Randomized Phase II Trial Comparing GA101 (Obinutuzumab) with Rituximab in Patients with Relapsed CD20 Indolent B-Cell Non-Hodgkin Lymphoma: Preliminary Analysis of the GAUSS Study

Abstract Abstract 269 Background: GA101 is the first type II glycoengineered CD20 monoclonal antibody in phase II/III clinical trials for CLL and NHL. In pre-clinical models GA101 mediated enhanced direct cell death and increased ADCC compared to other anti-CD20 antibodies. GA101 single-arm clinical studies have demonstrated responses in patients (pts) with relapsed/refractory NHL and CLL, but to date there have been no direct comparisons with rituximab. The aim of this randomized phase II trial was to compare efficacy and safety of monotherapy with GA101 versus rituximab in pts with relapsed indolent NHL. Study Design and Patients: Pts with relapsed indolent NHL requiring therapy who had demonstrated a prior response (CR/CRu or PR) to a rituximab-containing regimen lasting 6 months were eligible. A total of 175 pts (149 follicular (FL) and 26 non-follicular indolent NHL) stratified by histology were randomized 1:1 to receive 4 weekly infusions (Days 1, 8, 15, 22) of either GA101 (1000 mg, n87) or rituximab (375 mg/m2, n88). End of treatment response was assessed 2842 days after the last induction dose. Pts without evidence of progression following induction therapy received ongoing treatment with GA101 or rituximab every 2 months for up to 2 years at the same dose. The primary endpoint was overall response rate (ORR) in the FL population. Secondary endpoints included PFS, OS, and safety. Treatment arms were well balanced for standard prognostic features (age, ECOG PS, Ann Arbor stage, FLIPI risk score at initial diagnosis, LDH) and prior treatment characteristics. Pts in both arms had received a median of 2 prior lines of therapy (range: 17 GA101 arm; 16 rituximab arm) and 99 had received prior rituximab. At baseline, pts in the GA101 cohort had a larger volume of disease based on the median sum of product diameters; SPD GA101 cohort 2397 mm2(range 19229326 mm2) v SPD rituximab cohort 1934 mm2(range 25211255 mm2). Results: The primary efficacy analysis was conducted in the FL population at the end of induction. Based on investigator assessment, ORR for GA101 was 43.2 (32/74) v 38.7 (29/75) for rituximab. The difference in response rates was 4.6 (95 CI -12.0, 21.1). The CR/CRu rate in the GA101 arm was 10.8 v 6.7 for rituximab. At the time of analysis 28/149 pts had progressed, 15/74 on GA101 and 13/75 on rituximab. A central blinded radiology review (IRF) was performed to independently assess response. The difference in response rates by the IRF was 15.2 (95 CI -0.7, 31.2; ORR, GA101 v rituximab: 43.2 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\scriptstyle \raisebox{1ex}{32$}\!\left/ \!\raisebox{-1ex}{$74$}\right.}\]\) \end{document}v 28.0 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({\scriptstyle \raisebox{1ex}{21$}\!\left/ \!\raisebox{-1ex}{$75$}\right.}\]\) \end{document}). In the overall population (FL non-follicular indolent NHL), the ORR as assessed by investigators was 43.2 (38/88) v 35.6 (31/87) and by the IRF was 42.0 (37/88) v 24.1 (21/87) for GA101 and rituximab, respectively. Safety was analyzed in the overall population. No new safety signals were observed in either arm. One patient in the rituximab arm died from cardio-pulmonary arrest and 1 patient in the GA101 arm died from pulmonary aspergillosis. More pts discontinued therapy during induction in the rituximab arm (7 pts v 4 GA101 pts). Discontinuations with GA101 occurred as a result of infusion related reactions (IRR, 3 pts) and orthostatic hypotension (1 pt). A greater number of pts in the rituximab arm experienced an SAE during the induction period (9 pts v 5 GA101 pts). SAEs in the GA101 arm occurred as a result of IRR (2 pts), febrile neutropenia (1 pt), pleural effusion (1 pt) and nephrolithiasis (1 pt). More pts in the GA101 arm reported IRRs (GA101 v rituximab: any grade, 72 v 49; grade 3/4, 11 v 5). IRRs were primarily seen during the first infusion and decreased in both frequency and severity with subsequent infusions. Other AEs (any grade) that occurred at a 5 higher incidence with GA101 included fatigue (23 v 17), cough (10 v 1), back pain (7 v 2), decreased appetite (7 v 2) and insomnia (5 v 0). Conclusions: Treatment with GA101 in pts with relapsed NHL resulted in higher response rates compared to rituximab as assessed by both investigators and the IRF at an early time point. GA101 was well tolerated, although a higher rate of IRRs was noted, the majority were grade 1/2 in severity and did not result in significant differences in treatment discontinuation. This is the first head to head trial of GA101 against rituximab and has demonstrated higher response rates without appreciable differences in safety. GA101 is under study in phase III trials in combination with chemotherapy. Disclosures: Sehn: Roche/Genentech: Consultancy, Honoraria, Research Funding. Goy:Roche/Genentech: Consultancy, Honoraria. Friedberg:Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lasserre:Roche: Employment. Fine:Roche: Employment. Press:Roche/Genentech: Consultancy, Honoraria.

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