Nick Mulcahy

May 31, 2014

CHICAGO — The highly targeted agent ibrutinib (Imbruvica, Pharmacyclics) continues to garner praise from clinicians for its effectiveness and mild averse-effect profile in patients with relapsed chronic lymphocytic leukemia (CLL).

The latest round of applause was inspired by results from the phase 3 RESONATE study, highlighted today at a press briefing here at the 2014 Annual Meeting of the American Society of Clinical Oncology® and simultaneously published online in the New England Journal of Medicine.

Ibrutinib is the first-in-class inhibitor of Bruton's tyrosine kinase (BTK), which is essential for B-cell-receptor signaling, homing, and adhesion. The majority of B-cell tumors, including CLL, are dependent on BTK for proliferation and survival.

Dr. John Byrd

"Ibrutinib shows that you can greatly impact outcome, despite an absence of a single genetic abnormality as the target. That's a really big point, scientifically," said lead author John Byrd, MD, professor of medicine at the Ohio State University Comprehensive Cancer Center in Columbus.

"Ever since I was a fellow, I have heard opinion leaders say that we are not going to find a Gleevec for CLL," he told Medscape Medical News. "The success of ibrutinib and other B-cell kinase inhibitors disproves this."

The drug also represents a personal landmark for Dr. Byrd.

"The most humbling thing that has ever happened to me as a doctor is to see patients on ibrutinib for as many as 4 years now, patients who were once very sick and now have their normal lives back," he explained.

The RESONATE trial compared ibrutinib with the standard treatment of ofatumumab (Arzerra, GlaxoSmithKline) in patients with difficult-to-treat relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

At 12 months, overall survival was better with ibrutinib than with ofatumumab (90% vs 81%). This translated into a 57% reduction in the risk for death with ibrutinib (hazard ratio [HR], 0.43; P =.005).

The progression-free survival was even more impressive, in part because the overall survival results were blunted when patients crossed over from the standard treatment to ibrutinib when the trial was halted.

Median progression-free survival was not reached in the ibrutinib group (the rate was 88% at 6 months); it was 8.1 months in the ofatumumab group.

This translated into a 78% reduction in the risk for progression (which included death) with ibrutinib (HR, 0.22; P < .001).

Ibrutinib was granted accelerated approval by the US Food and Drug Administration (FDA) earlier this year on the basis of results from a smaller phase 2 trial.

The phase 3 RESONATE study "validates" ibrutinib as an effective treatment for relapsed/refractory CLL and SSL, Dr. Byrd noted. These relapsed patients have only had "from months to 1 to 2 years to live, on average, and the quality of life is often horrible because of infections," he explained.

Experts not involved in the study were effusive in their praise.

"This is a transformative drug. There's no other way to put it," said Olatoyosi Odenike, MD, associate professor of medicine at the University of Chicago. She served as an ASCO expert at the press conference.

"This drug's efficacy may transform the treatment of chronic lymphocytic leukemia, potentially replacing the more toxic chemotherapy," said press conference moderator Gregory Masters, MD, from the Helen F. Graham Cancer Center in Newark, Delaware.

"The RESONATE trial is an extremely exciting and 'game-changing' study in CLL," said Catherine M. Broome, MD, associate professor of medicine at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, in a press statement.

Dr. Broome observed that patients with relapsed or refractory disease generally have had little or no response to other therapies. In RESONATE, the overall response rate was 42.6% with ibrutinib and 4.1% with ofatumumab.

All patients, with few exceptions, should be offered this treatment in the relapse setting.

The benefits of ibrutinib make it the treatment of choice in the setting of relapsed/refractory disease, experts agreed.

"All patients, with few exceptions, should be offered this treatment in the relapse setting," said Dr. Byrd.

The oral therapy is "patient friendly" because it has no "prohibitive" adverse effects, he added.

The exceptions to the treat-everybody-with-ibrutinib rule might include patients on warfarin and patients with inflammatory bowel disease. Ibrutinib has diarrhea as an early adverse effect, but is "manageable" and "very modest" in most patients, he said.

Overall, 57% of patients on ibrutinib and 47% on ofatumumab experienced adverse events of grade 3 or higher.

Serious adverse events occurring more frequently with ibrutinib than with ofatumumab were diarrhea (4% vs 2%) and atrial fibrillation (3% vs 0%).

Bleeding of any grade — including petechiae and ecchymosis — was more common with ibrutinib than with ofatumumab (44% vs 12%). Rash (8% vs 4%), pyrexia (24% vs 15%), and blurred vision (10% vs 3%), mostly grade 1 or 2 in severity, were also more common with ibrutinib.

Treatment discontinuation because of adverse events was the same in the ibrutinib and ofatumumab groups (4% vs 4%)

"This means that patients will be able to receive an oral therapy with good tolerability. Most patients will have a sustained remission and go on to live the lives they had before CLL," said Dr. Byrd.

"It really is a game-changing treatment for CLL," he continued, echoing comments made previously by other experts.

The drug is also effective in difficult-to-treat CLL that is characterized by the del17p genetic aberration. Similar response rates and survival outcomes were seen regardless of whether patients had del17p or purine-analog-refractory disease.

"Ibrutinib works probably the best of any treatment for the deletion 17p group," he said.

The drug has had a "remarkable timeline," Dr. Byrd reported. The first clinical trial was in 2009 and FDA accelerated approval was granted in 2014.

Phase 3 studies examining ibrutinib in the first-line setting for CLL/SLL are ongoing.

The study was funded by Pharmacyclics. Dr. Byrd and some of his coauthors report financial ties to Pharmacyclics; a number are company employees. Dr. Odenike, Dr. Masters, and Dr. Broome have disclosed no relevant financial relationships.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO). Abstract LBA7008. To be presented June 2, 2014.


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