Though still in early-phase studies, novel B-cell receptor signaling inhibitors look very promising for the treatment of lymphoma, according to reports from the 2013 ASCO Annual Meeting.
Idelalisib in Non-Hodgkin Lymphoma
In non-Hodgkin lymphoma (NHL), idelalisib looked impressive as both a single agent and when given in combination with standard therapy. The drug is a first-in-class selective oral inhibitor of PI3K-delta, a pathway that is critical for the activation, proliferation, and survival of B cells. PI3K-delta signaling also plays a role in homing and retention in lymphoid tissues and is hyperactive in many B-cell malignancies.
In a phase I study of 79 previously treated patients with indolent NHL, patients who received idelalisib plus standard therapy achieved a response rate of 78%, including complete responses in 26%, according to John Leonard, MD, of Weill Cornell Medical College, New York.1 Dr. Leonard called idelalisib “an exciting new drug in various lymphoid malignancies,” and noted, “This particular PI3K inhibitor is relatively delta-specific, which may be important in terms of its activity and tolerability profile. Idelalisib in combination regimens could improve the efficacy of the standard of care in NHL.”
At the discretion of the treating physician, patients in the study received idelalisib in combination with rituximab (Rituxan), bendamustine (Treanda), or rituximab plus bendamustine. Patients were treated for six cycles, and responders could continue idelalisib for a total of 48 weeks. Median duration of treatment was 11 months.
Response rates were 72% for idelalisib/rituximab, 85% for idelalisib/bendamustine, and 71% for idelalisib/bendamustine/rituximab (which achieved the highest rate of complete responses, 43%).
“The vast majority had at least a partial response, whether we treated with two drugs or three,” he said. “The data suggest idelalisib produces high response rates combined with either ributiximab, bendamustine, or both, and we are pleased to see that they are durable.”
Median progression-free survival for the trial has not been reached. At 24 months, 62.5% of patients remained in remission, Dr. Leonard reported.
Single-agent activity for idelalisib was also confirmed in another phase I study of 64 patients conducted by Don M. Benson, MD, PhD, of Ohio State University Comprehensive Cancer Center, and colleagues.2 The response rate in this trial was 48%, rising to 67% among optimally dosed patients (> 100 mg twice daily). Median progression-free survival was 7.6 months but rose to almost 17 months among the optimally dosed cohort.
Idelalisib in Mantle Cell Lymphoma
In mantle cell lymphoma, single-agent idelalisib showed activity in phase I trials but was most beneficial when combined with other agents. In a phase I study of 33 patients reported by Nina D. Wagner-Johnston, MD, of Washington University, St. Louis, the combination of idelalisib and everolimus (Afinitor), bortezomib (Velcade), or bendamustine/rituximab yielded a 49% response rate, with 12% complete responses.3 In the bendamustine/rituximab arm, 100% of patients responded, however, unlike the other two arms this population had not been heavily pretreated. Median progression-free survival was 8 months.
The addition of idelalisib does not appear to increase the toxicity of treatment for lymphoma with current agents, the investigators noted in their presentations. “The toxicity profile is consistent with what we see for single agents. We did not see excess toxicity, at least within the limitations of the size of these studies,” Dr. Leonard observed. Liver enzyme elevation is a unique characteristic of idelalisib, but this is manageable with dose reductions. Phase III trials of the PI3K inhibitor are underway.
Ibrutinib in Non-Hodgkin Lymphoma
The Bruton’s tyrosine kinase inhibitor ibrutinib, which has received Breakthrough Therapy status from the U.S. Food and Drug Administration, was evaluated in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in a small phase I/II study of 33 previously untreated CD20-positive B-cell NHL patients.4 The combination produced responses in 100% of patients, including complete responses in 67%, reported Anas Younes, MD, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues. ■
Disclosure: Dr. Leonard has been a consultant or advisor for Gilead Sciences. Dr. Benson has received research funding from Gilead Sciences. Dr. Wagner-Johnston receives research funding from Celgene. Dr. Younes has been a consultant or advisor for Pharmacyclics, has received honoraria from Pharmacyclics, and has received research funding from Janssen and Pharmacyclics.
1. Leonard J, Wagner-Johnston ND, Coutre SE, et al: Tolerability and activity of combinations of the PI3K-delta inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma: Updated results from a phase 1 study. 2013 ASCO Annual Meeting. Abstract 8500. Presented June 1, 2013.
2. Benson DM, Kahl BS, Furman RR, et al: Final results of a phase 1 study of idelalisib, a selective inhibitor of PI3K. 2013 ASCO Annual Meeting. Abstract 8526. Presented June 3, 2013.
3. Wagner-Johnston ND, De Vos S, Leonard J, et al: Preliminary results of PI3K-delta inhibitor idelalisib (GS-1101) treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma. 2013 ASCO Annual Meeting. Abstract 8501. Presented June 1, 2013.
4. Younes A, Flinn I, Berdeja JG, et al: Phase 1b study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with CD20-positive B-cell non-Hodgkin lymphoma. 2013 ASCO Annual Meeting. Abstract 8502. Presented June 1, 2013.
At the 2013 ASCO Annual Meeting, Ranjana Advani, MD, the Saul A. Rosenberg, MD, Professor of Lymphoma at Stanford University Medical Center, Palo Alto, California, discussed the promise of the B-cell signaling inhibitors idelalisib and ibrutinib in lymphoma.