A trio of presentations at the ASCO Annual Meeting focused on two promising investigational drugs for the treatment of chronic lymphocytic leukemia (CLL). These two drugs—idelalisib and obinutuzumab—join a list of new approaches showing potential.
A phase I dose-ranging study of treatment with idelalisib for up to 48 weeks achieved a lymph node response of 81% and overall response rate of 72%.1 Responses were seen at all dose levels and in patients with high-risk mutations. The best nodal response was observed at doses of 150 mg twice daily, which is the recommended phase II dose.
The trial enrolled 54 patients with CLL; 70% had refractory disease and had received a median of five prior therapies. A total of 31 patients discontinued treatment due to progressive disease and other causes, and 23 entered an extension phase (10 are still in remission).
“Idelalisib is a highly selective inhibitor of PI3Kδ, which impacts upon multiple pathways that are involved in cell survival and proliferation. Idelalisib was well tolerated, with no dose-limiting toxicities. The best responses were seen at higher doses,” said lead author Jennifer R. Brown, MD, PhD, Director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, Boston. The pattern of response to single-agent idelalisib showed a rapid decline in lymphoid mass accompanied by a rise in lymphocyte count, Dr. Brown said.
Median time to response was 1 month, and median duration of response was 16.8 months. Treatment with idelalisib improved baseline cytopenias, which were seen in many patients (63% had low platelets, 46% had low hematocrit/anemia, and 28% had low neutrophils). Progression-free survival was 17.1 months, and median overall survival has not yet been reached.
Idelalisib plus Rituximab
In a phase II single-arm study with an extension phase, idelalisib in combination with rituximab (Rituxan) achieved an overall response rate of 97% (19% complete response and 78% partial response) in 64 patients who had not received any prior CLL therapy but required therapy at the time of study entry.2 At 24 months, 93% of participants had achieved progression-free survival.
The addition of rituximab shifted the pattern of response seen in the phase I study reported by Dr. Brown, showing a nodal response at 8 weeks, as well as a rapid decline of lymphocytosis. At 48 weeks, median lymphocyte count returned to normal.
“Idelalisib plus rituximab is a highly active combination in treatment-naive CLL. The high overall response rate and durable disease control observed in this phase II study suggest that idelalisib plus rituximab could become an important new therapeutic option for CLL patients new to treatment,” said Susan M. O’Brien, MD, Ashbel Smith Professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston. “No disease progression was observed in the study, including patients with 17p deletions and TP53 mutations,” she added.
The most common adverse effect was diarrhea and laboratory abnormalities in transaminases. Myelosuppression was infrequent. The rate of infection of any grade was 67%; 23% of patients had infections classified as grade 3 or higher.
Patients completing 48 weeks of therapy and free of progression could continue on an extension study; 43 patients completed 48 weeks, and 40 entered the extension phase. At the time of the ASCO Annual Meeting, 33 were still on treatment.
During the primary and extension study, grade 3 diarrhea and/or colitis occurred in 33% of patients, and were the most common reasons for late discontinuations. Dr. O’Brien and colleagues found that this could be managed with budesonide if colitis and diarrhea were recognized early. Grade 3 or higher pneumonia was reported in 17% of patients, and grade 3 or higher transaminase elevations were seen in 23%.
In older, sicker patients with CLL, the combination of chlorambucil (Leukeran) and obinutuzumab (GA101) improved progression-free survival and complete response rate over chlorambucil, according to final results of a pivotal phase III trial.3 The combination of chlorambucil and obinutuzumab doubled progression-free survival compared with chlorambucil alone, from 10.9 to 23 months (P < .0001).
Like rituximab, binutuzumab is an anti-CD20 monoclonal antibody, but it binds more strongly to B cells and may be more effective than rituximab per preclinical evidence.
“This is the first large phase III trial in elderly patients with comorbidities, a real-world population. Chlorambucil is the drug often used in these patients, because there is no conclusive evidence that any currently available therapy is superior to chlorambucil in older patients,” explained lead author Valentin Goede, MD, Resident at the University of Cologne, Germany.
The study had three stages: stage 1a compared obinutuzumab/chlorambucil (238 patients) vs chlorambucil (118 patients); stage 1b compared rituximab/chlorambucil (233 patients) vs chlorambucil (118 patients); and stage 2 compared obinutuzumab/chlorambucil vs rituximab/chlorambucil. Results reported at the Annual Meeting focused on stage 1a and 1b. The head-to-head comparison of chlorambucil plus either obinutuzumab or rituximab will be presented later.
In stage 1a, the overall response rate at the end of treatment was 76% with the combination of chlorambucil/obinutuzumab vs 30% for chlorambucil alone. The complete response rate was 22% vs 0%, respectively, and partial response rate was 53.3% vs 30.2%. In stage 1a, minimal residual disease–negative status in peripheral blood was achieved in 31.1% vs 0%.
In stage 1b, overall response rate was 65.9% with rituximab/chlorambucil vs 30% with chlorambucil alone, complete response rate was 8.3% vs 0%, and partial response rate was 57.8% vs 30%. Minimal residual disease–negative status in peripheral blood was achieved in 2% vs 0%.
Investigator-assessed progression-free survival in stage 1a was a median of 23 months for obinutuzumab plus chlorambucil vs 11 months for chlorambucil alone, representing an 86% reduction in risk of disease progression favoring the combination. Investigator-assessed progression-free survival in stage 1b was 16 months for rituximab/chlorambucil vs 11 months for chlorambucil alone, representing a 68% reduction in risk of disease progression.
Increased rates of grade 3 or higher neutropenia were seen in both combinations, but the rate was 34% with the obinutuzumab combination and 25% with the rituximab combination vs 15% with chlorambucil alone. Grade 3 or higher infusion-related reactions occurred in 21% of the obinutuzumab/chlorambucil group, but this was only with the first infusion, Dr. Goede said. ■
Disclosure: Drs. Brown and O’Brien have received research funding from Gilead Sciences. Dr. Goede is a consultant or advisor for and has received honoraria and research funding from Roche.
1. Brown JR, Furman RR, Flinn I, et al: Final results of a phase I study of idelalisib (GS-110), a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL. 2013 ASCO Annual Meeting. Abstract 7003. Presented June 4, 2013.
2. O’Brien S, Lamanna N, Kipps TJ, et al: A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab in treatment-naive patients ≥65 years with chronic lymphocytic leukemia or small lymphocytic leukemia. 2013 ASCO Annual Meeting. Abstract 7005. Presented June 4, 2013.
3. Goede V, Fischer K, Humphrey K, et al: Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab versus Clb alone in patients with chronic lymphocytic leukemia and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. 2013 ASCO Annual Meeting. Abstract 7004. Presented June 4, 2013.
“These three excellent, encouraging, tantalizing studies show that we really are making progress in the treatment of chronic CLL, whereas 10 to 12 years ago, we had no real progress to report,” stated Kanti R. Rai, MD, Chief, CLL Research Program, North Shore-LIJ Medical Center, New Hyde Park, NY....