Duvelisib Produces Responses in Indolent Non-Hodgkin Lymphoma

Ian Flinn, MD, PhD

Duvelisib (IPI-145), an inhibitor of PI3K-δ and PI3K-γ signaling, had a favorable risk:benefit profile in patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) in a phase I study, reported Ian Flinn, MD, PhD, at the 2014 Annual Meeting of the American Society of Hematology.

The rates of response, progression-free survival (PFS), and overall survival (OS) with duvelisib monotherapy were encouraging, with most adverse events being reversible and clinically manageable, he said.

“PI3K-δ and PI3K-γ support the growth and survival of B-cell and T-cell malignancies. They transmit signals from cell-surface receptors, such as the B-cell receptor, through phosphorylation of AKT, causing cell differentiation, proliferation, activation, and migration,” said Flinn, director of the Hematologic Malignancies Program at the Sarah Cannon Research Institute in Nashville, Tennessee.

Duvelisib is an oral drug that inhibits PI3K-δ and PI3K-γ, and thus the survival of malignant B-cells and T-cells. It has direct effects on tumor cells and also disrupts tumor cell interactions with the microenvironment. At doses of 25 mg twice daily or higher, duvelisib was previously shown to suppress PI3K-δ and PI3K-γ throughout the dosing interval.

Flinn presented the results of a phase I study in which duvelisib was administered continuously in 28-day cycles in 36 patients with iNHL, 18 of whom were treated with the 25-mg/day dosage that was selected for phase 2 and phase 3 development. Sixteen other patients received the maximum tolerated dose of 75 mg twice daily. One patient was treated with a dosage of 15 mg/day, and one with 50 mg/day.

Among the cohort receiving 25 mg/day, the median age of patients was 63 years and the median number of prior systemic therapies was three (58% received ≥3 prior systemic therapies). More than one third of the patients were less than 6 months from their previous therapy. Their time on treatment with duvelisib was a median 11.8 months; 26% of patients remain on 25 mg/day at 24 months or longer. Seven patients (37%) discontinued treatment because of adverse events and four (21%) discontinued for disease progression.

“Duvelisib reduced pharmacodynamic markers associated with the tumor microenvironment in B-cell malignancies, including CCL17 and IL-10. The magnitude of reduction was independent of dose, and these reductions were consistent through cycle 2, day 1,” Flinn said.

iNHL clinical responses were evaluated based on revised International Working Group (2007) criteria, with additional criteria for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma where appropriate.

Clinical activity was observed at all doses of duvelisib. Of 18 evaluable patients at 25 mg twice daily, the overall response rate (ORR) was 72%, including a complete remission (CR) rate of 33%. “These remissions occurred rapidly,” said Flinn. “The median time to response was 1.8 months, and fully 77% of patients [who] responded [did so ] by their first assessment.”

Response was consistent across different pathologies of iNHL. Among patients with follicular lymphoma, the ORR was 69% (9 of 13 evaluable patients), including a 38% CR rate (5 of 13 evaluable patients).

All patients had lymph node reduction on computed tomography scan, and 13 of 17 (76%) patients at 25 mg twice daily had at least a 50% reduction in adenopathy.

The median PFS and median OS have not yet been reached, with 69% PFS and 89% OS at 24 months.

Duvelisib had an acceptable safety profile across the dose range evaluated. At the 25 mg twice daily dosage level, diarrhea (32%) and increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were the most common grade 3 adverse events (32%), followed by neutropenia (11%) and pneumonia (11%). Eleven percent of patients had grade 4 neutropenia, 5% had grade 4 pneumonia, and 5% had a grade 4 increase in ALT or AST. The most common adverse events leading to discontinuation were ALT/AST increases (11%).

The findings support the ongoing evaluation of duvelisib as monotherapy as well as in combination, said Flinn. Phase 2 and 3 studies of duvelisib at 25 mg twice daily are currently ongoing in patients with iNHL.

Reference

Flinn I, Oki Y, Patel M, et al. a Phase 1 evaluation of duvelisib (IPI-145), a PI3K-δ,γ inhibitor, in patients with relapsed/refractory iNHL. Presented at: the 56^th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 802.

<<<

View more from the 2014 ASH Annual Meeting