CHICAGO – Adding the targeted agent ibrutinib to standard chemoimmunotherapy prolongs progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results of a phase III trial reported at the annual meeting of the American Society of Clinical Oncology.
Findings of the international trial, known as HELIOS, showed that the risk of progression or death was 80% lower for patients given ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK), than for counterparts given a placebo, each in addition to standard bendamustine and rituximab. As a result, the trial was unblinded and all patients were offered ibrutinib.
Dr. Asher-Chanan Khan
“Today the world for CLL relapsed patients will be different because of this particular drug,” lead study author Dr. Asher Chanan-Khan, professor of medicine at Mayo Clinic in Jacksonville, Florida, commented in a press briefing. “This becomes one of the most important changing points in the history of CLL, where the treatment of CLL patients will no longer be bendamustine and rituximab, but bendamustine and rituximab with ibrutinib.”
“This is very exciting for our CLL patients, who have a chronic cancer; all of them will relapse and recur,” noted Dr. Merry-Jennifer Markham, an ASCO Expert from the Division of Hematology & Oncology, University of Florida in Gainesville. “We have lots of options for treatment, but the results of this combination are so exciting for them. I think this is really going to be an important drug in combination with an established chemotherapy regimen. It will really help these patients live longer, and longer lives with better quality.”
Signaling through the BTK pathway plays a critical role in the survival and proliferation of CLL cells, making treatment with ibrutinib especially attractive, according to Dr. Chanan-Khan. Results of the sister RESONATE trial established that the drug performed well when given as monotherapy to patients with relapsed or refractory CLL (N. Engl. J. Med. 2014 ;371:213-2).
Last year, the U.S. Food and Drug Administration granted accelerated approval to ibrutinib for treating CLL in patients who have already received other treatments.
Dr. Merry-Jennifer Markham
In the new, Janssen-funded trial, 578 patients with CLL or small lymphocytic lymphoma, excluding those with the 17p deletion, were randomized evenly to receive ibrutinib (brand name Imbruvica) or placebo, each in addition to bendamustine (Treanda) and rituximab (Rituxan). On the basis of the sister trial’s data, the protocol was amended after the trial began to allow placebo patients to cross over to ibrutinib at the time of progression, noted Dr. Chanan-Khan.
The preplanned interim analysis, conducted after a median follow-up of 17 months, showed that median progression-free survival – the trial’s primary endpoint – was 13.3 months in the placebo group, whereas this landmark had not been reached in the ibrutinib group (hazard ratio, 0.20; P < .0001). Benefit was similar in the subgroup of patients with high-risk features.
Ibrutinib was also associated with a near-significant improvement in overall survival relative to placebo (HR, 0.63; P = .0598), a noteworthy finding as roughly a third of patients in the placebo arm had crossed over to the drug at progression, Dr. Chanan-Khan pointed out. The ibrutinib group had a superior overall response rate as well (82.7% vs. 67.8%; P < .0001).
“The side effect profile was very tolerable and expected for each of the individual drugs that were in this regimen,” he reported. The most common side effects – neutropenia, thrombocytopenia, diarrhea, and nausea – occurred in similar proportions in each group.
With respect to side effects known to be specific to ibrutinib, bleeding of any grade occurred in 31% of patients given the drug, compared with 17% given placebo, and serious bleeding occurred in 3.8%. Atrial fibrillation occurred in 7% with the drug, compared with 0.7% with placebo, but the proportion developing grade 3 or 4 atrial fibrillation was only about 2%.
As for future research, the investigators plan to evaluate ibrutinib alone and in combination with drugs targeting the CD20 protein in patients with newly diagnosed symptomatic and asymptomatic CLL.
Dr. Chanan-Khan reported having no financial disclosures. The trial was funded by Janssen.