Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Abstract

Idelalisib, a first-in-class oral inhibitor of phosphatidylinositol-3-kinase δ, has shown considerable antitumor activity as a monotherapy in recurrent indolent non-Hodgkin lymphoma (iNHL). To evaluate the safety and activity of idelalisib in combination with immunotherapy, chemotherapy, or both, 79 patients with relapsed/refractory iNHL were enrolled based on investigator preference in 3 treatment groups. Patients received continuous idelalisib in combination with (1) rituximab (IR; 375 mg/m2 weekly × 8 doses), (2) bendamustine (IB; 90 mg/m2 per day × 2, for 6 cycles), or (3) both bendamustine and rituximab at aforementioned doses (IBR; monthly × 6 cycles). Patients had a median age of 61 years, a median of 3 prior therapies, and 46% had refractory disease. The overall response rate was 75% (22% complete response) for IR, 88% (36%) for IB, and 79% (43%) for IBR. The median progression-free survival was 37.1 months overall: 29.7 months for IR, 32.8 for IB, and 37.1 months for IBR. The median duration of response was 28.6 months in the IR group and has not been reached in the IB and IBR groups. The most common grade ≥3 adverse events and laboratory abnormalities were neutropenia (41%), pneumonia (19%), transaminase elevations (16%), diarrhea/colitis (15%), and rash (9%). The safety and efficacy reflected in these early data, however, stand in contrast with later observations of significant toxicity in subsequent phase 3 trials in frontline chronic lymphocytic leukemia and less heavily pretreated iNHL patients. Our findings highlight the limitations of phase 1 trial data in the assessment of new regimens. This trial was registered at www.clinicaltrials.gov as #NCT01088048 (an extension study was registered at www.clinicaltrials.gov as #NCT01090414).

Figures

Graphical abstract

Figure 1.

Response end points: response rate and changes in SPD. (A) ORR (gray) and CR (black) rates in the combined primary and extension studies. (B) Waterfall plot of best on-treatment changes in the SPD of measured lymph nodes, by evaluable patient. Criteria for response according to Cheson et al.

Figure 2.

Time-to-event end points: TTR, DOR, and PFS. (A) KM estimates for TTR (n = 79) and time to CR (n = 24). (B) TTR by the 3 treatment groups. (C) KM estimate for overall DOR. Median DOR not reached. PFS at 24 months was 70%. (D) KM estimate for DOR for the 3 treatment groups. KM estimate for overall PFS. Median PFS not reached. PFS at 24 months was 63%. (E) KM estimate for overall PFS. Median PFS not reached. PFS at 24 months was 63%. (F) KM estimate for PFS for the 3 treatment groups. IDELA, idelalisib.