Combination offers ‘important new option’ for CLL, team says
Photo courtesy of ASH
ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic
lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the
international research team that conducted the phase 3 study of this combination.
Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1
months versus 11.1 months, respectively.
“And the benefit was seen across risk groups,” Dr Zelenetz said.
He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.
Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.
Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.
“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”
The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.
Study 115 design and population
Study 115 was a double-blind, placebo-controlled phase 3 study.
The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m2 on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m2 during cycle 1 and 500 mg/m2 cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.
The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.
Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.
The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.
Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.
Patient disposition and demographics
One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.
Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).
The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.
A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.
Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.
Efficacy
Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said, at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).
