hodgkin's lymphomas, making it the most common subtype of the disease. About 23,000 new cases are diagnosed and 10,000 people die from the disease each year in the U.S.

About half of patients are cured with chemotherapy and rituximab, but there has been a critical need for new treatments for the other half, he said, noting that there have been no major advances in the treatment of DLBCL in more than a decade.

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Biologic Rationale

However, studies over the past 12 years have shown that DLBCL is comprised of at least three molecular subtypes, each derived from B cells at unique stages of differentiation. The activated B-cell (ABC) subtype accounts for approximately 40% of cases and has the poorest clinical outcome with current therapy, he said.

Genetic studies found that receptors on the surface of B cells play an important role in the progression of ABC lymphomas, he continued. In normal B cells, these B-cell receptors help the cells recognize infections, but malignant B cells in ABC lymphomas provide signaling that promotes tumor survival. More than 20% of ABC tumors have mutations that alter the activity of the B-cell receptor.

Research also identified the enzyme Bruton's tyrosine kinase (BTK) as a key element in the B-cell receptor pathway required to maintain the survival of ABC lymphoma cells, Staudt said.

Based on the molecular research, the investigators tested ibrutinib (formerly called PCI-32765), a potent inhibitor of BTK–"It makes a stable bond with the BTK enzyme, so it is irreversible."

In a pilot study of 10 patients resistant to other treatments given single-agent ibrutinib, there were two complete responses, one partial response, and one case of stable disease. One patient continues to be in complete remission at 15 months.

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3 Patient Examples

Patients in the ongoing Phase II multicenter trial are being given a once-daily 560 mg ibrutinib pill until disease progression.

So far 10 of about 50 patients have completed treatment "with good results—one complete response and three partial responses," Staudt said. One patient has stable disease.

Ibrutinib was well tolerated without significant side effects. Treatment-related toxicities include diarrhea (Grade 1), nausea (Grade 1), and fatigue (Grades 1–2). "It has a wonderful side effects profile that will allow it to be combined [with other agents]," he said.

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At the meeting, Staudt highlighted the details of three of the patients:

  • Patient #2 in the Phase II trial, a 52-year-old female who had disease relapse following two prior chemotherapies was treated with ibrutinib alone. By week eight, she had a complete response, as evidenced on PET and CT scans. She had a complete remission for 16 months, with no side effects, and "she feels great," Staudt said.
  • Patient #9 in the Phase II trial, a 59-year-old woman, was refractory to every other therapy tried, including rituximab and two different chemotherapy combinations and three cycles of oxaliplatin and gemcitabine. She went on single-agent ibrutinib and had a near complete response by week 3 as shown on CT and PET. "She didn't have the mutation in the receptor, suggesting a broader role for BCR signaling in this lymphoma type," he said.
  • Patient #3 from the Phase I trial: Staudt showed a PET scan demonstrating massive disease pushing on her stomach, making it impossible for her to eat. By Week 3 of treatment, she had a partial response. "She has residual tumor, but it was a remarkable response in a disease that had never responded to anything." Indeed, before-and-after scans showed a dramatic resolution of tumor throughout her body.
LOUIS M

LOUIS M

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Discussion

"It is still early but we are "seeing basically the same responses, so we are excited about this drug," he said.

Said José Baselga, MD, PhD, Chief of the Division of Hematology and Oncology and Associate Director of Massachusetts General Hospital Cancer Center and Professor of Medicine at Harvard Medical School: "DLBCL is a very tough diagnosis. These were refractory patients, and this study is showing complete remissions with this agent.

"This validates [the approach]. This will change the way we treat lymphoma. This is one pill a day. It clearly will be practice-changing," he said.

Ibrutinib is also being tested against other forms of lymphoma as well as leukemia and multiple myeloma.

© 2012 Lippincott Williams & Wilkins, Inc.
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