Leukemia Drug Is 'Blessing From God,' But Trial Imperfect

Believers May Change Practice

Nick Mulcahy

June 05, 2015

CHICAGO — Like many hematologic oncologists, Asher Chanan-Khan, MD, from the Mayo Clinic in Jacksonville, Florida, is a believer in the therapeutic powers of ibrutinib (Imbruvica, Pharmacyclics) for the treatment of chronic lymphocytic leukemia (CLL).

But this week, Dr Chanan-Khan uniquely endorsed the drug, which other experts have called "transformative" and "game-changing," for patients with relapsed/refractory disease.

For "countless" CLL patients, "this drug has been a blessing from God," he said during a press conference here at the American Society of Clinical Oncology 2015 Annual Meeting.

The high praise came when Dr Chanan-Khan presented first results from the 578-patient HELIOS trial, which is the first randomized placebo-controlled phase 3 study of ibrutinib and standard therapy in relapsed/refractory disease.

He reported that ibrutinib plus bendamustine/rituximab reduced the risk for disease progression by 80%, compared with placebo plus bendamustine/rituximab. Median progression-free survival had not been reached in the ibrutinib group, but was 13.3 months in the placebo group (hazard ratio [HR], 0.20; P < 0.0001).

"This is remarkable. You cannot get a better hazard ratio than this," he proclaimed.

Progression-free survival is the study's primary end point. Median follow-up was 17 months.

The goal of therapy for CLL, which is incurable, is to induce remission and maintain remission for as long as possible, he reminded the audience.

You cannot get a better hazard ratio than this.

The combination of bendamustine/rituximab has been the standard of care for patients with relapsed disease for a "very, very long time", explained Dr Chanan-Khan, who was lead author. This combination is described as immunochemotherapy, whereas ibrutinib is a novel targeted agent — a first-in-class inhibitor of Bruton's tyrosine kinase.

These results change practice in relapsed/refractory disease, with ibrutinib plus bendamustine/rituximab being the new standard, he announced.

"This becomes one of the most important changing points in the history of CLL," he prophesized.

That faith was not shared by everyone.

"This might be an advance," opined Lloyd Damon, MD, from the University of California, San Francisco, who was the meeting discussant for the HELIOS trial.

His equivocation was not with ibrutinib but with the trial design.

Did the study ask the best question?

In his critique, Dr Damon wondered, "Did the study ask the best question?"

"Should not the question really be, 'What is the contribution of immunochemotherapy to ibrutinib?' " he challenged.

In other words, Dr Damon suggested that ibrutinib alone should have been the control group and been tested against itself plus standard immunochemotherapy. That way, it could be established whether ibrutinib monotherapy is sufficient for the treatment of these patients, and whether it is superior to the three-drug combination.

To make his point, he compared the HELIOS trial with two earlier ibrutinib studies; all were in the setting of relapsed/refractory disease. One was the single-group phase 1b trial that preceded HELIOS (Blood. 2015;125:2915), and the other was a single-group study of ibrutinib alone (Blood. 2015;125:2497).

Ibrutinib had "roughly" the same rates of response and progression-free survival in all three trials, he said.

In short, ibrutinib looked good on its own.

Dr Damon suggested that using immunochemotherapy is not ideal. Its complications include cytopenia and infection, he reported.

"Can chemotherapy be omitted as first-line treatment of CLL/SLL without damaging the long-term benefits of immunochemotherapy?" he asked.

This has been the hope — and the prediction — ever since the first results with ibrutinib in CLL were released. In a previous interview with Medscape Medical News, the principal investigator of the pivotal phase 3 RESONATE trial emphasized both the dramatic responses and the tolerability of ibrutinib.

"It's really blowing the pants off what we are standardly doing in elderly CLL patients," said John C. Byrd, MD, from the Ohio State University Comprehensive Cancer Center in Columbus. He predicted that in the near future, "we will be using ibrutinib, either alone or in combination with a monoclonal antibody, in place of chemotherapy for most CLL patients."

Adverse Events and More Efficacy Data

In the HELIOS trial, 88.9% of patients had CLL and 11.1% had small lymphocytic lymphoma (SLL), and all had failed at least one previous therapy. The patients had a performance status of 0 or 1, according to ECOG standards. The average age of participants was 64 years in the ibrutinib group and 63 years in the placebo group.

The overall response rate, assessed by an independent review committee, was significantly higher in the ibrutinib group than in the placebo group (82.7% vs 67.8%; P < .0001). And there were more complete responses in the ibrutinib group (10.4% vs 2.8%).

At the time of the analysis, 90 (31%) patients from the placebo group had already crossed over to the ibrutinib group; the crossover was allowed after data from the RESONATE study indicated that the targeted therapy improved survival.

Despite the crossover, ibrutinib still showed a 37% reduction in the risk for death compared with bendamustine/rituximab (HR, 0.63; P = .059). Median overall survival has not been reached in either group, which is understandable given the long course of this disease.

The adverse events seen with the combination of ibrutinib and bendamustine/rituximab were "very tolerable" and "expected," Dr Chanan-Khan reported.

Overall, the top four adverse events — neutropenia, nausea, diarrhea, and thrombocytopenia — were "comparable" in the two study groups. In other words, the addition of ibrutinib did not worsen these adverse effects.

However, there were more infections of grade 3 or higher in the ibrutinib group than in the placebo group (28.9% vs 25.0%). There was also more bleeding of all grades with ibrutinib (31% vs 14.6%), more major hemorrhages (3.8 % vs 1.7%), and more atrial fibrillation (7.3% vs 2.8%).

The study population did not include patients with the del17p genetic aberration, which is characterized by aggressive disease. Ibrutinib is indicated for the treatment of all patients with del17p genetic aberration and of patients with relapsed/refractory disease.

The study was funded by Janssen. Dr Chanan-Khan has disclosed no relevant financial relationships. Some of the study authors are employees of Janssen.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA7005. Presented May 30, 2015.


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