Immune-Based Triplet Demonstrates Activity in Relapsed/Refractory DLCBL

Charles Herbaux, MD, MSc

The triplet regimen of atezolizumab (Tecentriq), obinutuzumab (Gazyva), and venetoclax (Venclexta) demonstrated encouraging activity and safety in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to the primary analysis of a cohort from the phase 2 GATA trial (NCT03276468) that was presented at the virtual 2020 EHA Congress.

The overall metabolic response rate (OMRR) at the end of 8 weeks of induction therapy was 23.6% (n = 13), including a complete metabolic response rate (CMRR) of 18% (n = 10). The OMRR was significantly higher among patients with tumor bulk measuring less than 5 cm versus more than 5 cm, at 38.5% (n = 10) versus 10.3% (n = 3), respectively.

“The atezolizumab, obinutuzumab, and venetoclax combination appears well tolerated, with no unexpected safety signal,” said Charles Herbaux, MD, MSc, lead study author and assistant professor of Hematology at the Lille University School of Medicine in Lille, France, in a virtual presentation of the data. “[In terms of efficacy, the OMRR] seems better in patients with the highest diameter mass below 5 cm.”

In explaining the rationale for the triplet, Herbaux cited the antitumor immunity cycle, whereby obinutuzumab alone enhances the recognition of cancer cells by T cells, the combination of obinutuzumab and venetoclax leads to direct induction of apoptosis, and the addition of atezolizumab to the combination increases the priming and activation of antigen-presenting cells and effector T cells. 

The trial comprised patients with relapsed/refractory non-Hodgkin, B-cell lymphomas; data from the DLBCL cohort were presented during the meeting.

To be eligible for enrollment in the DLBCL cohort, patients 18 years or older had to have biopsy-confirmed DLBCL, relapsed/refractory disease after 1 or more rituximab (Rituxan) and anthracycline-containing regimens, an ECOG performance status (PS) of 0 to 2, and a 2-dimensional measurable lesion on PET or CT scan.

Patients were excluded from enrollment if they had CD20 negativity at their last biopsy, central nervous system involvement, positive serology for HIV, hepatitis B or C virus, creatinine clearance less than 50 mL/min, active infection and immune-related disease, or left ventricular ejection fraction less than 45%.

In the trial, patients received 1000 mg of intravenous (IV) obinutuzumab on day 1, 8, and 15 of the first 21-day cycle, and on day 1 in cycles 2 through 8; 1200 mg of IV atezolizumab on day 2 every 3 weeks of cycle 1, and on day 2 thereafter in each cycle for 24 cycles; and 800 mg/day of continuous venetoclax starting on day 8 o cycle 1 for 24 cycles.

Overall metabolic response rate by Lugano criteria, at the end of induction, or at premature treatment discontinuation served as the primary end point of the study. 

At the time of the primary analysis in January 2020, 58 patients had enrolled in the study.

Patients had a median age of 70 years (range, 39-85), and approximately half were male (53.4%). The majority of patients had Ann Arbor stage IV disease (84.5%), and 63.2% presented with an age-adjusted International Prognostic Index of 2 or more. The majority of patients had received at least 2 prior lines of therapy (83.6%), and 63.6% of patients were refractory to their last line of therapy.

Less than 20% of patients had bulky disease (≥10 cm; 15.5%), 19.0% had an ECOG PS of 2, 6.9% had a DH/TH genotype, and 4.6% had received autologous transplant.

At a median follow-up of 9 months (range, 6.9-11.8), patients have received a median of 4 cycles of therapy (range, 1-8). All 3 drugs were stopped in 78% of patients, primarily for progressive disease.

No difference in OMRR was found according to cell of origin. The OMRR was 20.8% in patients with germinal center disease versus 25.0% in patients with non-germinal center disease.

“One patient with primary mediastinal B-cell lymphoma and 4 patients with double- or triple-hit DLBCL were included; none responded to the combination,” said Herbaux.

Regarding safety, a total of 48 patients (84.2%) experienced grade 3/4 adverse effects (AEs); no grade 5 AEs occurred. Grade 3 or greater AEs included neutropenia (33.3%), lymphopenia (35.1%), thrombocytopenia (17.5%), and anemia (10.5%).

Regarding AEs of special interest, 1 case of grade 3 autoimmune colitis and 1 case of grade 1 hypothyroidism was reported. Six patients (10.5%) experienced an AE that led to treatment discontinuation.

Ancillary pathological and immunological studies are currently underway to better understand the disease and its microenvironment, said Herbaux.

“Our study includes 2 other cohorts: follicular lymphoma and indolent non-Hodgkin lymphoma. We are very much looking forward to presenting updated results of the whole study,” concluded Herbaux. 

Reference

Herbaux C, Casasnovas O, Feugier P, et al. Efficacy and safety of atezolizumab + obinutuzumab + venetoclax in patients with relapsed or refractory diffuse large B-cell lymphomas: primary analysis of a phase 2 trial from LYSA. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract p426-5.