SAFETY AND EFFICACY OF ATEZOLIZUMAB, OBINUTUZUMAB AND VENETOCLAX COMBINATION FOR RELAPSED/REFRACTORY NON‐HODGKIN LYMPHOMAS: RESULTS FROM THE SAFETY‐RUN OF A LYSA STUDY (2019)

Introduction: Despite major advances introduced by immunochemotherapy, relapse and refractory B-lymphomas (R/R NHLs) treatment remains challenging. Atezolizumab and obinutuzumab are monoclonal antibodies acting respectively to inhibit T-lymphocyte exhaustion or by inducing lymphoma cells cytotoxicity, whereas venetoclax is a small molecule inhibiting BCL-2. Combining tumor-targeted therapies with agents that enhance anti-tumor immunity represents an attractive treatment paradigm. The LYSA conducts a multicenter phase II trial (NCT03276468) evaluating the efficacy and safety of the chemotherapy-free combination of atezolizumab, obinutuzumab and venetoclax in R/R NHLs. We present safety and early response data of the patients included in the safety-run. Methods: Patients ≥18 years with biopsy-confirmed R/R NHL (DLBCL or FL) who failed at least one line of therapy (rituximab and anthracycline containing regimen) were eligible. An initial safety-run was performed to assess this novel therapeutic combination. Obinutuzumab was given IV at the dose of 1000 g on day (D) 1, 8 and 15 of cycle (C) 1 and on D1 from C2 to C8 every 3 weeks. Atezolizumab was given IV, 1200 g every 3 weeks, started at D2 of C1, then administered at D2 of each cycle for 24 cycles. Venetoclax was given orally at 800 mg/D at full dose, started on D8C1 for 24 cycles. The primary endpoint of the safety-run was to evaluate the safety of this combination. Before entering in the main study, the safety-run had to include at least 12 patients treated at least 6 weeks (2 cycles). Results: A total of 13 patients were enrolled in the safety-run between Feb and Apr 2018: 9 were DLBCL and 4 FL. Median age was 61.7 years [39-77]. With a median follow up of 4.4 months [3.5-5.1], and during the 4 first cycles of treatment, hematologic toxicity was the most common AE, with G≥3 neutropenia (7 [54%] pts) and G≥3 thrombocytopenia (4 [31%] pts). No patient experienced febrile neutropenia. The most common non-hematologic all-grade AE were infections (6 [46%] pts), back pain (3 [23%] pts), diarrhea (2 [15%] pts) and IRR (2 [15%] pts). All these non-hematologic AE were G1 or 2, except one G3 lung infection. No tumor lysis syndrome was observed. Four patients (3 DLBCL and 1 FL) have permanently discontinued study treatment, all of them due to progression. At intermediate analysis (after C4), 12 patients were evaluable for response: 3 (25%, 3 DLBCL) achieved complete metabolic response (CMR) and 5 (42%, 3 FL and 2 DLBCL) achieved partial metabolic response (PMR). The Overall Metabolic Response Rate (OMRR) was 67% (8 out of 12). A pseudo-progression was observed retrospectively in one FL patient. He was in tumoral metabolic progression at C4, and has showed a CMR at C8. Conclusion: The atezolizumab, obinutuzumab and venetoclax combination appears to be well tolerated. The Data and Safety Monitoring Board decided to add primary prophylaxis of neutropenia. The OMRR of 67% is encouraging for a chemo-free regimen in R/R NHLs. Treatment and follow-up of these patients are currently ongoing and updated data will be presented at the congress. Keywords: B-cell lymphoma; immune system; venetoclax.