Ibrutinib/Venetoclax Yields Long-Term Efficacy in Japanese R/R MCL Trial

Combining ibrutinib (Imbruvica) with venetoclax (Venclexta) demonstrated sustained efficacy and a manageable safety profile among a small cohort of patients with relapsed/refractory mantle cell lymphoma (MCL) in Japan, according to findings from the phase 2 M20-075 study (NCT04477486) published in the International Journal of Clinical Oncology.¹

With a median follow-up of 37.2 months (range, 2.3-43.3) among 13 patients who received ibrutinib/venetoclax, data showed an objective response rate (ORR) of 83% (n = 10/12; 95% CI, 51.6%-97.9%); all patients with a response achieved a complete response (CR). The 36-month rate of response was 90% (95% CI, 47.3%-98.5%), and the median duration of response (DOR) was not reached.

Seven patients had minimal residual disease (MRD) positivity at baseline, and 6 of those patients achieved a CR and experienced undetectable MRD following treatment. Neither the median progression-free survival (PFS) or overall survival (OS) were reached. The rates of PFS and OS, respectively, were both 84.6% (95% CI, 51.2%-95.9%) at 12 months and 69.2% (95% CI, 37.3%-87.2%) and 76.9% (95% CI, 44.2%-91.9%) at 36 months.

“To date, there is limited availability of data about long-term outcomes in patients with [relapsed/refractory] MCL. In a non-Japanese phase 2 study, the combination of venetoclax and ibrutinib has demonstrated durable responses and treatment-free remissions with an estimated 7-year PFS [rate] of 30% and OS of 43% and an acceptable toxicity profile,” lead study author Hideki Goto, MD, PhD, from the Department of Hematology at Hokkaido University Hospital, wrote with coauthors in the publication.^1,2 “Considering these results along with the long-term outcomes of M20-075 in Japanese patients, the combination of venetoclax and ibrutinib emerges as a promising treatment option for [relapsed/refractory] MCL in Japan.”

In the open-label, single-arm, phase 2 study, patients were assigned to receive ibrutinib at 560 mg orally and 400 mg of venetoclax orally once daily for a maximum of 24 months followed by ibrutinib alone until progressive disease, unacceptable toxicity, or withdrawal of consent. Patients received ramp-up dosing of venetoclax at 20 mg followed by 50 mg, 100 mg, 200 mg, and 400 mg across 4 weekly dose increases.

The trial’s primary end point was the CR rate per independent review committee assessment. Secondary end points included ORR, DOR, undetectable MRD rate among those with a CR, PFS, OS, and safety.

Patients 20 years and older with pathologically confirmed MCL per local testing; at least 1 measurable site of disease; 1 to 5 prior regimens for MCL, including 1 previous line of rituximab (Rituxan) or anti-CD20 therapy; and a lack of partial response or better following the most recent line of treatment were eligible for enrollment on the trial.³ Those with prior treatment with ibrutinib or other Bruton tyrosine kinase inhibitors were ineligible for study entry.

Among 13 patients in the full-analysis set, the median age was 71 years (range, 59-81), and most were male (77%). Most patients had relapsed disease (100%), an ECOG performance status of 0 (85%), an intermediate MCL International Prognostic Index (MIPI) score (54%), typical MCL histology (54%), and Lugano stage IV disease (62%).

All patients (100%) experienced adverse effects (AEs) of any grade, with 62% having grade 3 or higher AEs and 46% experiencing serious AEs. The most common hematological AEs of any grade included neutropenia (54%), leukopenia (38%), anemia (31%), and thrombocytopenia (31%). Non-hematological AEs included diarrhea (54%), constipation (38%), pyrexia (38%), skin infection (31%), and decreased appetite (23%). Overall, 38% and 54% of patients had treatment-emergent AEs leading to discontinuation of ibrutinib and venetoclax, respectively.

“Limitations of this study include a small sample size and the single-arm design with no control group for comparison of long-term outcomes in Japanese patients with MCL. In addition, biomarker testing including TP53 and BTK mutational status was not performed,” the study authors wrote.¹ “Nonetheless, findings from this analysis strengthen the evidence supporting the continued evaluation of the ibrutinib plus venetoclax combination for patients with [relapsed/refractory] MCL, where there remains the need for novel effective treatment strategies to improve long-term outcomes.”

References

1. Goto H, Ito S, Kizaki M, et al. Long-term outcomes of venetoclax and ibrutinib in Japanese patients with relapsed/refractory mantle cell lymphoma. Int J Clin Oncol. 2025;30(11):2352-2361. doi:10.1007/s10147-025-02865-4.
2. Handunnetti SM, Anderson MA, Burbury K, et al. Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions. Blood. 2024;144(8):867-872. doi:10.1182/blood.2023023388.
3. Study to assess effect of oral venetoclax tablet in combination with oral ibrutinib capsule on best overall response of complete response in adult Japanese participants with relapsed/​refractory mantle cell lymphoma. ClinicalTrials.gov. Updated July 9, 2025. Accessed December 3, 2025. https://tinyurl.com/bde2ct2u