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ASCO 2014: Pharmacyclics’ Imbruvica beats GSK’s Arzerra in elderly CLL patients

By Randy Osborne, Staff Writer

CHICAGO – As the American Society of Clinical Oncology (ASCO) meeting entered day two, coffee-sipping attendees perked to a first-in-the-morning discussion of the phase III data with Pharmacyclics Inc.’s ibrutinib (branded Imbruvica) in relapsed chronic lymphocytic leukemia (CLL), the first time an oral drug has yielded survival improvement over standard therapy.

CLL is usually treated with chemo-immunotherapy, which combines chemotherapy with an antibody such as rituximab (Rituxan, Biogen Idec Inc.), but elderly patients – the bulk of those afflicted with CLL – often can’t hold up to chemo, and end up getting the anti-CD20 antibody ofatumumab (Arzerra, Glaxosmithkline plc).

It was ofatumumab to which Pharmacyclics, of Sunnyvale, Calif., compared ibrutinib, an oral Bruton’s tyrosine kinase inhibitor developed with Johnson & Johnson unit Janssen Biotech Inc. as a single agent to treat patients with mantle cell lymphoma who received at least one prior therapy. The compound won FDA approval last year. Ibrutinib, which blocks signals that stimulate malignant B cells to grow and divide uncontrollably, won U.S. marketing clearance in CLL in February by way of accelerated review. (See BioWorld Today, Nov. 14, 2013.)

Gregory Masters, of ASCO, who moderated a panel that included the results from the trial known as Resonate, predicted that ibrutinib’ “may in fact transform the treatment of CLL, potentially replacing more toxic chemotherapy. It’s really impressive to see an overall survival [OS] benefit in CLL, a disease where the progress is slow” but where patients tend to last relatively long. Lower toxicity and strong efficacy “can be really encouraging for patient options.”

The study enrolled 391 patients with relapsed or refractory CLL or the CLL subtype small lymphocytic lymphoma who had progressed after two or more previous therapies. Their median age was 67 years, and 40 percent were older than 70. All were randomly assigned to either ofatumumab or ibrutinib.

At the median follow-up of 9.4 months, the response rates proved dramatically higher in the ibrutinib arm compared to the ofatumumab arm (42 percent vs. 4 percent). Another 20 percent of patients treated with ibrutinib showed a partial response with persistent lymphocytosis, an increase in white blood cells. Ibrutinib was associated with an 80 percent lower risk of their disease getting worse.

John Byrd, presenting author at ASCO, noted that “in spite of a crossover that was allowed after the first 57 patients [had progressed], ibrutinib significantly performed in overall survival, with a 57 percent reduction [in the risk of dying] in the ibrutinib arm over ofatumumab.” Even in high-risk CLL groups – patients with 17p deletions and purine-analog refractory – ibrutinib came on strong.

Patient follow-up continues, but researched expect the median OS to land in the range of several years.

Both compounds were well tolerated, with diarrhea, minor bleeding, and atrial fibrillation more common in the ibrutinib arm, whereas ofatumumab patients were more likely to have peripheral neuropathy. Byrd described the diarrhea as “very modest and manageable in most patients, and it goes away after the first couple of months. Most patients in trials do well with it. There’s really not a good reason outside of a few circumstances to not consider [ibrutinib].” Patients on warfarin might be “transitioned to something else,” since early safety signals of bleeding and subdural hematomas appeared in that segment, he said. Another group would be patients with inflammatory bowel disease, “because the drug does skew T cells.”

See the next edition of BioWorld Today for more on this story.