June 2013, Vol 2, No 4

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First-in-Class PI3K Inhibitor Shows Remarkable Phase 1 Results in CLL

Alice Goodman


A first-in-class PI3 kinase (PI3K) inhibitor achieved dramatic responses in a phase 1 study of heavily pretreated relapsed/refractory chronic lymphocytic leukemia (CLL). Idelalisib (GS-1101) produced rapid and durable tumor shrinkage in about half the patients who received the drug. These results were reported at a pre-ASCO press cast and at the 2013 ASCO Annual Meeting.

“This is a dramatic finding. The expected time to progression with a sixth-line treatment in this setting would be 6 to 12 months,” said lead author Jennifer Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, Boston, MA.

“There are currently few effective treatment options for relapsed CLL. Patients go into remission, but the time between remissions gets shorter and shorter. It appears that we are now reaching a point in CLL where we will have several agents that are very effective. Drugs like idelalisib are probably going to change the landscape of the disease in the next few years,” Brown commented.

Idelalisib is a potent selective blocker of PI3K-delta, a subtype of PI3K protein that is overexpressed in B-cell lymphoma and promotes tumor growth. Idelalisib joins ibrutinib as a potential new treatment that could change outcomes in this disease. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is in phase 3 testing, and FDA approval is expected soon.

The phase 1 study enrolled almost 200 patients with previously treated hematologic malignancies. Brown presented results from 54 patients with CLL. Median age was 63 years; 70% of patients had bulky lymphadenopathy; 70% had refractory disease; 91% had unmutated IGHV; 24% had del(17p) and/or TP53 mutation; 28% had del(11q); and 17% had a NOTCHI mutation. Median number of prior lines of therapy was 5.

Idelalisib was given orally in doses of 50 to 350 mg once or twice a day continuously in 28-day cycles. The average duration of treatment with idelalisib was 9 months.

Idelalisib was well tolerated. The most commonly reported adverse events included asymptomatic elevation of liver enzymes, diarrhea, and rash. Treatment discontinuation due to treatment-related events was seen in 7%.

Response (tumor shrinkage) was observed in 30 of 54 patients for an overall response of 56%; 2 patients had a complete response and 28 patients had a partial response. Stable disease was observed in 21 patients (39%). Forty-four patients (81%) had a lymph node response. Idelalisib achieved deep and durable responses independent of the presence of del(17p) or TP53 mutation, both prognostic of poor risk.

Regardless of the dose, median progression-free survival was 17 months, and median duration of response was 18 months.

“We also saw a decrease in symptoms of CLL and improvement of baseline cytopenias. Low blood cells are common at the start of treatment,” she said.

The dose of 150 mg bid was selected for phase 2 and 3 studies. Phase 3 trials of idelalisib in combination with rituximab or bendamustine/rituximab are now in progress.

“This drug represents another exciting and early success in precision medicine. In heavily refractory patients and older patients, this is a great response, with an overall response rate of 56%. Even more striking is progression-free survival of 17 months. Two patients are still in remission. This is incredible. We may soon have a new alternative to chemotherapy and a simpler oral treatment that improves patient quality of life,” said ASCO President Sandra Swain, MD.

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