ORLANDO – Adding the PI3K inhibitor idelalisib to a standard regimen of bendamustine and rituximab significantly reduced the risk of both disease progression and death for patients with relapsed and/or refractory chronic lymphocytic leukemia, results of a phase III randomized trial showed.

At a median follow-up of 12 months, the primary endpoint of median progression-free survival was 23.1 months for patients treated with idelalisib (Zydelig), bendamustine, and rituximab (idel+BR), compared with 11.1 months for bendamustine and rituximab (BR) plus a placebo, reported Dr. Andrew Zelenetz of Memorial Sloan Kettering Cancer Center, New York.

“Median overall survival was not reached in either arm. However, there was a significant improvement in overall survival, with a 45% reduction in the risk of death [with idel+BR],” he said in a late-breaking abstract session at the annual meeting of the American Society of Hematology.

The trial was stopped early after a data review at the first planned interim analysis showed significant superiority for the three-drug combination.

The results were consistent across subgroups, including patients with high-risk features such as deletion 17p and mutated TP53 (del[17p]/TP53), unmutated immunoglobulin heavy chain variable region (IgHV), and treatment-refractory disease.

The rationale behind adding idelalisib, an inhibitor of the phosphatidylinositol-3 kinase (PI3K), is that signaling via the PI3K pathway is hyperactive and can be targeted, Dr. Zelenetz explained.

Study 115 was a phase III trial with accrual from June 2012 through August 2015. Investigators enrolled 416 patients with relapsed /refractory CLL and randomly assigned them to receive BR for six 28-day cycles of bendamustine (70 mg/m² on days 1 and 2 of each cycle) and rituximab (375 mg/m² for cycle 1, and 500 mg/m² for cycles 2 through 6), plus either idelalisib 150 mg b.i.d. or placebo, each administered continuously until disease progression, intolerable toxicity, withdrawal of consent, or death.

The patients were stratified by mutational and disease status (refractory defined as CLL progression less than 6 months from completion of prior therapy, or relapsed CLL progression 6 months or more from completion of prior therapy.

The trial was halted early after the first planned interim analysis, which was conducted after 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The data cutoff was June 15, 2015.

The intention-to-treat analysis included 207 patients assigned to idelalisib and 209 assigned to placebo. Three-fourths (76%) of the patients were male.

In all, 46% of patients had Rai stage III/IV disease. The median time since the completion of the last therapy was 16 months.

The proportions of patients with high-risk features included del(17p)/p53 mutation in 32.9%, unmutated IgHV in 83.2%, and treatment-refractory disease in 29.8%.

As noted, the median progression-free survival with idelalisib at a median follow-up of 12 months was 23.1 months vs. 11.1 months for placebo. That translated into a hazard ratio of 0.33 (P less than .0001).

Among patients with neither del(17p) nor TP53 mutations, the HR for progression was 0.22. Among patients with either del(17p) or a TP53 mutation, the HR was 0.50 (95% confidence intervals show statistical significance for both).

Overall response rates were 68% among patients who received idelalisib, and 45% for those who received placebo. There were five complete responses (2%) in the idelalisib group and none in the placebo group.

The idelalisib group also had a higher proportion of patients with a greater than 50% reduction in involved lymph nodes (96% vs. 61%), and had better organomegaly responses (spleen and liver) and hematologic responses (hemoglobin, neutrophils, and platelets).

Grade 3 or greater adverse events occurred in 93% of patients on idelalisib, compared with 76% of those on placebo. The proportion of patients with any serious adverse event was 66% vs. 44%, respectively.

Adverse events leading to drug dose reduction were seen in 11% of idelalisib-treated patients, compared with 6% of placebo controls, and therapy was discontinued in 26% vs. 13%, respectively.

Ten patients in the idelalisib arm and seven in the placebo arm died during the study.

Adverse events that occurred more commonly with idelalisib included neutropenia, pyrexia, diarrhea, febrile neutropenia, pneumonia, rash, and elevated liver enzymes.

Session moderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston asked Dr. Zelenetz how idelalisib plus BR stacked up to ibrutinib (Imbruvica) plus BR in this population.

Dr. Zelenetz noted that patients were excluded from the HELIOS trial of ibrutinib plus BR if they had del(17p). Comparing the subset of patients in Study 115 without del(17p) with patients in the ibrutinib study, “the results are virtually superimposable,” Dr. Zelenetz said, and “the two treatments are really remarkably similar.”

The overall survival benefit was larger in the HELIOS trial, Dr. Zelenetz noted, but that was largely because the trial allowed patients to cross over from placebo to the active drug.

Gilead Sciences funded Study 115. Dr. Zelenetz disclosed receiving research funding from the company and discussing off-label use of idelalisib for relapsed/refractory CLL.

ASH: Idelalisib plus standard therapy boosts survival in relapsed CLL