A PHASE IB STUDY EVALUATING THE SAFETY AND CLINICAL ACTIVITY OF ATEZOLIZUMAB COMBINED WITH OBINUTUZUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY NON‐HODGKIN LYMPHOMA (NHL)

Abstract

Background: Even with modern chemo-immunotherapy regimens, outcomes for patients (pts) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) remain poor. Atezolizumab (atezo), a humanized engineered IgG1 monoclonal antibody (mAb) against programmed deathligand 1 (PD-L1), blocks the interaction between PD-L1 and its receptors PD- 1 and B7.1, thereby preventing inhibition of T-cell activity. Atezo monotherapy has demonstrated clinical activity in multiple types of cancers, including non- Hodgkin lymphoma (NHL). Increased PD-L1/PD-1 expression has been reported in DLBCL and FL on cancer cells, stromal cells and tumor-infiltrating immune cells and may represent escape from immune surveillance. Obinutuzumab (obi) is a next-generation anti-CD20 mAb with enhanced ADCC. Aims: To determine whether the combination of atezo and obi can activate both innate and adaptive immunity to enhance anti-tumor responses in lymphoma. Methods: This multicenter, open-label Phase Ib study (NCT02220842) is assessing atezo combined with obi in pts with relapsed or refractory DLBCL or FL. Primary endpoints are safety and tolerability; secondary endpoints are pharmacokinetics and clinical activity. Key eligibility criteria were measurable disease and treatment with ≥1 prior chemo-immunotherapy regimen. Prior autologous stem cell transplant was allowed but not allogeneic stem cell transplant. In cycle 1, pts received obi intravenously (IV) alone on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg). From cycles 2-8, atezo (1200 mg) and obi (1000 mg) were administered IV on day 1 q3w. Atezo consolidation followed (1200 mg q3w) for an additional 6 mo. Objective response rate (ORR) was assessed by IWG NHL criteria. Pretreatment biopsies and on-treatment samples were collected to determine PD-L1 expression levels and examine other biomarkers of response and resistance. Results: As of Feb 5, 2016, 31 pts (17 DLBCL; 14 FL) were evaluable for safety. Median age was 60 yrs (range 26-90) and 58% of pts were male. Median disease burden at baseline was 3027.9 mm2 (range 598.0-31400.0). Median duration of therapy was 43 days (range 2-387) for DLBCL and 117 days (range 2-211) for FL. 1 potentially atezo-related adverse event (AE) (Grade 2 myalgia) led to treatment discontinuation. AEs led to study drug interruptions in 7 pts. 26 pts experienced ≥1 treatment emergent (TE) AE (Gr 1- 4). The most common Gr 3-4 TEAEs were neutropenia (12.9%) and abdominal pain (6.5%). 4 deaths (3 due to disease progression; 1 unknown cause) were reported. 20 pts with ≥1 imaging assessment were evaluable for efficacy and had a median of 3 prior therapies (range, 2-7). At the first response assessment (after cycle 4), the ORR was 15%; 2 FL pts achieved a complete response, and 1 FL pt had a partial response. 6 pts had stable disease (1 with DLBCL; 5 with FL). PD-L1 expression was detected in DLBCL and FL; corresponding measurements of biomarkers associated with immune activity including infiltration by CD8+ T cells were seen. Updated safety, efficacy and biomarker data will be presented. Summary/Conclusions: Preliminary results indicate that atezo combined with obi is well tolerated with evidence of clinical activity in pts with heavily pretreated relapsed or refractory DLBCL and FL.