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EHA 2024: Brukinsa/Venclexta for CLL/SLL lacks control arm in SEQUOIA trial

At the 2024 Congress of the European Hematology Association (EHA 2024) on 14 June, preliminary results from the SEQUOIA Phase III clinical trial (Arm D) were presented. This trial evaluated the efficacy of AbbVie/Roche’s Venclexta (venetoclax) and BeiGene’s Brukinsa (zanubrutinib) as first-line therapy in treating patients with small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) that had TP53 mutations or del(17p) mutations.

CLL and SLL are among the most common haematological malignancies in adults. According to the GlobalData epidemiology report, the number of diagnosed prevalent cases of CLL/SLL in the seven major markets (7MM: France, Germany, Italy, Japan, Spain, the UK and the US) will reach 462,168 by 2030. Although several targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and B cell lymphoma 2 (BCL-2) inhibitors, either alone or in combination, are now standard-of-care for treatment-naive CLL/SLL patients with del(17p) and/or TP53 mutation, there is still a need for treatments that provide durable responses and extend overall survival compared to existing therapies.

The median follow-up for the SEQUOIA trial was 28.6 months, and 66 patients with del(17p) and/or TP53 mutation were enrolled. The trial achieved an overall response rate of 100%, with a complete response plus a notable incomplete haematologic recovery rate of 45%. In addition, 48% of patients achieved undetectable minimal residual disease in ≥1 peripheral blood sample. The median progression-free survival (PFS) was not achieved, and the estimated 36-month PFS reached 92%. Adverse events (AEs) were common, with 97% of patients experiencing at least one treatment-emergent AE. Most importantly, the risk of tumour lysis syndrome was substantially reduced, with high-risk patients decreasing from 35% at screening to 3% after three cycles of Brukinsa administration with no TLS cases or new safety signals reported.

The ALPINE study previously showed the superior PFS of Brukinsa in comparison to AbbVie’s Imbruvica (Ibrutinib), with a hazard ratio of 0.65. Additionally, the prevalence of cardiovascular and severe AEs was lower in Brukinsa than in Imbruvica.

Despite these promising results, there are significant limitations in the SEQUOIA trial results. The non-randomised design of the trial and the absence of a control arm limits the ability to compare the Brukinsa + Venclexta combination to other treatment options for this patient population. The absence of a Venclexta monotherapy arm in Arm D is another critical omission. This arm would have enabled a more thorough evaluation of the efficacy of the combination compared to Venclexta alone.

According to GlobalData’s analyst consensus forecast, Brukinsa’s global sales will reach more than $4.7 billion, whereas potential rival AstraZeneca‘s Calquence (acalabrutinib) has projected global total sales of around $4.1 billion by 2030. However, in the absence of head-to-head tests, it remains difficult to directly compare Brukinsa and Calquence. Furthermore, Eli Lilly’s Jaypirca (pirtobrutinib), a highly selective BTK inhibitor, is undergoing a Phase III clinical trial (BRUIN CLL-313) for treatment-naïve CLL/SLL patients, and if the trial results show higher efficacy and lower toxicity, Brukinsa will face intense competition to maintain its current market share.

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