Update on a Phase 2 Study of Idelalisib in Combination with Rituximab in Treatment-Naïve Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Background: The selectivePI3K-delta inhibitor Idelalisib (Zydelig®, IDELA), in combination with rituximab (R), has been previously reported to yield a 97% ORR in treatment naïve patients (pts) ≥65 years with CLL or SLL (O’Brien, ASCO 2013). This report is an update on that initial cohort of study pts.

Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m² weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 weeks without progression could continue to receive idelalisib on an extension study. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, based on modified IWCLL guidelines (Hallek 2008, Cheson 2012).

Results: 64 pts were enrolled, 59 CLL/5 SLL, median age 71 yrs (range: 65-90), 63% male, Rai stage III/IV 13/30 (%), nodes ≥5 cm in 11%, WHO 0/1/2 in 42/56/2 (%). Adverse risk factors: del(17p) and/or TP53 mutation in 14%, del(11q) in 16%, IGHV unmutated in 58%, median β2-microglobulin 4.0 mg/L (range 1.9-15.8). Disposition: 43 pts completed the 48 wk primary study and 41 entered the extension study. 21 pts discontinued from the primary study (17 AE, 1 withdrawn consent, 3 deaths [pneumonitis; sepsis; metastatic melanoma with pneumonia]); an additional death occurred within 30 days of discontinuation due to pneumonitis. There were 17 discontinuations from the extension study (9 AE, 2 withdrawn consent, 1 investigator request, 4 PD, 1 death [myocardial infarction]), leaving 24 pts ongoing. The median IDELA exposure is 22.9 mos (range 0.8-45.3), with 13 (20%) pts treated for more than 36 months. The ORRis 97% (78% PR, 19% CR) with 3% nonevaluable; median time to response is 1.9 mos (range 1.6-5.7). The Kaplan-Meier (KM) estimated median PFS is not reached (NR), 95% CI (37.3 mo, --). The KM estimated DOR is NR, 95% CI (35.4,--). Of note, 9/9 pts with del(17p) and/or TP53 mutation responded (3 CR, 6 PR); 5 discontinued for AE (4) or investigator request (1) and 4 remain on treatment for 28, 34, 40 and 41 months. The most frequent Gr ≥3 AEs (%) were diarrhea/colitis (42), pneumonia (19), rash (13), dehydration (8), UTI (6), dyspnea (5) and respiratory failure (5). In addition, pneumonitis developed in 2 pts (3%), both Gr 5, and one pt with diverticulitis developed bowel perforation. The median time to onset of Gr ≥3 diarrhea/colitis was 9.5 mo, (range 3-29). Rechallenge was attempted in 21 of the 27 pts with Gr ≥3 diarrhea/colitis, and 12 pts were able to resume IDELA for ≥ 120 days.

15 (23%) pts developed Gr ≥3 ALT or AST elevation, all recovering, with successful resumption of IDELA, at a reduced dose, in 12. In total, 29 (45%) pts had one or more treatment-emergent AEs leading to IDELA dose reduction.

Conclusions: IDELA + R is highly active, rapidly inducing responses in 97% of treatment-naïve older pts with CLL and SLL. The responses are durable, including in those with del(17p)/TP53 mutation. Diarrhea/colitis was the most common Gr ≥3 AE, and IDELA was successfully reintroduced in 44% of the affected pts. Ongoing studies are further investigating the role of IDELA in the frontline setting.