Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapsed or refractory diffuse-large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) remain poor, and more effective therapies are sorely needed. Immune checkpoint inhibitors (anti-PDL1 or anti-PD-1) represent a novel class of therapeutics with great promise. Atezolizumab (MPDL3280A) is a fully humanized IgG1 monoclonal antibody that blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, thereby preventing inhibition of T-cell activity. Clinical activity of atezolizumab has been seen in multiple tumor types, including NHL as monotherapy. Increased PD-L1 expression has been reported in DLBCL and FL on tumor cells, stromal cells and tumor-infiltrating immune cellsand may represent a mechanism of tumor escape from immune surveillance. Obinutuzumab is a next generation anti-CD20 monoclonal antibody with enhanced ADCC activity. The combination of atezolizumab and obinutuzumab has the potential to activate both innate and adaptive immunity to enhance anti-tumor responses in lymphoma.
Methods: This multi-center, open-label, Phase Ib (NCT02220842) study is evaluating atezolizumab in combination with obinutuzumab in patients with relapsed or refractory DLBCL or FL. Primary endpoints were safety and tolerability, with secondary endpoints of PK and clinical activity. Key eligibility criteria included measurable disease and treatment with ≥ 1 prior chemo-immunotherapy regimen. Previous autologous stem cell transplant was allowed, but not allogeneic stem cell transplant. During cycle 1, patients received obinutuzumab alone on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg). From cycles 2-8, atezolizumab (1200 mg) and obinutuzumab (1000 mg) were administered on day 1 every 3 weeks. This was followed by atezolizumab consolidation (1200 mg q3 weeks) for an additional 6 months. ORR was assessed by IWG NHL criteria (Cheson et al, J Clin Oncol 2007). Pre-treatment biopsies and on-treatment samples are being collected to determine PD-L1 expression and other biomarkers of response and resistance.
Results: As of July 28, 2015, all 6 patients (2 male, 4 female) evaluable for safety have completed at least 4 cycles of therapy. Median age was 68.5 years (range, 58-81 years). Three patients had FL, and 3 patients had DLBCL. The median number of prior therapies was 4 (range, 2-6). All patients have received at least one prior rituximab-containing chemo-immunotherapy regimen. One patient with DLBCL had received a prior autologous stem cell transplant, as well as CD19 CAR T-cell therapy. The median disease burden at baseline was 2717.4 mm2 (range, 990-7247 mm2). The median duration of therapy was 118 days (range, 64-212 days). One dose-limiting toxicity (Grade 3 thrombocytopenia) was observed. Three patients experienced 1 treatment-emergent Grade 3 AE each (thrombocytopenia, ileus, intestinal obstruction). No Grade ≥ 3 infusion-related reactions, Grade 4 or 5 AEs, treatment related deaths or discontinuations due to study treatment have been seen. Responses for 5 patients who have completed the first disease assessment time point are available. Preliminary efficacy evaluation (CT scan) after 4 cycles (3 months) of therapy are as follows: 2 PRs (up to 68.6% reduction; 1 pt with DLBCL and 1 pt with FL), 2 SDs and 1 PD. Three of 4 patients, experiencing SD or better have ongoing clinical benefit. Expansion cohorts in FL and DLBCL are currently enrolling, and updated safety and efficacy data will be presented. Biomarker data will also be discussed.
Conclusions: Preliminary results indicate that the combination of atezolizumab and obinutuzumab appears well tolerated with early evidence of activity in patients with heavily pretreated relapsed or refractory DLBCL and FL.
Till:Roche-Genentech: Research Funding. Park:TEVA: Research Funding; Seattle Genetics: Research Funding; Jannsenn: Other: Travel. Goy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/JNJ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Penuel:Genentech, Inc.: Employment. Venstrom:Genentech: Employment. Liu:Genentech: Employment. Fingerle-Rowson:F.Hoffmann-LaRoche: Employment. Byon:Genentech: Employment. Woodard:Genentech: Employment.
Asterisk with author names denotes non-ASH members.