New PI3K-delta Inhibitor Prolongs Survival in Chronic Lymphocytic Leukemia


The novel selective PI3K-delta inhibitor idelalisib produced rapid and prolonged tumor shrinkage in patients with relapsed or refractory chronic lymphocytic leukemia who received the drug as a monotherapy.

Jennifer R. Brown, MD, PhD

A phase I study has found that the novel selective PI3K-delta inhibitor idelalisib (formerly known as GS-1101) produced rapid and prolonged tumor shrinkage in half the patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received the drug as a monotherapy, suggesting that this drug could be an effective treatment for a patient population that faces limited success with current approved therapies.

Results of the study, the first to test any PI3K inhibitor specifically in patients with CLL, were presented in a press briefing held Wednesday by the American Society of Clinical Oncology (ASCO).

“The substantial clinical activity of idelalisib that we observed justifies its further clinical development in CLL,” said Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia center at Dana-Farber Cancer Institute in Massachusetts and lead author of the study.

Typically diagnosed through a routine blood test, CLL is characterized by a slow increase in B lymphocytes, causing cancer cells to spread through the blood and bone marrow as well as the lymph nodes, liver, and spleen. According to the National Cancer Institute, approximately 15,680 patients will be diagnosed with CLL and 4,580 will die from the disease in 2013.

Currently, patients are often prescribed a combination of chemotherapy and immunotherapy, but the vast majority will relapse after initial treatment, and approximately 20% of patients have refractory disease that relapses within six months or does not respond to therapy at all.

The PI3K pathway is hyperactive in CLL, and the PI3K-delta isoform is the predominant hyperactive subtype. Idelalisib is the first drug that selectively inhibits this PI3K subtype and is designed to reduce proliferation, enhance apoptosis, and inhibit homing and retention of malignant B cells.

In this phase I study, 54 patients with relapsed or refractory CLL were treated continuously for up to 48 weeks with idelalisib as a single agent from 50-350 mg/dose twice daily in 28-day cycles, although 10 patients received the 300 mg dose once daily in 28-day cycles. Patients had received a median of five prior therapies (range: 2—14), and 70% of patients were refractory to their most recent prior regimen. Patients were exposed to idelalisib for a median of 9 months (0–41+), with 25 patients (46%) completing the primary study and 23 patients (43%) enrolling in an extension study.

The study found that idelalisib was generally well-tolerated. Adverse events associated with the drug included elevated liver function tests that were asymptomatic and resolved, diarrhea, and rash. Low neutrophil counts and infections, particularly pneumonia, were also observed.

Brown explained that the overall response was based on patients who experienced a typical partial response where the white blood cell count and lymph nodes decrease (39%) as well as patients who experienced nodal responses and an improvement in cytopenias, such as platelet count and hemoglobin levels, despite the fact that their white blood cell count remains high (33%), so a total of 72% of patients responded based on those criteria.

“When you start patients on the drug, you see a very rapid nodal response, and then they also feel better more or less right away, even before their counts start to improve,” Brown said. “And then relatively soon after, you start to see their white counts improve, too.”

The median time to first response was 1.9 months (0.9—12.9). The median progression-free survival (PFS) was 17.1 months and the median duration of response was 18 months. The PFS was better than what is typically expected for a sixth-line therapy, where the benefit might last for between six and 12 months.

In future studies, investigators will use a 150 mg dose twice daily. Brown explained that this dose was chosen because there appears to be a plateau of dose exposure and nodal response at around 150 mg twice daily, and elevated liver function tests, though not common, occurred more frequently in patients who received higher doses of the drug in the expansion cohorts.

Three phase III trials studying the efficacy of idelalisib are currently enrolling patients with previously treated CLL, and all three trials involve testing the drug in combination with other agents, specifically ofatumumab (NCT01659021), rituximab (NCT01539512), and a combination of rituximab and bendamustine (NCT01569295).

Sandra Swain, MD, president of ASCO, said that the data presented was quite striking and represented another success in the development of personalized medicine.

“This study demonstrates that we may soon have a new alternative to chemotherapy for slow-growing blood cancers that is a simpler treatment, since it is an oral treatment, and therefore improve patient quality of life,” Swain said.

Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL. J Clin Oncol. 2013 (suppl; abstr 7003).


View more from the 2013 ASCO Annual Meeting

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