Ajay Gopal, MD
Treatment with the oral PI3K-delta inhibitor idelalisib produced an overall response rate (ORR) of 57% with an average response duration of 12.5 months in heavily pretreated patients with indolent non-Hodgkin’s lymphoma (iNHL), according to pivotal phase II data.
The results were presented in December at the 55th Annual Meeting of the American Society of Hematology (ASH) and were recently published in The New England Journal of Medicine
The FDA has accepted a New Drug Application for idelalisib in refractory iNHL based on these data, with an approval decision expected on or before September 11, 2014.
Indolent non-Hodgkin’s lymphoma is currently treated with a combination of rituximab (Rituxan) and chemotherapy. This treatment is not curative and has shown decreasing efficacy with each administration.
The single-agent, phase II Study 101-09 involved 125 patients with various types of iNHL, including follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström’s macroglobulinemia (10). The majority of patients (89%) had stage III or IV disease and all patients had not responded favorably to rituximab and an alkylating agent or had relapsed within 6 months of treatment.
The median patient age was 64 years and the median number of therapies patients previously received was 4 (range, 2-12). Thirty percent of patients had elevated lactate dehydrogenase levels, 26% had lesions that were ≥7 cm in at least one dimension, 15% had a hemoglobin level <10 g/dL, and 14% had a neutrophil count <1500/mm3. Lead author Ajay Gopal, MD, director of Clinical Research for Hematology at the Seattle Cancer Care Alliance, and colleagues treated patients with 150 mg of idelalisib twice daily until disease progression or withdrawal from the study. ORR was the primary endpoint. Duration of response, progression-free survival (PFS), and safety were secondary endpoints.
The 57% ORR was determined by a ≥50% reduction in tumor size in 71 of 125 patients. Complete response (no measurable evidence of cancer) was reached in 6% of patients.
The median time to response was 1.9 months. Median PFS was 11 months. At the time of the analysis, the median overall survival (OS) was 20.3 months, with an estimated 1-year OS of 80%. The most commonly reported grade ≥3 adverse events were diarrhea (13% of patients), pneumonia (7%), and dyspnea (3%). Neutropenia (27%) and elevations in levels of serum alanine or aspartate aminotransferase (13%) were the most frequent grade ≥3 laboratory abnormalities that occurred during treatment. Additionally, the rates of grade ≥3 thrombocytopenia and anemia were 6% and 2%, respectively.
During the study, 28 deaths (22%) were reported. Of those, 11 deaths occurred during study treatment or within 30 days of the last dose. Causes of death included progressive disease (3 patients), pneumonia (3), and one case each of cardiac arrest, cardiac failure, splenic infarction, septic shock, and pneumonitis. The remaining 17 deaths occurred during long-term followup and were predominantly due to progressive disease. There was no evidence of cumulative toxic effects documented.
Gilead Sciences, Inc, which manufactures idelalisib, has also submitted a New Drug Application for the drug to treat patients with relapsed chronic lymphocytic leukemia (CLL). Idelalisib has received the FDA’s Breakthrough Therapy designation for this indication.
The CLL submission was based on the phase III Study 116, which found that the combination of idelalisib and rituximab significantly improved OS, PFS, and response rate in patients with high-risk relapsed/refractory CLL. The results of the study were also presented at the 55th ASH Annual Meeting and published in The New England Journal of Medicine
Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma [published online January 22, 2014]. N Engl J Med. doi:10.1056/NEJMoa1314583.
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia [published online January 22, 2014]. N Engl J Med. doi:10.1056/NEJMoa1315226.