Ongoing trials are testing idelalisib in combinations for CLL as well. “Certainly, there’s a number of strategies, and as with ibrutinib, it’s difficult for me to identify a rational combination or a clear combination that I think is going to be superior or a significant advance,” he said. Trials are also testing other PI3 kinase inhibitors, such as duvelisib (IPI-145), now in a phase III registration trial in patients with relapsed or refractory disease.
BCL-2 inhibitors
The investigational agent venetoclax (formerly ABT-199/GDC-199) inhibits BCL-2, which is overexpressed in CLL and renders the cells resistant to apoptosis. It has advanced to a pair of phase III trials, one testing it when combined with rituximab and the other when combined with obinutuzumab (Gazyva).
When used as monotherapy for patients with relapsed disease, venetoclax achieved an overall response rate of 77% and a complete response rate of 23% (EHA 2014. Abstract S702). Benefit was similar among high-risk groups, including patients with the 17p deletion or fludarabine-refractory disease. With a median follow-up of 5.3 months, median progression-free survival for patients treated at the full dose has not been reached.
In earlier trials, venetoclax was associated with a problematic tumor lysis syndrome, according to Dr. Wierda. But that issue has largely been resolved by starting at a low dose and escalating gradually to a full dose; in the trial, it was seen in 7% of patients. The most common grade 3 or 4 adverse event was neutropenia, seen in 33% of patients; however, this toxicity can usually be managed with growth factors and dose reduction, he said.
The combination of venetoclax with rituximab in relapsed CLL yields an 88% overall response rate and a 31% complete response rate (ASH 2014. Abstract 325). Respective values were 78% and 22% in patients with 17p deletion. Moreover, some patients were found to have become negative for minimal residual disease on the combination, although it was not systematically assessed, Dr. Wierda noted.
“Venetoclax is a drug we will hear more about. … It has activity. I think it has a future in treating CLL, and it will be approved in time,” he said.
Leveraging targeted therapies
These new targeted agents, and others in the pipeline, could potentially be leveraged in several ways to improve CLL treatment strategies, according to Dr. Wierda.
Importantly, if ibrutinib becomes approved for universal frontline therapy, a large share of patients are likely to achieve partial remission. “We know if patients are in partial remission, you can’t really stop their treatment on ibrutinib; they will progress. And there was some data reported at ASH [American Society of Hematology] this past year that patients who were on a lower dose or patients who had dose interruption did poorer,” he said. Furthermore, most patients don’t like to be on treatment indefinitely.
“So we’re working on trials to expand our options for consolidation strategies in patients who have been on ibrutinib. We are trying to push them over into a complete remission by adding additional agents,” he explained.
For example, an ongoing trial is testing addition of nivolumab (Opdivo), an immune checkpoint inhibitor, in patients who have been on ibrutinib for at least 9 months and still have a partial remission. “The strategy with that is to try to consolidate them and to get them into a deep remission, where we can have a discussion about holding their treatment or stopping their treatment, or at least to the point where we are comfortable doing that,” he said.
Dr. Wierda disclosed that he has various relationships with AbbVie, Ascerta, Celgene, Emergent BioSolutions, Genentech, Genzyme, Gilead Sciences, GlaxoSmithKline, Juno Therapeutics, Karyopharm, Kite Pharma, Merck, Novartis Pharmaceuticals, Pharmacyclics, Roche Laboratories, and Sanofi-Aventis U.S.