Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin’s lymphoma, with around 3,600 newly diagnosed cases in the US every year. AbbVie’s Imbruvica (ibrutinib) is a Bruton’s tyrosine kinase inhibitor (BTKi) approved for MCL patients who have received at least one prior therapy. While Imbruvica improved patient outcomes, primary and acquired resistance to BTKi presents a significant problem. AbbVie’s Venclexta (venetoclax), a BCL-2 inhibitor, is not currently approved for MCL. The combination of these two drugs, which have distinct and complementary modes of action, has the potential to improve clinical response in the underserved relapsed/refractory (R/R) MCL population.
At the 65th American Society of Hematology (ASH) Annual Meeting from 9 December to 12 December 2023, new data was presented from the multinational, randomised, double-blind, Phase III SYMPATICO study (NCT03112174). The study enrolled adult patients with a median age of 68 years suffering from R/R MCL, who had received between one and five prior therapies, had an Eastern Co-operative Oncology Group (ECOG) performance status of two or less, and had received at least one prior anti-CD20 regimen or rituximab.
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Patients were randomised to receive Imbruvica (560mg once daily), combined with Venclexta (n=134) or placebo (n=133) for two years, followed by single-agent Imbruvica (560mg once daily) until progressive disease (PD) or unacceptable toxicity. Venclexta was given in a five-week ramp-up schedule to 400mg once daily. Patients were stratified based on their ECOG performance status, prior lines of therapy, and tumour lysis syndrome (TLS) risk.
At a median follow-up of 51.2 months, median progression-free survival (PFS) was significantly longer with the Venclexta group versus single-agent Imbruvica (31.9 versus 22.1 months). The median overall survival was 44.9 with the Venclexta group versus 38.6 months with single-agent Imbruvica. At the time of the analysis, 30% of patients in the Venclexta arm and 20% of patients in the Imbruvica arm remained on single agent Imbruvica. The Imbruvica + Venclexta combination significantly improved complete response rates (54% in the combination arm versus 32% on single-agent Imbruvica) and time to next treatment (median not reached [NR] in the combination arm versus 35.4 months on single-agent Imbruvica). Adverse effects (AE) occurred in 84% of the Venclexta arm versus 76% in the single-agent Imbruvica arm, and grade 3 or higher AEs occurred in 60% of patients in both arms. TLS occurred in seven patients in the Venclexta arm and three patients in the single-agent Imbruvica arm. The safety profile of the combination was consistent with known AEs for each agent, with no new safety signals observed. Overall, these results demonstrate a favourable benefit-risk profile for the Imbruvica + Venclexta combination, providing better outcomes for the patients in the R/R MCL setting.
In terms of commercial impact, if approved, the combination would make a modest contribution to AbbVie’s footprint in NHL, given the low number of MCL patients. However, it would make up for falling Imbruvica sales due to the upcoming patent expiration in 2026 in the US and in 2029 in the five major European markets (5EU: France, Germany, Italy, Spain and the UK) and the anticipated market entrance of generics. GlobalData estimates the combined sales for Venclexta and Imbruvica in MCL in the US and 5EU to be at $116.2 million in 2023 ($6.2 million and $110 million respectively) and $138.7 million by 2027 ($29.5 million and $109.2 million respectively).
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