Potent Activity Shown for First-in-class PI3K-delta Inhibitor in Chronic Lymphocytic Leukemia 

Get Permission

Drugs like idelalisib are probably going to change the landscape of this disease in the next few years.

—Jennifer R. Brown, MD, PhD

Heavily pretreated patients with chronic lymphocytic leukemia (CLL) responded robustly to the first-in-class small-molecule inhibitor idelalisib (formerly GS1101), in a phase I dose-finding study reported in a press briefing prior to the 2013 ASCO Annual Meeting.1 Idelalisib, a specific inhibitor of PI3K-delta, led to rapid, major lymph node responses in about two-thirds of patients who would otherwise have few if any treatment options, reported Jennifer R. Brown, MD, PhD, Assistant Professor of Medicine at Dana-Farber Cancer Institute in Boston.

“Drugs like idelalisib are probably going to change the landscape of this disease in the next few years,” Dr. Brown predicted. PI3K-delta is the predominant isoform in an aberrantly hyperactivated signaling pathway that drives CLL, she explained.

Study Details

The phase I study involved 54 patients with relapsed/refractory CLL, who had received a median of five prior regimens; 70% were refractory to their most recent regimen. Patients received idelalisib at 50 to 350 mg twice daily by continuous oral dosing in 28-day cycles for 48 weeks. Therapy continued as long as the patient benefited.

Responses were observed in 39 of the 54 patients, leading to a median progression-free survival of 17.1 months, Dr. Brown reported.

“Idelalisib rapidly induced deep and durable lymph node responses in the vast majority of patients,” she told the media. “The nodal responses appeared to be independent of the very high-risk mutations, deletion 17p or TP53.”

Laboratory studies showed that idelalisib significantly inhibited PI3K-delta in CLL cells (P < .0001 vs baseline). Hemoglobin, platelet counts, and absolute neutrophil counts improved during treatment.

The drug was well tolerated, and the most common drug-related adverse events were elevated liver function tests, diarrhea, and rash, said Dr. Brown.

“While this research is still early and ongoing, we hope this drug, along with others like it, will lead to prolonged survival and eventually help turn CLL into a condition that is treated like high blood pressure,” she said.

Alternatives to Chemotherapy

Idelalisib joins another drug recently garnering great interest in CLL, the Bruton’s tyrosine kinase inhibitor ibrutinib. Dr. Brown would not compare the activity of the two drugs, and pointed out that ibrutinib is in phase II trials, whereas hers was a phase I dose-finding study. “But I would say that these are both extremely promising drugs, and we in the CLL community are excited to have them both,” she said. “There is certainly interest in thinking about how to combine them to further downregulate their pathways, which do intersect.”

Meanwhile, she said, these drugs may provide alternatives to chemotherapy in elderly patients who tend not to tolerate chemotherapy well.

“We believe the substantial clinical activity of idelalisib justifies further clinical development in CLL, and phase III trials are in progress,” she said. A dose of 150 mg twice daily was chosen for future studies. ■

Disclosure: Dr. Brown has served as a consultant for Pharmacyclics.


1. Brown JR, Furman RR, Flinn A, et al: Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3K-delta, in patients with relapsed or refractory CLL. 2013 ASCO Annual Meeting. Abstract 7003. Presented June 4, 2013.

Related Articles

Expert Point of View: Sandra M. Swain, MD, FACP

Sandra M. Swain, MD, FACP, Immediate Past President of ASCO commented on the findings. “This is an exciting discovery and an example of early success in precision medicine. It’s targeting PI3K-delta, which is overactive in B-cell malignancies and is used in a disease that is very refractory to...