Ibrutinib plus venetoclax represents ‘new standard therapy’ for advanced mantle cell lymphoma
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Key takeaways:
- Researchers observed significantly longer PFS with ibrutinib plus venetoclax vs. ibrutinib plus placebo.
- No new safety issues emerged from using the combination of venetoclax and ibrutinib.
Ibrutinib plus venetoclax demonstrated superior PFS and a higher complete response rate compared with ibrutinib plus placebo in patients with relapsed or refractory mantle cell lymphoma, according to study results.
Findings from the phase 3 SYMPATICO study — presented at ASH Annual Meeting and Exhibition — additionally showed that the safety profile of ibrutinib (Imbruvica; Janssen, Pharmacyclics) plus venetoclax (Venclexta; AbbVie, Genentech) remained consistent with already known adverse events of either agent alone, according to the researchers.
Background
“The combination of these two agents leverages complementary modes of action and has demonstrated synergistic antitumor activity in preclinical models of mantle cell lymphoma,” Michael Wang, MD, a professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center, said during a press briefing.
The multicenter placebo-controlled phase 3 study included 267 patients with relapsed or refractory mantle cell lymphoma randomly assigned to either 560 mg once-daily ibrutinib plus 5-week ramp up to 400 mg once-daily venetoclax for 2 years (n = 134) or 560 mg once-daily ibrutinib plus placebo for 2 years (n = 133).
“An open-label, safety run-in phase demonstrated that concurrent initiation of ibrutinib and venetoclax was safe and well-tolerated,” Wang said.
Investigator-assessed PFS served as the study’s primary endpoint. Secondary endpoints included complete response rate, time to next treatment, OS and overall response rate.
Findings
At a median follow-up of 51.2 months, results showed median PFS of 31.9 months with ibrutinib plus venetoclax compared with 22.1 months with ibrutinib plus placebo (HR = 0.65; 95% CI, 0.47-0.88).
Researchers additionally observed a 54% complete response rate with the combination vs. 32% with placebo, with a median duration of response of 42.1 months with the combination vs. 27.6 months with placebo.
Additional analysis showed median OS of 44.9 months with the combination compared with 38.6 months with placebo (HR = 0.85; 95% CI, 0.62-1.19).
“The safety profile of ibrutinib plus venetoclax was consistent with known adverse events for each single agent, with no new safety signals observed,” Wang said.
Implications
Overall, the addition of venetoclax to ibrutinib has a favorable risk-benefit profile in patients with relapsed or refractory mantle cell lymphoma, according to Wang.
“This combination should be a new standard therapy in countries where ibrutinib is indicated for this patient population,” he said.
Perspective
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Brian Hill, MD, PhD
Management of patients with relapsed or refractory mantle cell lymphoma has historically been challenging. Fortunately, over the past decade, outcomes have dramatically improved with the introduction of covalent and noncovalent oral BTK inhibitors, as well as CD19-directed CAR T-cell therapy. However, the median duration of disease control with BTK inhibitor monotherapy is limited and enhanced treatments are needed.
The oral BCL-2 inhibitor venetoclax has significant clinical activity in CLL as monotherapy or in combinations, but data on the efficacy in mantle cell lymphoma has been limited to single arm clinical trials and real-world data. Specifically, in patients with heavily pretreated mantle cell lymphoma, venetoclax monotherapy has relatively short median PFS. However, using venetoclax in combination with BTK inhibitors such as ibrutinib has been shown to be safe and highly active.
In the randomized SYMPATICO trial presented as a late-breaking abstract at ASH Annual Meeting, investigators compared the safety and efficacy of ibrutinib monotherapy, with placebo, vs. combination treatment with ibrutinib and venetoclax. Consistent with previous reports, the safety and tolerability of this combination was manageable, with no signal of significant excess toxicities beyond the contribution of each agent individually. In terms of efficacy, the complete response rate was significantly higher in combination treatment vs. ibrutinib monotherapy (54% vs. 32%), with significantly longer 24-month PFS (57% vs. 45%), respectively.
This study represents the first randomized trial to demonstrate a clinical advantage to the addition of venetoclax to BTK inhibitor treatment for patients with previously treated mantle cell lymphoma. Although there was no statistically significant survival advantage, there was a numeric trend in this direction which is likely to make venetoclax + BTK inhibitor-based combinations an attractive therapeutic option for this high-risk patient population.
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Wang M, et al. LBA-2. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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