Ibrutinib, Obinutuzumab, Venetoclax Triplet Elicits Sustained Clinical Benefit in Mantle Cell Lymphoma

Steven Le Gouill, MD

The combination of ibrutinib (Imbruvica), obinutuzumab (Gazyva), and venetoclax (Venclexta) was associated with prolonged survival in patients with newly diagnosed or relapsed/refractory mantle cell lymphoma (MCL), according to long-term follow-up data from the phase 1/2 OAsIs trial (NCT02558816) presented at the 2023 EHA Congress.¹

Findings showed that at a median follow-up of 46 months (range, 36-49) for patients with newly diagnosed MCL in cohort C (n = 15), the median duration of response (DOR) and progression-free survival (PFS) were not yet reached (NR). The 4-year PFS rate was 80%, and the 4-year overall survival (OS) rate was 93%.

At a median follow-up of 48 months (range, 42-66) for patients with relapsed/refractory MCL treated with the triplet in cohort B (n = 24), the median DOR and PFS were also NR. The 4-year PFS and OS rates were both 50%.

“Extended follow-up [of OAsIs] confirms that [the] frontline chemotherapy-free obinutuzumab, ibrutinib, and venetoclax combination is associated with a prolonged clinical benefit, without overwhelming toxicities,” lead study author Steven Le Gouill, MD, of Institut Curie Hospital in Paris, France, and colleagues, wrote in a poster presentation. “This combination is also very effective in the relapsed/refractory setting, [yielding] prolonged DOR, PFS, and OS.”

The prospective, open-label, multicenter phase 1/2 trial conducted at 5 centers in France and 1 in the United Kingdom evaluated the combination of obinutuzumab plus ibrutinib with or without venetoclax in patients with MCL. Previously reported data at a median follow-up of 14 months (range, 5-19) for untreated patients treated with the triplet showed that 86.6% experienced a complete response (CR) at the end of cycle 6, and the 1-year PFS rate was 93.3% (95% CI, 81.5%-100%).²

At a median follow-up of 17 months (range, 10-35) for patients with relapsed/refractory MCL given the triplet, the CR rate at the end of cycle 6 was 67%, and the 2-year PFS and OS rates were 69.5% (95% CI, 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%), respectively.

Cohorts A and B included patients with relapsed/refractory MCL, and cohort C consisted of patients with newly diagnosed MCL. All patients were required to have stage II to IV MCL in need of treatment, an ECOG performance status of 0 to 2, and a life expectancy of more than 3 months.³

Key exclusion criteria included clinically significant cardiovascular disease, major surgery within 4 weeks of enrollment, and known central nervous system lymphoma.

Patients in cohort A received 1 g of intravenous obinutuzumab on days 1, 8, and 15 of cycle 1, on day 1 of cycles 2 to 6, and once every 2 months thereafter, plus 560 mg of ibrutinib per day until disease progression.¹

Those in cohort B were treated with the same regimen of obinutuzumab and ibrutinib in combination with escalating doses of venetoclax at 400 mg, 600 mg, or 800 mg per day. Patients in cohort C received obinutuzumab and ibrutinib on the same dosing schedule with a fixed dose of 400 mg of venetoclax.

Safety served as the trial’s primary end point. Secondary end points included overall response rate, time to progression, and OS.³

In cohort C, all patients presented with stage III/IV classical MCL. Seventy-three percent of patients had a MCL International Prognostic Index (MIPI) score of intermediate, and 27% had a high MIPI score. In cohort B, 37% of patients presented with blastoid/pleomorphic MCL, and 88% of patients had stage II or IV disease. Thirty-three percent of patients had an intermediate MIPI score, and 29% had a high MIPI score. This cohort received a median of 1 (range, 1-3) prior line of therapy.¹

In cohort C, 2 patients prematurely discontinued treatment due to early progressive disease after 4 months (n = 1) and neuropathy after 9 months (n = 1). The patient with early progressive disease did not have an adverse effect or a TP53 alteration. Notably, 1 patient in this cohort who harbored a TP53 mutation was still experiencing sustained disease control at long-term follow-up.

Regarding safety in cohort C, 1 patient experienced atrial fibrillation, 1 had acute cardiac failure, and 1 patient died due to progressive multifocal leukoencephalopathy following the completion of treatment without the presence of active hematological disease. Moreover, 1 patient who experienced progressive disease at cycle 4 received subsequent R-CHOP, and 1 patient who relapsed after treatment completion was administered glofitamab (Epkinly).

In cohort B, no late-onset toxicities were reported. However, 2 patients died due to a COVID-19 infection following study completion. Moreover, 8 patients experienced progression. Six patients proceeded to receive a bendamustine-containing regimen with bortezomib (Velcade), 1 was treated with subsequent R-CHOP, and 1 patient was not treated. Additionally, 1 patient relapsed following treatment completion and was subsequently treated with odronextamab (REGN1979).

The ongoing phase 2 OAsIs II trial (NCT04802590) is evaluating the combination of ibrutinib, venetoclax, and an anti-CD20 antibody vs ibrutinib plus an anti-CD20 antibody in previously untreated patients with MCL.

References

1. Le Gouill S, Morschhauser F, Chiron D, et al. Long term follow-up of untreated/relapsing MCL patients with the ibrutinib, obinutuzumab, and venetoclax combination. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P1090.
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(7):877-887. doi:10.1182/blood.2020008727
3. A trial of obinutuzumab, GDC-0199 plus ibrutinib in relapsed/refractory mantle cell lymphoma patients (OAsIs). ClinicalTrials.gov. Updated March 13, 2020. Accessed June 19, 2023. https://clinicaltrials.gov/ct2/show/NCT02558816