Chanan-Khan, MD
© ASCO/Zach Boyden-Holmes
CHICAGO—Interim results of the phase 3 HELIOS trial suggest that adding ibrutinib to treatment with bendamustine and rituximab (BR) improves outcomes for patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Patients who received ibrutinib and BR had significantly higher response rates and a significantly longer progression-free survival than patients who received BR with placebo.
There was no significant difference between the arms with regard to overall survival, but the researchers said these results were confounded by the fact that 31% of patients in the placebo arm crossed over to the ibrutinib arm after they progressed.
“We found that ibrutinib can be safely paired with existing therapy to powerfully prolong remissions and improve patients’ well-being,” said study investigator Asher Alban Akmal Chanan-Khan, MD, of the Mayo Clinic in Jacksonville, Florida.
Dr Chanan-Khan presented these findings at the 2015 ASCO Annual Meeting (abstract LBA7005). The research was funded by Janssen Research & Development, LLC, the company co-developing ibrutinib with Pharmacyclics.
The study included 578 patients with previously treated CLL/SLL, excluding those with del(17p). The patients were randomized to receive 6 cycles of BR plus once-daily ibrutinib (n=289) or 6 cycles of BR plus placebo (n=289). Ibrutinib and placebo were given until disease progression or unacceptable toxicity.
Dr Chanan-Khan said baseline characteristics were comparable between the treatment arms. For each arm, the median number of prior treatments was 2, more than 50% of patients had bulky disease, and about 80% of patients had unmutated IGVH.
“[However,] advanced Rai-stage disease was observed in a slightly [greater] proportion of patients in the control arm versus the ibrutinib arm,” Dr Chanan-Khan noted. “Conversely, a higher proportion of patients with del(11q) was noted in the ibrutinib-containing arm.”
Ultimately, 81.9% (n=235) of patients in the ibrutinib arm and 77.4% (n=222) of those in the placebo arm received their assigned 6 cycles of BR. At the time of analysis, the rate of treatment discontinuation was 29.1% (n=84) in the ibrutinib arm and 64.7% in the placebo arm (n=187).
Those patients who progressed on placebo were allowed to cross over to the ibrutinib arm, and 90 patients had crossed over at the time of the interim analysis.
Response and survival
The study’s primary endpoint was progression-free survival, as assessed by an independent review committee (IRC), in the intent-to-treat population (n=289 in each arm).
At a median follow-up of 17 months, progression-free survival was 13.3 months in the placebo arm and was not reached in the ibrutinib arm (P<0.0001).
“The hazard ratio on this particular survival curve is 0.20, which translates into a reduced risk of progression or death by 80%,” Dr Chanan-Khan said. “This is remarkable. You cannot get a better hazard ratio than this.”
Dr Chanan-Khan also noted that the overall response rate was significantly higher in the ibrutinib arm than the placebo arm. The rates were 82.7% and 67.8%, respectively (P<0.0001), according to the IRC, and 86.2% and 68.9%, respectively (P<0.0001), according to investigator assessment.
The rate of complete response plus complete response with incomplete blood count recovery was 10.4% in the ibrutinib arm and 2.8% in the placebo arm, according to the IRC. According to investigator assessment, the rates were 21.4% and 5.9%, respectively.
The median overall survival was not reached in either arm, and the hazard ratio was 0.628 (P=0.0598).
Adverse events
Dr Chanan-Kahn said the safety profile of the ibrutinib-BR combination was consistent with the safety profiles of each individual drug.
The incidence of adverse events was 70.7% in the ibrutinib-BR arm and 70% in the placebo-BR arm. The most common events were neutropenia (58.2% and 54.7%, respectively), nausea (36.9% vs 35.2%), diarrhea (35.5% vs 23.7%), thrombocytopenia (30.7% vs 24.4%), pyrexia (24.7% vs 22%), anemia (22.6% vs 28.9%), and fatigue (21.6% vs 22.6%).
The incidence of grade 3/4 adverse events was 28.9% in the ibrutinib arm and 25% in the placebo arm. The most common of these were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15% in both arms).
Atrial fibrillation was seen in 7.3% of patients in the ibrutinib arm and 2.8% in the placebo arm. Grade 3/4 atrial fibrillation occurred in 2.8% and 0.7% of patients, respectively. The incidence of tumor lysis syndrome was 3.5% in both arms.
The rate of bleeding was 31% in the ibrutinib arm and 14.6% in the placebo arm. And the rates of major hemorrhage were 3.8% and 1.7%, respectively.
Adverse events were the primary reason for discontinuation in patients who received ibrutinib—14.2%, compared to 11.8% of patients who received placebo. The primary reason for discontinuation in the placebo arm was progressive disease or relapse—45%, compared to 4.8% in the ibrutinib arm.
Taken together, the results of this trial suggest treatment with ibrutinib and BR is superior to standard BR therapy in patients with relapsed CLL/SLL, Dr Chanan-Kahn said.
“This was one of the most rigorous clinical trials ever conducted in CLL,” he said, “and it truly validates ibrutinib as an important drug for this cancer.”
