In a phase II trial (MOLTO) reported in the The Lancet Oncology, Tedeschi et al found that the combination of the PD-L1 blocker atezolizumab, the BCL2 inhibitor venetoclax, and the anti-CD20 antibody obinutuzumab was active in Richter transformation diffuse large B-cell lymphoma (DLBCL-RT).

Study Details

In the study, 28 patients were enrolled from sites in Italy and Switzerland between October 2019 and October 2022. Patients received 21-day cycles of obinutuzumab (100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8 and 15 of cycle 1; 1,000 mg on day 1 of cycles 2–8), atezolizumab (1,200 mg on day 2 of cycle 1 and 1,200 mg on day 1 of cycles 2–18), and continuous venetoclax (ramp-up from 20 mg/d on day 15 of cycle 1, then 400 mg/d from day 1 of cycle 3 to day 21 of cycle 35).

Patients could not have received prior treatment with any of the study drugs and had no prior specific treatment for DLBCL-RT. The primary outcome measure was overall response rate at day 21 of cycle 6; an overall response rate of at least 67% was considered clinically active, rejecting the null hypothesis of a rate up to 40%.

Responses

Median follow-up was 16.8 months (interquartile range = 7.8–32.0 months). At day 21 of cycle 6, an objective response was observed in 19 of 28 patients (67.9%; 95% confidence interval [CI] = 47.6%–84.1%), with a complete response in 8 (28.6%). Among the 19 patients with a response at cycle 6, 11 (57.9%) were still in response at 12 months. Conversion from partial to complete remission occurred after cycle 6 in two patients, yielding a best complete response rate of 35.7%.

At 12 months, progression-free survival was 42.9% (95% CI = 24.6%–60.0%), and overall survival was 64.3% (95% CI = 43.8%–78.9%). Progression-free survival at 12 months was 87.5% among patients with complete remission and 36.4% among those with partial remission.

Adverse Events 

The most common adverse events of any grade were neutropenia (43%), neutropenic fever (18%), and COVID-19 infection (18%). Grade ≥ 3 adverse events occurred in 61% of patients, most commonly neutropenia (39%) and thrombocytopenia (11%).

Serious adverse events occurred in 29% of patients, most commonly infections (18%). No treatment-related deaths were observed. Immune-related adverse events occurred in 21% of patients, with none leading to treatment discontinuation. No tumor-lysis syndrome was observed.

The investigators concluded: “The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT.”

Alessandra Tedeschi, MD, of the Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Niguarda Cancer Center, Milan, is the corresponding author of The Lancet Oncology article.

DISCLOSURE: The study was funded by Roche. For full disclosures of the study authors, visit thelancet.com.