Breaking Ground: Ibrutinib and Venetoclax Synergy Delivers Significant Progression-Free Survival Boost in Relapsed/Refractory Mantle Cell Lymphoma

Ibrutinib, an oral BTK inhibitor, holds approval in numerous countries for the treatment of R/R MCL. Similarly, venetoclax, an oral BCL2 inhibitor, has gained approval in multiple countries for managing chronic lymphocytic leukemia and untreated acute myeloid leukemia. The SYMPATICO study, a multinational, double-blind trial, recruited patients with relapsed/refractory MCL who had undergone 1 to 5 prior therapies for the condition. The findings presented at the ASH 2023 conference demonstrated that, the median assessed PFS was 31.9 months in the ibrutinib plus venetoclax arm, compared with 22.1 months in the ibrutinib plus placebo arm. Moreover, the overall response rate (ORR) in the combination arm was 82%, with a 54% CR rate, vs. 74%, with a 32% CR rate, in the placebo arm. Additionally, the median duration of response (DOR) was 42.1 months vs. 27.6 months, respectively. Further insights from the study unveiled a numerical enhancement in overall survival (OS) within the combination arm compared to the placebo arm during this interim analysis. Specifically, the median OS extended to 44.9 months in the combination group, surpassing the corresponding of 38.6 months observed in the placebo group. These findings suggest a potential positive impact on overall survival with the implemented combination approach.

Regarding safety, a majority of patients in both the combination (n = 134) and placebo (n = 132) arms encountered grade 3 or higher adverse effects (AEs), with 84% and 76%, respectively. The incidence of serious AEs was comparable between the two groups, with both the combination and placebo arms reporting 60%. Noteworthy grade 3 or higher AEs in the experimental arm, in contrast to the placebo arm, included neutropenia (31% vs. 11%), pneumonia (13% vs. 11%), thrombocytopenia (13% vs 8%), anemia (10% vs 3%), diarrhea (8% vs. 2%), leukopenia (7% vs. 0%), and worsening of MCL without disease progression(7% vs. 12%).

KOL Insights

“While Imbruvica solo stumbled in MCL, the medicine could still have a future as a combination regimen. In my personal opinion, this combination in the countries where ibrutinib is indicated should be a new standard therapy for relapsed/refractory mantle cell lymphoma.”–Expert Opinion.

Conclusion

In summary, the combination of ibrutinib and venetoclax demonstrated a statistically significant enhancement in progression-free survival when compared to the use of ibrutinib with a placebo. Notably, this combination exhibited consistently robust advantages across various sensitivity analyses. The introduction of venetoclax alongside ibrutinib presents a favorable balance between benefits and risks in individuals grappling with R/R MCL. This conclusion underscores the potential of this therapeutic combination as a promising and well-tolerated strategy in the management of MCL.

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