Treatment with the BTK inhibitor ibrutinib (Imbruvica) in combination with venetoclax (Venclexta) in patients with relapsed/refractory mantle cell lymphoma (MCL) exhibited high and sustained response rates in addition to being deemed well tolerated by patients, according to long-term data from the phase 2 M20-075 study (NCT04477486).1
Patients in the study (full analysis set [FAS], n = 13; per-protocol set [PPS], excluding 1 FAS patient with non-evaluable [NE] disease, n = 12) had relapsed/refractory MCL and received 560-mg doses of ibrutinib and 400-mg doses of venetoclax. Regarding efficacy, at a median follow-up of 37.2 months (range, 2.3-43.3), patients had achieved overall response rates (ORRs) of 83.3% (95% CI, 51.6-97.9%) and 77% (95% CI, 46.2%-95.0%) in the PPS and FAS populations, respectively. Moreover, in the PPS population, 83% (n = 10) of patients achieved a complete response (CR), whereas 17% (n = 2) of patients experienced progressive disease (PD). In the FAS population, the CR and PD rates were 77% (n =10) and 15% (n = 2), respectively, with the response of 1 patient being NE.
Multifaceted MCL Efficacy Displayed by Long-Term Ibrutinib Plus Venetoclax
- Among patients with relapsed/refractory MCL who received ibrutinib plus veletoclax, the ORR rates were 83.3% (95% CI, 51.6-97.9%) and 77% (95% CI, 46.2%-95.0%) for patients in PPS and FAS populations, respectively.
- A 36-month DOR rate of 90% (95% CI, 47.3%-98.5%) and a 76.9% (95% CI, 44.2%-91.9%) 36-month OS rate were shown for all patients in the study.
- The combination was deemed well tolerated in patients and demonstrated a predictable safety profile.
The 36-month duration of response (DOR) rates were 90.0% (95% CI, 47.3%-98.5%) in each population. Additionally, the median DORs were NR (95% CI, 18.5 months-NE) in each population.
“To date, there is limited availability of data about long-term outcomes in patients with relapsed/refractory MCL. In [this study], the combination of venetoclax and ibrutinib has demonstrated durable responses and treatment-free remissions,” lead study author Hideki Goto, MD, PhD, and coauthors wrote in a paper of the data published in the International Journal of Clinical Oncology. Goto is a professor in the Department of Hematology at the Hokkaido University Hospital in Sapporo, Japan.
What were the rationale and design for the study evaluating ibrutinib plus venetoclax in MCL?
Investigators of the trial wanted to evaluate potential treatment options for relapsed/refractory MCL to both improve the poor prognosis of the disease and add to the limited pool of available long-term data in the setting.
The open-label study enrolled patients who were at least 20 years of age with relapsed/refractory MCL that was pathologically confirmed.2 Patients also needed to have received 1 to 5 prior lines of therapy, 1 of which needed to be a regimen with rituximab (Rituxan) or other anti-CD20 treatment.
Patients in the FAS population needed to receive at least 1 dose of ibrutinib plus venetoclax, and the PPS population did not include patients who had NE disease at baseline.
If patients had received prior therapy with ibrutinib or other BTK inhibitors, or had a history of central nervous system lymphoma, they were not included in the trial.3
Patients received once-daily oral, 560-mg doses of ibrutinib and 400-mg doses of venetoclax for up to 24 months.1 Combination dosages were then followed by ibrutinib monotherapy until disease progression, unacceptable toxicities, or withdrawal occurred.
The trial’s primary end point was CR rate per independent review committee. Secondary endpoints were ORR, DOR, undetectable minimal residual disease in patients with CR, progression-free survival (PFS), overall survival (OS), and safety.
Baseline characteristics for patients in the FAS population revealed that patients had a median age of 71 years (range, 59-81) and were mostly male (77%). All patients had relapsed MCL. Most patients had received 2 prior lines of therapy (54%), whereas fewer patients had received 3 or more (31%) or 1 (15%) prior line of therapy. Most patients had an ECOG performance status of 0 (85%), with fewer having a performance status of 1 (15%). The types of MCL histology included typical, blastoid, pleomorphic, and other, which occurred at rates of 54%, 23%, 15%, and 15%, respectively. Finally, slightly more patients had low tumor lysis syndrome risk (54%) compared with high risk (46%).
What were the additional efficacy and safety data with ibrutinib plus venetoclax in the M20-075 trial?
The 12-month PFS rates for patients in the trial were 83.3% (95% CI, 48.2%-95.6%) and 84.6% (95% CI, 51.2%-95.9%) for the PPS and FAS populations, respectively. Furthermore, the 36-month PFS rates in each population were 75.0% (95% CI, 40.8%-91.2%) and 69.2% (95% CI, 37.3%-87.2%). The 12- and 36-month OS rates in the FAS population were 84.6% (95% CI, 51.2%-95.9%) and 76.9% (95% CI, 44.2%-91.9%), respectively.
Regarding safety, across all patients in the trial, common any-grade hematological treatment-emergent adverse effects (TEAEs) were neutropenia, leukopenia, anemia, and thrombocytopenia, which occurred at respective rates of 54%, 38%, 31%, and 31%. Diarrhea, constipation, pyrexia, and skin infections were other common any-grade nonhematological TEAEs in the trial, experienced in 54%, 38%, 38%, and 31% of patients, respectively. Common grade 3 or higher TEAEs among patients were neutropenia (46%), leukopenia (23%), COVID-19 pneumonia (15%), anemia (8%), and pyrexia (8%).
Only 1 patient discontinued the study agents due to a TEAE (squamous cell carcinoma of the lung, which was deemed unrelated to study treatment). In total, 38% of patients had ibrutinib dose reductions due to TEAEs, and 54% of patients discontinued venetoclax due to TEAEs. Finally, 62% of patients had either ibrutinib or venetoclax dose interruptions due to TEAEs.
“Longer exposure to venetoclax with this combination regimen demonstrated a predictable and well-tolerated safety profile,” Goto and coauthors added.
References
- 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;30:2352-2361. doi:10.1007/s10147-025-02865-4
- Goto H, Ito S, Kizaki M, et al. Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma. Int J Clin Oncol. 2024;29:232-240. doi:10.1007/s10147-023-02443-6
- 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 February 11, 2026. https://clinicaltrials.gov/study/NCT04477486
