Phase II Single-Arm "Window-of-Opportunity" Study of a Combination of Obinutuzumab and Venetoclax in Early Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) - First Results of the AGMT NHL15B Study

Background: Patients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis with a median overall survival (OS) of less than 2 years. Relapse immuno-chemotherapy followed by autologous stem cell transplantation is the standard of care, but response rates are still not satisfactory and a substantial number of patients are ineligible for transplant or aggressive therapies. Novel antibodies, small molecules and CAR-T cell therapies have been explored for this population. We initiated a study with obinutuzumab and venetoclax to evaluate the effect of a chemo-free regimen in these refractory or early relapsing DLBCL patients with the option to prepare these patients for cell therapy.

Study design and Methods: Twenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression and CD20 positivity were included in this prospective, Fleming-design Phase II single-arm study. Obinutuzumab was given i.v. at a dose of 1000 mg on days 1, 8, 15 in cycle 1 and on day 1 of each following 21-day cycles. Venetoclax was given at 800mg daily p.o. Treatment was repeated for up to 3 cycles. Eligible patients were planned to either proceed to stem cell transplantation or receive up to 9 cycles of maintenance if ineligible for transplant. The primary endpoint was objective response rate by Lugano 2014 criteria after 3 cycles (investigator assessed). Secondary objectives included dose-limiting toxicities, response duration, progression-free and overall survival and ability to proceed to further stem cell transplantation. A biomarker program investigated histopathologic, genomic and biological factors associated with outcome. The trial was registered under Eudract Nr. 2016-001760-10 andNCT02987400.

Results: The ITT population consisted of 21 patients (median age 64 years, 9 M, 12F) with refractory or early relapsed DLBCL after 1 (N=11) to 4 previous lines of therapy. The majority of patients received 3 cycles of obinutuzumab-venetoclax (range 1-8). The regimen was well tolerated. No DLTs were observed. Adverse events were observed in 85.7% with gastrointestinal disorders and administration site conditions being most prominent. Cytopenias were reported in 23.8% and infections in 19%. Severe adverse events were observed in 19%.

The objective response rate was 38.1% (8/21 patients) with a best response of 5 CR (23.8%) and 3 PR (14.2%). Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and an overall survival of 59.3% at 168 days. All deaths were due to underlying disease. Three of 6 responding patients eligible for transplant went on to ASCT, while 2 CR patients refused. Overall, 6 patients received ASCT and 3 patients anti-CD19 CAR-T cells. Three patients received further maintenance cycles. At final visit, 20% of patients were still in CR while 73.3% of patients had progressed. Overall the data indicate that this therapy creates a response period of approximately 3 months in responding patients. Progressive disease was treated with various regimens including chemo-immunotherapy, bispecific agents, antibody-drug conjugates, immunomodulators or small molecules. To date, 7 patients have died.

Characteristics of responding patients include very good or good R-IPI as well as low number of previous therapies (median=1). BCL2 expression and genomic features are currently being analysed and will be presented at the meeting.

Conclusion: Obinutuzumab and Venetoclax represents a chemo-free relapse regimen with low toxicity for DLBCL with the ability to induce objective responses in 38.1% of patients including complete remissions. Its potential to serve as a "window-of-opportunity", relapse- or bridging-treatment in preparation for stem cell or CAR-T cell therapies will be further increased by identification of clinical or biological predictors of response.

Supported by a grant from Roche Austria.