Efficacy and Safety of Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma: Results From a Phase I/II Study (BO20999)
Authors: Salles Gilles Andre , Morschhauser Franck , Thieblemont Catherine , Solal-Celigny Philippe , Lamy Thierry , Tilly Herve , Feugier Pierre , Le Gouill Steven , Gyan Emmanuel , Bouabdallah Reda , Wenger Michael K. , Wassner-Fritsch Elisabeth , Asikanius Elina , Cartron Guillaume 
Published: October 2019

Abstract
Abstract 268
Obinutuzumab (GA101) is the only type II glycoengineered, humanized anti-CD20 monoclonal antibody in clinical development for the treatment of lymphoma and chronic lymphocytic leukemia. The efficacy of GA101 monotherapy in patients with relapsed/refractory indolent non-Hodgkin's lymphoma (iNHL) is under investigation, and here we report response and long-term results from a Phase I/II study (BO20999).
Phase I was a non-randomized dose-escalating study (3 + 3 design; n = 21) with GA101 monotherapy (50–2,000 mg) on Days 1 and 8 of Cycle 1, and Day 1 of Cycles 2–8 (21-day cycles). The primary objective was to determine the safety and pharmacokinetics of GA101 in patients with NHL. In Phase II patients with iNHL were randomized to receive GA101 at one of two doses: 1,600 mg on Days 1 and 8 of Cycle 1 and then 800 mg on Day 1 of Cycles 2–8 (1,600/800 mg; n = 22), or 400 mg on Days 1 and 8 of Cycle 1 and on Day 1 of Cycles 2–8 (400/400 mg; n = 18). The primary efficacy endpoint was end of treatment response, assessed 4 weeks after the last infusion. Secondary endpoints included safety, pharmacokinetics, best overall response (BOR), and progression-free survival (PFS).
In indolent patients that entered Phase I (n = 16), response was observed in 9 (56%) patients, with a complete response (CR) in 5 (31%) patients and a partial response (PR) in 4 (25%) patients. No clear dose-response relationship was observed. In Phase II, baseline patient characteristics were similar for each cohort (Table 1) with most patients having follicular lymphoma (FL). In the subpopulation of patients with FL, BOR was observed in 5/14 (35.7%) patients (CR unconfirmed: 1 [7.1%]; PR: 4 [28.6%]) in the 400/400 mg cohort; for the 1,600/800 mg cohort, 12/20 (60%) patients with FL responded (CR: 3 [15%]; CR unconfirmed: 1 [5.0%]; PR: 8 [40%]). After a median observation time of 23.1 months, median PFS for patients with FL was 11.8 months (range: 1.8–22.8 months) for the 1,600/800 mg cohort and 6.0 months (range: 1.0–30.0 months) for the 400/400 mg cohort (HR: 0.77 [95% CI 0.34–1.77) (Figure 1). In the 400/400 mg cohort, 2 patients with FL are in continued responses at 16.9+ and 19.3+ months; 2 others experienced a delayed lasting response (time to response: 13.8 and 12.1 months; duration of response: 7.0 and 10.8 months). Of the 12 responders with FL in the 1,600/800 mg cohort, 3 patients have ongoing response for ≥ 19 months (19.8, 19.9 and 20.4 months). One patient with lymphocytic lymphoma also experienced a response duration of 20.3 months. Efficacy results in the overall population are in line with the FL subpopulation. In patients refractory to rituximab treatment (n = 22), response was observed during the study in 3/12 patients (25%) and in 6/10 patients (60%) in the 400/400 mg cohort and the 1600/800 mg cohort respectively. In Phase II, GA101 was well tolerated in both iNHL cohorts. Infusion-related reactions (IRRs) were the most common adverse event (AE) (400/400 mg: 72%; 1,600/800 mg: 73%). Grade 3/4 AEs occurring in >5% of all patients (both cohorts) included infections and infestations (14%; Herpes zoster, haemophilus, lung infection, one patient each), neutropenia (14%) and IRRs (9%) in the 1,600/800 mg cohort, with none in the 400/400 mg cohort. Re-treatment with GA101 on relapse was permitted as per protocol. To date, 3 patients from Phase II and 2 from Phase I have been re-treated with GA101, with 3 of these 5 patients responding again to GA101.Table 1.Patient baseline characteristics (Phase II)Characteristic400/400 mg (n = 18)1,600/800 mg (n = 22)All (n = 40)Histology, nFollicular142034Other426Clinical stage at diagnosis (Ann Arbor)I–II033III–IV171835Unknown112Median age, years (range)51.0 (42–79)61.5 (44–76)60.5 (42–79)Median number of prior treatments (range)3 (1–8)3 (1–11)3 (1–11)Prior stem cell transplant, n6814Previous rituximab, n172138Rituximab refractory*, n121022*Rituximab refractory: those patients who have had no response or a response of <6 months to a rituximab-containing regimen (rituximab monotherapy or in combination with chemotherapy) at any point during their treatment history.Figure 1Progression-free survival (Phase II, follicular non-Hodgkin's lymphoma)Figure 1. Progression-free survival (Phase II, follicular non-Hodgkin's lymphoma)
In conclusion, GA101 monotherapy shows encouraging efficacy with a higher response observed at a higher dose (1,600/800 mg vs 400/400 mg). Phase III trials are ongoing in GA101 in combination with chemotherapy for first-line treatment of patients with advanced iNHL.

Disclosures:
Salles: Roche: Consultancy, Honoraria. Morschhauser:Roche: Honoraria; Celgene: Consultancy, Honoraria. Wenger:Hoffmann La Roche: Employment. Wassner-Fritsch:Roche: Employment. Asikanius:Roche: Employment. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria.