Extremely favorable comments on ibrutinib, in particular regarding the LACK OF TOXICITY. My strong hunch is that the combination of efficacy in end-stage patients and very low toxicity is going to lead to earlier FDA approval then any of the analysts are prediciting. There will be huge pressure on the FDA to get this drug in the mouths of desperate patients
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From Medscape Medical News > Conference News
Excitement Over Ibrutinib Responses in Aggressive Lymphomas
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April 2, 2012 (Chicago, Illinois) — The experimental agent ibrutinib has shown a few remarkable responses in patients with aggressive and refractory diffuse large B-cell lymphomas (DLBCL). Although these findings are very preliminary, experts are excited about the results that have been seen.
Results showing that ibrutinib (under development by Pharmacyclics) exerted significant anticancer responses with a low level of adverse effects were presented here at the plenary session of the annual meeting of the American Association for Cancer Research (AACR).
"This is a very difficult population to treat, and this study is showing complete remissions with this agent," commented Jose Baselga, MD, chief of hematology/oncology at Massachusetts General Hospital Cancer Center in Boston. He was not involved with the study.
"This is one of the most exciting new targets and I think it will change the way we treat lymphoma," he commented.
Although these are "still very early days," he told Medscape Medical News, "in my mind, there is no question about it. This is practice changing."
Ibrutinib is an oral first-in-class oral agent that selectively inhibits Bruton's tyrosine kinase (BTK), which is a critical signaling kinase in the B-cell receptor pathway. The drug is under development for the treatment of several B-cell malignancies, both as monotherapy and to be used in combination with other agents.
"These studies are the culmination of about 13 years of genomic studies and studies of molecular biology of these aggressive lymphomas that led us to the rational target with B cell receptor and successful targeting of ibrutinib," said lead author Louis Staudt, MD, PhD, deputy chief of the Metabolism Branch at the National Cancer Institute (NCI), Bethesda, Maryland.
Since the addition of rituximab to chemotherapy, there have been no advances in the treatment of DLBCL, explained Dr. Staudt. "We are able to cure about half of all patients," he said during a press briefing, "but there are about 10,000 deaths every year. We urgently need other therapies for the other half."
to be cont.
Aggressive and Mutated
DLBCL are aggressive cancers and represent 30% to 40% of newly diagnosed lymphomas. Research has revealed that DLBCL is composed of at least 3 molecular subtypes, each derived from B cells at unique stages of differentiation. The activated B-cell (ABC) subtype of DLBCL accounts for approximately 40% of cases and has the poorest clinical outcome with current therapy.
This research "led us to appreciate that there is a cascade of kinases and signaling molecules that lead from the B-cell receptor down to a survival pathway known as NF-kB," he said. "This pathway is rich in therapeutic targets."
Recent functional and structural genomics studies have revealed a chronic active form of B-cell receptor signaling that activates the pro-survival NF-kB pathway in ABC DLBCL. In vitro studies showed that the "knockdown" of B-cell receptor signaling components, which include the BTK kinase, destroyed lymphoma cells.
More than 20% of ABC DLBCL tumors have mutations in the BCR subunits CD79B and CD79A, and in 18% of cases, these mutations occur in a single tyrosine residue in the critical "ITAM" signaling motif of CD79B, explained Dr. Staudt.
On the basis of these findings, the NCI researchers turned to a partnership with Pharmacyclics, he said, which had developed ibrutinib, a drug that inactives the BTK irreversibly.
Dr. Staudt and colleagues first evaluated the use of ibrutinib in a pilot trial at NCI in ABC DLBCL. The drug is currently being evaluated in an ongoing multicenter study, also in patients with DLBCL.
All patients in the pilot trial had ABC DLBCL, and results from the pilot along with individual cases from the ongoing trial indicate that the use of ibrutinib as a single agent can elicit major antilymphoma effects with minimal side effects.
Dr. Staudt reported on the outcome of 2 patients from the pilot trial. The first patient was a 52-year-old woman with a CD79BY196C mutation and MYD88 wild type. She had relapsed after 2 previous treatment cycles with chemotherapy, to which she had experienced a complete response. She was treated with ibrutinib, and by week 8 a complete response was verified by computed tomography and positron emission tomography.
"She is now at 16 months for sustained remission, with no discernible side effects and feels great," he reported.
The second patient was a 59-year-old woman with primary refractory disease in whom 3 previous treatment regimens had failed. Her tumor lacked genetic mutations, which shows that mutations are not absolutely required for the activity of this drug, noted Dr. Staudt. The patient had "massive disease" in her abdomen, with the tumor pushing on her stomach to the point that she was unable to eat.
She felt well within 1 week and was able to leave the hospital. By week 3, the tumor had largely resolved, although it was not a complete response. "She still has residual tumor," he said, "But it is a remarkable response, for a single agent targeted therapy to a disease that had not previously responded."
The patient remained in partial response for a month and a half.
To be cont.