In patients with indolent B-cell non-Hodgkin lymphoma (NHL) refractory to both rituximab (Rituxan) and an alkylating agent, monotherapy with the selective oral PI3K-delta inhibitor idelalisib produced a high response rate, with responses persisting for 1 year in the average patient, according to mature response data from a phase II study presented at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans.1
“Idelalisib may provide meaningful disease control in ‘double-refractory’ indolent B-cell NHL patients,” suggested principal investigator Ajay Gopal, MD, of the University of Washington School of Medicine, Seattle.
Bruce D. Cheson, MD, Professor of Medicine, Deputy Chief of Hematology/Oncology, and Head of Hematology at the Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, commented during the discussion period, “[These are] very exciting data, and [the results] are potentially practice-changing.”
Why PI3K-Delta Inhibition?
“Patients with indolent B-cell NHL refractory to rituximab and alkylating agents have few or no remaining viable treatment options and are an understudied population, due to the lack of an effective therapy. We hypothesized that idelalisib’s novel mechanism of action could be efficacious in double-refractory indolent B-cell NHL,” he said.
PI3K-delta signaling is critical for the activation, proliferation, and survival of B cells and is hyperactive in many B-cell malignancies. PI3K-delta inhibition impacts many of these critical pathways and suppresses the homing and retention of malignant B-cells in lymphoid tissues, reducing B-cell survival.
Study 101-09 included 125 previously treated patients with follicular lymphoma (58%), small lymphocytic lymphoma (22%), marginal zone lymphoma (12%), and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (8%). Patients were refractory to both rituximab and an alkylating agent and had received a median number of four prior therapies. These were most commonly bendamustine (Treanda)/rituximab and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP); 11% of patients had undergone prior stem cell transplantation.
Patients received idelalisib at 150 mg twice daily until disease progression. As of the data cutoff in June 2013, approximately one-third of patients remained on treatment and two-thirds had discontinued therapy due to disease progression (32%), adverse event (20%), death (6.4%), investigator request (5.6%), or withdrawal of consent (3.2%).
Mean duration of idelalisib treatment was 8.1 months; median duration was 6.6 months, ranging from 0.6 to 23.9 months.
High Response Rates
Seventy-one patients responded for an overall response rate of 57%, including complete responses in 6%, partial responses in 50%, and a minor response in one patient with Waldenstrom’s macroglobulinemia. Another 34% of patients had stable disease, while 8% had disease progression, and 2% were not evaluated. Responses were consistent across subsets, with the highest response rate (80%) seen in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia patients.
Responses were high, regardless of disease histology, number of prior regimens, refractoriness to bendamustine, or tumor bulk. By number of prior therapies, responses were observed in 50% of patients with fewer than four lines and 62% of those with four or more lines of prior treatment.
Time to response was rapid—less than 2 months for the average patient. The median duration of response was 12.5 months, he said. The waterfall plot of lymph node responses showed that 90% of patients had an improvement in lymphadenopathy and 57% had at least a 50% decrease from baseline.
“Virtually all patients had some degree of tumor reduction,” Dr. Gopal said. “A number had prolonged stable disease, and this is also what I’ve seen in my clinic.”
Acceptable Safety Profile
“Idelalisib was well tolerated and had an acceptable safety profile,” he reported. The primary adverse event was diarrhea, which occurred in 43% (all grades), including grade ≥ 3 in 13%. Pneumonia ≥ grade 3 developed in 7%. Serious adverse events included pyrexia (10.4%), pneumonia (7.2%), and diarrhea (7.2%), with a few patients developing colitis, dehydration, neutropenic fever, acute renal failure, and pneumonitis.
Neutropenia ≥ grade 3 was observed in 27%, but 5% of patients were neutropenic at baseline. Transaminase elevations were fairly common, with grade 1 or 2 observed in 35%, grade 3 in 10%, and grade 4 in 2%.
“Grade 1 and 2 transaminase elevation resolved with continued idelalisib treatment, and grade 3 and higher was reversible with drug interruption,” he said. “Fourteen out of 16 patients with grade 3 or 4 transaminase elevations were rechallenged, and 10 of them had no recurrences.” ■
Disclosure: The study was funded by Gilead Sciences. For full disclosures of the study authors, view the study abstract at ash.confex.com/ash/2013/webprogram/start.html.
1. Gopal A, Kahl BS, De Vos S, et al: Mature response data from a phase 2 study of PI3K-delta inhibitor idelalisib in patients with double (rituximab and alkylating agent)-refractory indolent B-cell non-Hodgkin lymphoma (iNHL). 2013 ASH Annual Meeting. Abstract 85. Presented December 8, 2013.