Updated Survival Analysis from the CLL11 Study: Obinutuzumab Versus Rituximab in Chemoimmunotherapy-Treated Patients with Chronic Lymphocytic Leukemia

Introduction:

Optimized therapeutic targeting of CD20 is one among several currently explored strategies to improve the overall prognosis of patients with chronic lymphocytic leukemia (CLL). Obinutuzumab (GA101) is an optimized (i.e. glycoengineered and type 2) CD20-targeting antibody that has been investigated in the CLL11 study comparing obinutuzumab plus chlorambucil (G-Clb) with rituximab plus chlorambucil (R-Clb) and with chlorambucil alone (Clb) in patients with previously untreated CLL and comorbidities. The study had demonstrated clinically meaningful and statistically significant superiority of G-Clb over Clb (with regard to PFS and OS) and over R-Clb (with regard to PFS, but not for OS) at previous pre-planned analyses. Here, we report updated results on survival and time to next treatment (TTNT) from a pre-planned analysis with data cut-off in May 2015.

Methods:

A total of 781 treatment-naïve patients with CLL in need of therapy and cumulative illness rating scale (CIRS) total score > 6 and/or estimated creatinine clearance (CrCl) < 70 mL/min were randomized in a 1:2:2 fashion to receive Clb alone (0.5 mg/kg po d1 and d15 q28 days, 6 cycles), R-Clb (rituximab: 375 mg/m² iv d1 cycle 1, 500 mg/m² d1 cycles 2-6), or G-Clb (obinutuzumab: 100 mg iv d1, 900 mg d2, 1000 mg d8 and d15 of cycle 1, 1000 mg d1 cycles 2-6). The study was powered for PFS as the primary endpoint, but not for OS and TTNT as secondary endpoints. P values are taken from a log rank test, hazard ratios (HR) from stratified Cox regression.

Results:

The study population was characterized by a median age of 73 years and median CIRS total score of 8. No new safety signals have been identified in this updated analysis.

Updated results of the G-Clb (n=238) vs. Clb (n=118) comparison: The median observation time was 42.4 months. Confirming previously reported results, treatment with G-Clb compared with Clb alone was associated with substantially improved outcome (median PFS 31.1 vs. 11.1 months - HR 0.20, 95%CI 0.15-0.26, p<0.0001; median TTNT 51.1 vs. 15.1 months - HR 0.24, 95%CI 0.17-0.34, p<0.0001; median OS not reached vs. 58.5 months - HR 0.62, 95%CI 0.42-0.92, p=0.0167).

Updated results of the G-Clb (n=333) vs. R-Clb (n=330) comparison: The median observation time was 39.0 months. Updated PFS and TTNT analyses confirmed previously reported superiority of G-Clb over R-Clb (median PFS 28.7 vs. 15.7 months - HR 0.46, 95%CI 0.38-0.55, p<0.0001; median TTNT 51.1 vs. 38.2 months - HR 0.57, 95%CI 0.44-0.74, p<0.0001). OS analysis continued to demonstrate a trend of benefit of G-Clb over R-Clb (HR 0.77, 95%CI 0.57-1.05, p=0.0932) (Figure 1). OS medians were not reached; 22% (74/333) and 28% (93/330) of the patients had died in the G-Clb and R-Clb treatment arms, respectively. As expected from a generally older and comorbid study population, a sizeable proportion (38%) of observed deaths in the two treatment arms were categorized as CLL-unrelated or of unknown cause, while 41% were categorized as CLL-related and 11% as due to infection. OS analysis in pre-specified and non-pre-specified patient subgroups (with gender, age, ECOG performance status, CIRS, CrCl, b-microglobulin, ZAP-70, IGHV status as categories) was in support of an OS benefit of G-Clb over R-Clb, with hazard ratios below 1 in almost all of these subgroups. Only more advanced renal impairment (defined as CrCl < 50mL/min; patients with CrCl < 30mL/min were not eligible to the trial) was not associated with improved OS in patients receiving G-Clb, although the PFS benefit was maintained.

Conclusions:

Updated results from CLL11 confirm that in patients with CLL and comorbidities frontline chemoimmunotherapy with obinutuzumab plus Clb results in (i) substantial PFS, TTNT, and OS benefit compared with Clb alone, and (ii) clinically meaningful PFS and TTNT benefit compared with rituximab plus Clb. Notably, patients treated with obinutuzumab plus Clb remained without new antileukemic treatment for a remarkably long time (over 50 months on average). Current results confirm the previously observed trend of OS benefit of obinutuzumab over rituximab in an elderly and comorbid patient population characterized by competing risks of death. Taken together, optimization of CD20-targeting by antibody-engineering is a valid strategy to improve the overall prognosis of patients with CLL.

Figure 1: PFS, TTNT, and OS for G-Clb vs. R-Clb in CLL11