BY ROBERT H. CARLSON
CHICAGO -- The Food and Drug Administration accelerated the approval of ibrutinib earlier this year for treatment of patients with relapsed/refractory chronic lymphoid leukemia (CLL) on the basis of a single-arm, Phase II trial with only 48 patients, albeit a trial with compelling results (OT 3/10/14 issue).
That decision has now been supported with final results of the Phase III RESONATE trial, presented here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA7008), the full data for which was published simultaneously online ahead of print in the New England Journal of Medicine (Byrd et al: DOI: 10.1056/NEJMoa1400376).
The results continue to impress: The progression-free survival rate for patients receiving this oral Bruton's tyrosine-kinase inhibitor was 88 percent at six months versus 65 percent for the comparator arm with ofatumumab, which was approved by the FDA in 2009 for previously treated CLL. At a median follow-up of 9.4 months, the median duration of response had not yet been reached in the ibrutinib group, compared with a median of 8.1 months for ofatumumab.
At 12 months, overall survival rate was 90 percent in the ibrutinib arm versus 81 percent in the ofatumumab group. Overall response was also greatly significantly higher in the ibrutinib arm: 42.6 versus 4.1 percent, respectively.
An additional 20 percent of ibrutinib-treated patients had a partial response with lymphocytosis. Throughout the trial, similar responses were seen, even in patients with a chromosome 17p13.1 deletion or resistance to purine analogues.
ASCO 2013-2014 President Clifford Hudis, MD, noted that when the Data Monitoring Committee for RESONATE analyzed the interim results, the trial had essentially exceeded its planned target and the board recommended accepting those as the final results. “This was a slam dunk,” Hudis said. “Ibrutinib is oral, highly effective, with no dramatic toxicities, and I think it will change practice quickly.”
In the multicenter, open-label study, which was funded by Pharmacyclics and Janssen, 391 patients with CLL or small lymphocytic leukemia (SLL) who had disease progression after two or more prior therapies were randomly assigned to 420 mg oral ibrutinib daily until progression (195 patients), or intravenous ofatumumab at 300-2,000 mg for 12 doses (196 patients).
The primary endpoint was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary endpoints.
The median age of patients was 67; 40 percent were age 70 or older; 57 percent had Rai stage III/IV disease; and 30 percent had deletion 17p.
Ibrutinib patients had received a median of three prior therapies versus two prior therapies for patients in the ofatumumab group. Median follow-up was 9.4 months.
The most frequent adverse events for ibrutinib versus ofatumumab were diarrhea (48% vs. 18%), fatigue (28% vs. 30%), and nausea (26% vs. 18%). Atrial fibrillation was more frequent with ibrutinib (5.1% vs. 0.5%). Major hemorrhages were reported in two patients (1%) in the ibrutinib group (including one patient with a subdural hematoma) and three patients (2%) in the ofatumumab group.
Drug discontinuation due to adverse events was necessary in 4.1 percent versus 3.6 percent, respectively; and the problem of Richter's transformation occurred in two patients in each group.
Speaking at an ASCO news conference that featured highlighted abstracts in targeted therapies, lead author John C. Byrd, MD, Chair of Leukemia Research, Director of the Division of Hematology, and Professor of Medicine and Medical Chemistry at Ohio State University Comprehensive Cancer Center, said, “This is a very important study, showing for the first time that ibrutinib beats a standard of care approved for relapsed or refractory CLL.”
‘Will Change the CLL Landscape’
A designated ASCO hematology expert interviewed at the meeting, Olatoyosi M. Odenike, MD, Associate Professor of Hematology/Oncology at the University of Chicago, was also enthusiastic: “Ibrutinib is an amazing drug, the first time in CLL we have had an oral agent with such remarkable activity and relatively good tolerability. And that activity was uniformly seen against all subgroups, even in historically tough to treat subgroups, such as older patients or genetic abnormalities such as 17p deletion.”
She also noted that the study alleviates concerns about kidney problems that were raised in the Phase II ibrutinib study.
The standard treatment today for newly diagnosed CLL patients is FCR (fludarabine-cyclophosphamide-rituximab), which is effective but carries a high risk of toxicity for older patients. “The median age at time of CLL diagnosis is about 70, and physicians are hesitant to use FCR for those patients, so the prospect of using ibrutinib is fantastic,” she said.
Another patient population to benefit may be younger patients with 17p deletion who would otherwise be considered for allogeneic stem cell transplant. “The presence of ibrutinib is going to change the landscape now and force us to reevaluate in a meaningful way how to approach these patients,” Odenike said.
Also asked for his opinion for this article Anthony Mato, MD, Director of the Center for Chronic Lymphocytic Leukemia at the University of Pennsylvania, said: “By far this is a transformative drug; it is transforming the way we treat patients with CLL.”
Mato said he was impressed that ibrutinib appears to overcome the traditional poor-risk factors for patients with CLL. “Patients generally respond well whether or not they have unmutated CLL or a chromosome-17 abnormality -- patients who would have traditionally done poorly, especially in the relapsed/refractory setting. And when those response rates are translated to duration of response, the duration is very impressive with a median progression-free survival that has not been reached.”
Mato said this trial is one of the few examples in CLL where a novel approach was compared with a standard approach and survival is actually improved. The most recent example he could recall of a successful new approach was from the CLL-8 trial which added rituximab to fludarabine-cyclophosphamide (FCR), and at three years achieved 65 percent progression-free survival versus 45 percent for FC (Hallek et al: Lancet 2010; 376:1164-1174).
He predicted that the success of RESONATE will lead to an acceleration of research in B-cell receptor signaling, which will translate into the development of more targeted drugs for CLL. “Ibrutinib is probably the tip of the iceberg [for that direction of research], as we are recognizing more and more how important B-cell receptor signaling is.”
A question to answer now is how to combine ibrutinib with current standards, particularly rituximab, he said. “Rituximab is not approved for use as a single agent -- it's usually combined with fludarabine and cyclophosphamide, but studies presented at previous meetings looking at the combination of ibrutinib and rituximab had response rates exceeding 80 percent.”
He cited a Phase II study of the ibrutinib-rituximab combination presented at the most recent American Society of Hematology Annual Meeting, which showed responses exceeding 90 percent (ASH Abstract 675).
“I have had many of my own CLL patients who were almost to the point of having hospice discussions, and with ibrutinib therapy I've seen them come back in so many ways, in performance and quality of life.”