The PI3 kinase (PI3K) pathway is altered in many cancers, but early studies with PI3K inhibitors suggested that their efficacy might be limited by toxicity. Now, the final results from a Phase I study of a first--in-class, isoform-specific PI3K-delta inhibitor, idelalisib (formerly called GSE1101), indicate that the more narrowly targeted agent may have overcome that limitation.
In a population of heavily pretreated patients with chronic lymphocytic leukemia (CLL), the median progression-free survival time was 17.1 months, researchers reported during an American Society of Clinical Oncology news conference held before the Annual Meeting designed to highlight key research advances.
“This is another exciting discovery and early success in precision medicine,” said ASCO 2012-2013 President Sandra M. Swain, MD. She called the progression-free survival time “really pretty incredible” in this disease setting and patient population.
The study (Abstract 7003), which was funded by Gilead Sciences, enrolled more than 200 patients with advanced hematologic malignancies. Jennifer R. Brown, MD, PhD, Director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, reported the final results regarding the 54 patients with CLL.
Patients received twice-daily doses of idelalisib by mouth (50 to 350 mg) for up to 48 weeks in the prescheduled portion of the trial. However, patients were allowed to continue on treatment in an extension trial as long as they were benefiting from therapy.
The patient population was “very high risk,” she said. The median number of prior regimens was five (range of two to 14), 70 percent of patients had been refractory to their most recent regimen, and 80 percent had bulky lymphadenopathy.
The median time on idelalisib was nine months, with a range of zero to more than 41 months, with some patients continuing on therapy. Twenty-five patients (46%) completed the primary study of 48 weeks and 23 (43%) enrolled in the extension study.
The most common adverse events were fatigue (31% any grade; 2% grade 3 or higher), diarrhea (30%; 6%), pyrexia (30%; 4%), rash (22%; 0%), upper respiratory tract infection (22%; 0%), and pneumonia (20%; 19%). Additionally, two percent of patients had Grade 3 or higher liver enzyme elevations. Overall 15 percent of patients discontinued treatment due to adverse events, with seven percent of them possibly related to treatment. The team detected no dose--limiting toxicities.
The overall response rate was 56 percent, with two patients developing a complete response and 28 having partial responses. Twenty-one patients had stable disease, and three were non-evaluable. Additionally, 44 patients (81%) had a lymph node response of 50 percent or greater shrinkage.
Patient responses were rapid and durable, Brown noted. The median time to response was 1.9 months (range of 0.9 to 12.9 months) and the median duration of response was 18 months.
In addition to the tumor responses, there were also improvements in patients' blood cell counts: Anemia improved in 17 of 25 patients, thrombocytopenia in 27 of 34, and neutropenia in 15 of 15. Splenomegaly also improved in 14 of the 20 affected patients.
Further Studies Underway
PI3K is composed of two subunits, p85 and p110. The p110 subunit has three different isoforms: alpha, beta, and delta, each of which is encoded by a different gene and each of which appears to differ somewhat in its biological function. In general, however, PI3K receives signals from a variety of cell surface receptors, including the B cell receptor. PI3K passes the signal by phosphorylating AKT, which itself promotes survival and proliferation.
In CLL patient samples, the researchers saw that idelalisib, which is designed to block the p110-delta isoform specifically, reduced the level of phosphorylated AKT to normal B cell levels from the abnormally high levels seen in untreated CLL cells.
Brown noted that the dose used in future studies is 150 mg twice daily and that several Phase III studies are already underway.
Idelalisib vs. Ibrutinib
When asked how this agent compares with the BTK tyrosine kinase inhibitor ibrutinib, which has also shown activity in CLL, she said it was hard to compare. “This is a Phase I study in very heavily pretreated patients and treated at different dose levels,” she said. “Ibrutinib has reported Phase II data.
“I would say they are both extremely promising drugs, and we in the CLL community are excited about both of them,” Brown continued. “Currently one thing we are interested in thinking about is how best to combine them, or combine either of them with other agents. I think potentially many of us are interested in combining ibrutinib and idelalisib to potentially even further down-regulate the pathways, because they do intersect downstream—but that is still all in the future.”
Swain noted that the treatment paradigm for CLL patients is likely to change in the future given the newly reported results. “This study demonstrates that we may soon have—based on the Phase III results certainly—a new alternative to chemotherapy for slow-growing blood cancers, and offering a simpler treatment [since this is an oral treatment] and, therefore, an improved quality of life.”