SAKK 35/15: a phase 1 trial of obinutuzumab in combination with venetoclax in patients with previously untreated follicular lymphoma

Abstract

This phase 1 study evaluated safety, tolerability, and preliminary efficacy of obinutuzumab in combination with venetoclax in patients with previously untreated grade 1-3a follicular lymphoma in need of systemic therapy. Two DLs of venetoclax were evaluated with an expansion cohort at the recommended phase 2 dose. Twenty-five patients were enrolled. The recommended phase 2 dose was venetoclax 800 mg OD continuously for 6 cycles starting on day 2 of cycle 1, with obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6, followed by obinutuzumab maintenance every 2 months for 2 years. Only 1 patient had a DLT consisting of grade 4 thrombocytopenia after the first obinutuzumab infusion. Neutropenia was the most common adverse event of grade ≥3 at least possibly attributed to study treatment. Twenty-four patients were evaluable for response after cycle 6 by computed tomography (CT) and 19 by positron emission tomography/CT (PET/CT): overall and complete response rates were 87.5% (95% CI, 67.6% to 97.3%) and 25% (95% CI, 9.8% to 46.7%) in the CT-evaluated patients and 84.2% (95% CI, 60.4% to 96.6%) and 68.4% (95% CI, 43.4% to 87.4%), respectively, in the PET/CT-evaluated patients. One-year progression-free survival was 77.8% (95% CI, 54.6% to 90.1%) and 79% (95% CI, 47.9% to 92.7%) for CT and PET/CT-evaluable patients, respectively, whereas progression-free survival at 30 months was 73.2% (95% CI, 49.8%, 87.0%) as assessed by CT and 79.0% (95% CI, 47.9%, 92.7%) by PET/CT. Despite the activity observed, our results do not support further development of the combination in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02877550.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Kaplan-Meier plot for PFS based on CT assessment.

Figure 2.

Clonal evolution with the fishplot package in 6 patients. The vertical axis of the upper graph represents the log fold change in ctDNA load. The horizontal axis of both upper graph and fishplot shows the treatment timepoints. The fishplot shows the clonal evolution across the timepoints, with the list of mutated genes detected, represented as descent in the form of parental relationships. Patients FL 017, FL 022, and FL 024 had quantifiable levels of ctDNA that disappeared under treatment. Patients FL 025, DFL023, and FL 006 had quantifiable levels of ctDNA that persisted under treatment. Only patient FL 006 had a clinical and radiological progression of disease detected after cycle 5. Imaging in this patient was performed before end of cycle 6 due to an increase of LDH levels. C, cycle; EoM, end of maintenance; M, maintenance.

Figure 3.

Correlation of clonal evolution and MTV in 5 patients with both data available. Only patient 006 had evidence of progressive disease by PET. C, cycle; CMR, complete metabolic remission; EoM, end of maintenance; M, maintenance; PD, progressive disease.