A phase I study found that idelalisib produced rapid and prolonged tumor shrinkage in half of patients with relapsed or refractory CLL who received the drug as monotherapy.
Jennifer R. Brown, MD, PhD
A phase I study presented at ASCO 2013 has found that the novel selective PI3K-delta inhibitor idelalisib (formerly GS-1101) produced rapid and prolonged tumor shrinkage in half of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received the drug as monotherapy. The findings suggest that the drug could be an effective treatment for a patient population that faces limited success with current approved therapies. The study is the first to test any PI3K inhibitor specifically in patients with CLL.
“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 Boston, Massachusetts and lead author of the study.
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 4580 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% have refractory disease that relapses within 6 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 with a 50-mg to 350-mg dosage twice daily in 28-day cycles, although 10 patients received the 300-mg dosage 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 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.
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 remained high (33%); 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 6 and 12 months.
In future studies, investigators will use a 150-mg dosage twice daily. Brown explained that this dosage 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 dosages 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 were 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 will improve patient quality of life,” Swain said.