Ibrutinib/venetoclax produces long-term efficacy in Japanese R/R MCL trial

In a small subset of Japanese patients with relapsed/refractory mantle cell lymphoma (MCL; non-Hodgkin lymphoma), according to published results from the Phase 2 M20-075 study (NCT04477486) , combining ibrutinib/Ibrutinib with venetoclax-Venclexta showed sustained efficacy and a manageable safety profile.

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

Seven patients had mildly positive residual disease (MRD) at baseline, of whom six achieved CR and had undetectable MRD after treatment. Median progression-free survival (PFS) or overall survival (OS) was not reached. The incidence rates of PFS and OS were 84.6% (95%CI, 51.2%-95.9%) respectively at 12 months, and 69.2% (95%CI 37.3%-87.2%) and 76.9% (95%CI-44.2%-91.9%) respectively at 36 months.

To date, there are limited data on long-term outcomes for patients with [relapsed/refractory] MCL. In a non-Japanese phase 2 study, the combination of venetoclax and ibrutinib showed durable responses and treatment-free remissions, with an estimated 7-year progression-free survival rate of 30% and overall survival of 43%, with acceptable toxicity. Considering these results and 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] MC.

In this open-label, single-arm, Phase 2 study, patients were assigned to receive 560 mg of ibrutinib orally and 400 mg of venetoclax orally once daily for up to 24 months, followed by ibrutinib alone until disease progression, unacceptable toxicity, or withdrawal of consent. The patient received 20 mg of venetoclax in ascending doses, followed by 50 mg, 100 mg, 200 mg, and 400 mg in increasing doses every 4 weeks.

The primary endpoint of the trial is CR rate as assessed by an independent review committee. Secondary endpoints included rate of undetectable MRD in patients with ORR, DOR, CR, PFS, OS and safety.

Based on local testing,Patients 20 years and older with pathologically confirmed MCL; at least 1 measurable site of disease; 1 to 5 prior regimens for MCL, including 1 prior rituximab (Rituxan) or anti-CD20 therapy; and patients who lacked a partial response or a better response after their most recent treatment were eligible for the trial. Those patients who had previously received ibrutinib or other Bruton's tyrosine kinase inhibitors were not eligible to participate in the study.

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

Limitations of this study include a small sample size and a single-arm design, without a control group to compare long-term outcomes among JapaneseMCL patients. Additionally, biomarker testing including TP53 and BTK mutation status was not performed; nevertheless, the results of this analysis strengthen the evidence supporting the continued evaluation of ibrutinib plus venetoclax in patients with [relapsed/refractory] MCL (where new effective treatment strategies are still needed to improve long-term outcomes).

References:https://www.cancernetwork.com/view/ibrutinib-venetoclax-yields-long-term-efficacy-in-japanese-r-r-mcl-trial