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Atezolizumab + Obinutuzumab + Venetoclax in patients with relapsed or refractory diffuse large B-cell lymphomas: primary analysis of LYSA trial


The treatment of relapsed or refractory diffuse large B-cell lymphoma ( R/R DLBCL ) remains challenging.
Atezolizumab ( Tecentriq ) and Obinutuzumab ( Gazyvaro ) are monoclonal antibodies acting respectively to inhibit T-lymphocyte exhaustion or by inducing lymphoma cells cytotoxicity, whereas Venetoclax ( Venclyxto ) is a small molecule inhibiting BCL-2.
Combining tumor-targeted therapies with agents that enhance anti-tumor immunity represents an attractive treatment paradigm.

The LYSA multicenter phase 2 trial is evaluating the combination of Atezolizumab, Obinutuzumab and Venetoclax in R/R B lymphomas.

Researchers have presentrd primary efficacy and safety data from the DLBCL cohort.

Patients greater than or equal to 18 years with biopsy-confirmed R/R DLBCL who failed at least one line of therapy were eligible.
Obinutuzumab was given IV at the dose of 1 g on day ( D ) 1, 8 and 15 of cycle ( C ) 1 and on D1 from C2 to C8 every 3 weeks.
Atezolizumab was given IV, 1.2 g every 3 weeks, started at D2 of C1, then administered at D2 of each cycle for 24 cycles.
Venetoclax was given orally at 800 mg/D at full dose, started on D8C1 for 24 cycles.

The primary endpoint was OMRR ( Overall Metabolic Response Rate ) by Lugano criteria at the end of induction ( EOI ) after 8 cycles of Atezolizumab, Obinutuzumab and Venetoclax ( M6 ) or at premature treatment discontinuation.

At the time of the primary analysis ( 03 Jan 2020 ), 58 patients were enrolled and the median follow-up was 9 months [ 6.9-11.8 ].
Baseline characteristics were: median age, 70 years; male, 53.4%; Ann Arbor stage IV, 84.5%; age-adjusted IPI ( aaIPI: greater than or equal to 2 ), 63.2%; more than 2 prior lines of therapy, 83.6%; and refractory to last line of prior regimen, 63.6%.

The OMRR at the end of induction was measured at 23.6% [ 14.58%-34.93% ], including 18% of complete metabolic response ( CMR ). To date, these responses seem durable with only 3 reported relapses.

According to the highest diameter mass, OMRR was 38.5% versus 10.3%, less than 5 cm and more than 5 cm respectively; P = 0.02.

All three treatments were stopped in 78% of patients, mostly for progressive disease.

At the time of analysis, a median of 4 cycles [ 1-8 ] has been administered.

A total of 48 ( 84.2% ) patients experienced grade 3–4 adverse event and 6 ( 10.5% ) had an adverse effect that led to discontinuation of any drug.
Adverse effects of grade 3 or more reported in at least 20% of patients were neutropenia ( 33.3% ) and lymphopenia ( 35.1% ).
Of note, a grade 3 autoimmune colitis and a grade 1 hypothyroidism were reported during induction.

In conclusion, the Atezolizumab, Obinutuzumab and Venetoclax combination appears to be well tolerated.
The OMRR rate at the end of induction is comparable with currently available treatment options in this population, with durable responses.
The OMRR seems better in patients with a low tumor burden. ( Xagena )

Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020

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