At the American Society of Hematology (ASH) Annual Meeting, held on 6-9 December updated results from the global, multi-centre, open-label, Phase III BRUIN CLL-313 clinical trial were presented. This trial evaluated the safety and efficacy of Eli Lilly’s Jaypirca (pirtobrutinib), a highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, in patients with chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL).
In BRUIN CLL-313, 282 patients with CLL/SLL without 17p deletion were randomised 1:1 to receive Jaypirca monotherapy (n=141) or the chemoimmunotherapy combination of Biogen’s Rituxan (rituximab) + bendamustine (n=141) as first-line therapy. Jaypirca reduced the risk of disease progression or death by approximately 80% assessed by the independent review committee, compared to standard chemoimmunotherapy Rituxan + bendamustine (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.107–0.367; p<0.0001) at a median follow-up of 28.1 months. At 24 months, the progression-free survival rate was 93.4% (95% CI 87.6–96.5) with Jaypirca versus 70.7% (95% CI 61.5–78.1) with Rituxan + bendamustine, and this benefit was consistent across all sub-groups and in patients with or without immunoglobin heavy chain variable (IGHV) mutations.
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Despite a high crossover rate of 52.9% (18/34 patients with investigator-assessed progressive disease), the overall survival (OS) hazard ratio for Jaypirca versus Rituxan + bendamustine was 0.26 (95% CI 0.070–0.934; p=0.0261), although the OS data has yet to mature. The median treatment duration was 32.3 months for the 140 patients treated with Jaypirca and 5.6 months for the 132 patients treated with Rituxan + bendamustine. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 40.0% of patients treated with Jaypirca and 67.4% of those receiving Rituxan + bendamustine. Treatment discontinuation due to TEAEs occurred in 4.3% of patients on Jaypirca and 15.2% of patients on Rituxan + bendamustine.
Jaypirca was previously approved as a third-line or later therapy for patients who had not benefited from prior treatment with BTK and B-cell lymphoma 2 (BCL2) inhibitors. Eli Lilly also presented positive Phase III results from the BRUIN CLL-314 trial at this meeting, the first head-to-head Phase III study to compare the covalent BTK inhibitor AbbVie and Johnson & Johnson’s Imbruvica (ibrutinib) with Jaypirca in treatment-naïve patients with CLL/SLL. These results suggest Jaypirca has strong first-line potential in CLL/SLL, with an impressive hazard ratio versus other BTK inhibitor results; however, a fixed-duration regimen, clear post-Jaypirca sequencing strategies if the cancer returns, and practical guidance on managing infections given Jaypirca interactions with common antibiotics and antifungals will be critical for broad adoption.
If approved, Jaypirca, a new standard-of-care treatment, would enter a crowded first-line CLL/SLL space dominated by covalent BTK inhibitors such as AstraZeneca’s Calquence (acalabrutinib), Imbruvica, and BeOne Medicines’ Brukinsa (zanubrutinib). Pricing will also shape Jaypirca’s first-line uptake, particularly in the US, where the Inflation Reduction Act enables the US Centers for Medicare and Medicaid Services to negotiate reduced Medicare prices for high-spend oral oncology drugs such as Imbruvica, increasing pressure on Eli Lilly to justify any premium with clear clinical and sequencing advantages over covalent BTK inhibitors. According to GlobalData’s patient-based forecast, in the Chronic Lymphocytic Leukemia: Opportunity Assessment and Forecast – Update report, Jaypirca sales are projected to increase from $401m in 2025 to $1.3bn in 2032 across seven major markets. Over the same period, Calquence sales are expected to decline from $3.1bn to $1.3bn and Imbruvica sales from $3.2bn to $79m, reflecting the patent cliff for both drugs and the growing uptake of Jaypirca, which binds to BTK non-covalently and can be used after prior exposure to other BTK inhibitor classes.
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