PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma

Abstract

Background: Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.

Methods: In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.

Results: The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).

Conclusions: In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).

Figure 1. Best Overall Response

The best response with respect to tumor size during idelalisib treatment, according to assessment by an independent review committee, is shown for the 125 patients in the study. Among the 122 patients with measurable lesions both at baseline and after baseline, 110 patients (90%) had improvements in lymphadenopathy, as assessed by changes in the sums of the products of the perpendicular dimensions (SPD) of index lesions. The dashed line shows the percentage change that represents the criterion for lymphadenopathy response, according to Cheson et al. FL denotes follicular lymphoma, LPL/WM lymphoplasmacytic lymphoma with or without Waldenström's macro-globulinemia, MZL marginal-zone lymphoma, and SLL small lymphocytic lymphoma.

Figure 2. Forest Plot of Overall Response Rate

A forest plot is shown of the overall response rate, in the total cohort and according to subgroups, among patients with refractory indolent non-Hodgkin's lymphoma. The response rate was assessed by an independent review committee. The dashed line shows the null hypothesis response rate of 20%. LD denotes longest diameter.

Figure 3. Kaplan–Meier Curves for Secondary End Points

Kaplan–Meier curves are shown for the secondary end points of the time to response (Panel A), the duration of response (Panel B), progression-free survival (Panel C), and overall survival (Panel D) among patients with refractory indolent non-Hodgkin's lymphoma who were treated with idelalisib (intention-to-treat population). The end points were assessed by an independent review committee.