Ibrutinib/Venetoclax/Obinutuzumab Controls Disease at 5 Years in Newly Diagnosed MCL

The triplet combination of ibrutinib (Imbruvica), venetoclax (Venclexta), and obinutuzumab (Gazyva) is associated with long-term disease control in patients with newly diagnosed mantle cell lymphoma (MCL), including those with high-risk disease profiles, according to 5-year updated results from the phase 1/2 OAsIs trial (NCT02558816) presented at the 2024 ASH Annual Meeting.1

In cohort C (n = 15), which included patients with newly diagnosed MCL, at a median follow-up of 61 months (range, 48-68), the median progression-free survival (PFS) and overall survival (OS) were both not reached (NR); at 5 years, the PFS and OS rates were 80% and 93%, respectively. Of note, 1 patient with TP53 wild-type disease who experienced early disease progression had no observed adverse effects, and 1 patient with a TP53 mutation experienced sustained disease control after treatment.

Furthermore, in cohort B (n = 24), which included patients with relapsed/refractory MCL, at a median follow-up of 58 months (range, 47-78), the median PFS and OS were both 5 years, and the median duration of response (DOR) was 58 months. The estimated 5-year DOR rate was 45%.

“With the present work, we extend the follow-up for [patients in] cohorts B and C, in order to define overall patients’ outcomes and detect unexpected toxicities in the OAsIs trial,” Benoit Tessoulin, MD, PhD, of the Department of Hematology at Nantes University Hospital in France, and coauthors wrote on the poster.

OAsIs Background and Design

The prospective, open-label, multicenter OAsIs trial evaluated the efficacy and safety of the triplet combination in 2 populations of patients with MCL: those newly diagnosed and those with relapsed/refractory disease.2 Previously reported findings showed that at a median follow-up of 14 months (range, 5-19) in cohort C, the 1-year PFS and OS rates were 93.3% (95% CI, 81.5%-100%) and 100%, respectively; the median DOR was NR. At a median follow-up of 17 months (range, 10-35 months) in cohort B, the 1-year PFS rate was 74.5% (95% CI, 58.8%-94.5%), and the 1-year OS rate was 87.5% (95% CI, 75.2%-100%); the median DOR was NR.

At a median follow-up of 46 months (range, 36-49) in cohort C, the median PFS and DOR were both NR.3 The estimated 4-year PFS and OS rates, respectively, were 80% and 93%. In cohort B, at a median follow-up of 48 months, the 4-year PFS rate was 50%.

Eligibility criteria included patients at least 18 years of age (France; ≥ 16 years of age from the United Kingdom).4 Patients needed to have relapsed/refractory MCL after at least 1 previous line of treatment (steps A and B) or have been untreated with histologically confirmed MCL (step C) within 3 months before baseline; stage II to IV disease in need of treatment; and an ECOG performance status of 0 to 2.

Patients on the study were enrolled at the time of MCL relapse (cohort A), progression (cohort B) or new diagnosis (cohort C).1 In cohort A, patients were treated with obinutuzumab (1g intravenously [IV] on days 1, 8, and 15 of cycle 1; day 1 of cycles 2-6; and every 2 months thereafter until cycle 24) plus ibrutinib (560 mg per day) until disease progression. In cohort B, patients received obinutuzumab (1g IV on days 1, 8, and 15 of cycle 1; day 1 of cycles 1b-8; and every 2 months thereafter until cycle 23) plus ibrutinib (560 mg per day) plus escalating doses of venetoclax (400 mg per day, 600 mg per day, and 800 mg per day). Patients in cohort C were treated with the same obinutuzumab and ibrutinib doses as cohort B, in combination with a fixed dose of venetoclax (400 mg).

The aim of the 5-year follow-up was to identify updated results in cohorts C and B. Previously, in step B of the trial, the primary end point was to determine the maximum tolerated dose of the triplet in cohort B via the Continual Reassessment Method.4 In step C, the primary end point was to confirm the safety of the triplet at fixed doses (ibrutinib at 560 mg per day plus obinutuzumab at 1000 mg per day and venetoclax at 400 mg per day). Secondary end points for both steps B and C included efficacy, safety, and establishment of a biobank to explore biomarkers and mechanism of action, including resistance.

Patient Baseline Characteristics

In cohort C, patients had a median age of 65 years (range, 51-77), most patients had a MCL International Prognostic Index (MIPI) score of intermediate risk (73%), more than half of patients had a biological MIPI (MIPIb) score of high risk (55%), the most common histology was pleomorphic (7%), and 13% of patients had mutated TP53.1

In cohort B, patients had a median age of 66 years (range, 45-76) and had received a median of 1 previous lines of therapy (range, 1-3). A total of 54% of patients had received prior stem cell transplantation, the most common MIPI score was low risk (38%), the most common MIPIb score was high risk (61%), the most common histology was blastoid (33%), and 21% of patients had mutated TP53.

Additional Efficacy and Safety Findings

In cohort C, 1 patient had disease progression at cycle 4 and subsequently received R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin [Adriamycin], vincristine, and prednisone), and 1 patient relapsed after study treatment completion and was then treated with glofitamab-gxbm (Columvi).

In cohort B, 8 patients had disease progression, 7 of whom were treated with a chemotherapy-based salvage regimen of bendamustine with or without bortezomib (Velcade), or R-CHOP; The remaining patient with disease progression did not receive subsequent treatment. Additionally, one patient relapsed after treatment completion and was treated with odronextamab.

Notable toxicities observed in cohort C included atrial fibrillation, acute cardiac failure, and death from a progressive multifocal leukoencephalopathy after completing treatment without active hematological disease (n = 1 each). In cohort B, there were no observed late-onset toxicities; 2 patients died due to COVID-19 infection after study completion.

References

1. Tessoulin B, Morschhauser F, Chiron D, et al. 5-y follow-up of combination of ibrutinib, obinutuzumab and venetoclax for patients with newly diagnosed mantle cell lymphoma, the Oasis trial. Blood. 2024;144(suppl 1):1657. doi:10.1182/blood-2024-206778
2. Le Gouill S, Morschhauser F, Chiron D, et al. Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood. 2021;137(suppl 7):877-887. doi:10.1182/blood.2020008727
3. Le Gouill S, Morschhauser F, Chiron D, et al. P1090: long term follow-up of untreated/relapsing MCL patients with the ibrutinib, obinutuzumab, and venetoclax combination. Hemasphere. Published online August 8, 2023. doi:10.1097/01.HS9.0000971256.60488.02
4. A trial of obinutuzumab, GDC-0199 plus ibrutinib in relapsed/refractory mantle cell lymphoma patients (OAsIs). ClinicalTrials.gov. Updated March 13, 2020. Accessed February 25, 2025. https://clinicaltrials.gov/study/NCT02558816