Eli Lilly’s Jaypirca outpaces Imbruvica in landmark CLL head‑to‑head trial

Eli Lilly and Company (NYSE: LLY) has announced pivotal results from its head-to-head Phase 3 trial comparing Jaypirca (pirtobrutinib), a next-generation non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). The BRUIN CLL-314 study met its primary endpoint of non-inferiority for overall response rate (ORR) and showed a numerically higher ORR for Jaypirca at 87 percent versus 78.5 percent for Imbruvica in the intent-to-treat (ITT) population.

The Phase 3 trial, considered the first of its kind comparing a covalent and non-covalent BTK inhibitor, marks a significant milestone in CLL therapy. Eli Lilly and Company disclosed that while progression-free survival (PFS) data remain immature, early trends strongly favor Jaypirca. Among treatment-naïve patients — the subgroup with the longest follow-up — the study showed a 76 percent reduction in the risk of disease progression or death.

These findings were simultaneously published in the Journal of Clinical Oncology and are being presented during the Late-Breaking Abstract Session at the 2025 American Society of Hematology (ASH) Annual Meeting in Orlando, Florida.

What makes the BRUIN CLL-314 study a landmark in CLL drug comparisons?

The BRUIN CLL-314 trial enrolled 662 patients across both treatment-naïve and relapsed/refractory categories, all of whom were BTK inhibitor-naïve. Participants were randomized 1:1 to receive either Jaypirca (n=331) or Imbruvica (n=331). The study’s primary endpoint was ORR as assessed by an independent review committee.

Jaypirca demonstrated a statistically significant advantage in ORR, achieving 87.0 percent (95% CI, 82.90–90.44) compared to 78.5 percent (95% CI, 73.73–82.85) for Imbruvica. The nominal p-value of 0.0035 supports the superiority of Jaypirca in terms of tumor response. This efficacy benefit was consistent across key pre-specified subgroups, including those with 17p deletion, unmutated IGHV status, and complex karyotypes.

While overall survival data are not yet mature, there was no detriment observed in the ITT population. The hazard ratio for OS was 0.961 (95% CI, 0.55–1.69), suggesting early parity on survival outcomes while PFS continues to evolve.

How does Jaypirca compare to Imbruvica in early progression-free survival analysis?

Although the PFS endpoint has not reached full maturity, the data cutoff as of June 10, 2025, offers strong directional signals. Jaypirca showed a hazard ratio of 0.569 (95% CI, 0.388–0.834) for disease progression or death across the ITT population.

In treatment-naïve patients — a cohort often considered the benchmark for long-term control — Jaypirca posted a hazard ratio of 0.239 (95% CI, 0.098–0.586), translating into a 76 percent relative risk reduction. Median follow-up durations were 22.0 months for ITT, 18.4 months for relapsed/refractory, and 22.5 months for treatment-naïve groups.

This suggests that Jaypirca could potentially not only match but exceed Imbruvica’s performance in delaying disease progression, a key goal in CLL treatment. A formal superiority analysis for PFS is planned in future readouts, which could provide further clarity on long-term disease control.

What does the safety profile reveal about Jaypirca’s real-world potential?

Jaypirca’s tolerability profile, a major consideration in BTK inhibitor therapy, remains consistent with previous studies and continues to show advantages over covalent BTK inhibitors.

Treatment-emergent adverse events were generally lower or comparable in frequency between the two arms. Specifically, Jaypirca was associated with fewer instances of atrial fibrillation or flutter (2.4 percent versus 13.5 percent for Imbruvica) and less hypertension (10.6 percent versus 15.1 percent).

In terms of treatment modification due to adverse events, dose reductions occurred less frequently in the Jaypirca arm (7.9 percent versus 18.2 percent), and discontinuations due to toxicity were also slightly lower (9.4 percent versus 10.8 percent).

This safety differentiation, combined with comparable or superior efficacy, strengthens the case for Jaypirca in both frontline and relapsed/refractory settings.

How does Jaypirca’s mechanism offer an edge over existing BTK therapies?

Jaypirca (pirtobrutinib) is a highly selective, non-covalent BTK inhibitor that reversibly binds to BTK with over 300-fold selectivity compared to 98 percent of other kinases tested in preclinical assays. Unlike covalent inhibitors such as Imbruvica, which form irreversible bonds, Jaypirca’s reversible binding potentially allows it to retain activity in patients with resistance mutations affecting covalent binding sites.

Its molecular design was initially validated in mantle cell lymphoma (MCL), and its regulatory trajectory has accelerated since its FDA approval for relapsed or refractory CLL/SLL in patients previously treated with a covalent BTK inhibitor.

Eli Lilly and Company continues to expand the BRUIN program to assess Jaypirca’s full potential across multiple treatment settings, including earlier lines of therapy and patients with high-risk cytogenetics.

What other late-stage data on Jaypirca are being presented at ASH 2025?

In addition to BRUIN CLL-314, Eli Lilly and Company is presenting results from BRUIN CLL-313, a Phase 3 study comparing Jaypirca with chemoimmunotherapy in treatment-naïve CLL/SLL patients without 17p deletion. These data are being showcased during the ASH 2025 press program and are expected to provide further insight into Jaypirca’s frontline competitiveness.

As the BRUIN development program evolves, Jaypirca is being positioned as a platform BTK inhibitor with utility across various B-cell malignancies. This includes studies on time to next treatment (TTNT), duration of response, patient-reported outcomes, and longer-term survival markers — all of which are critical in treatment decision-making.

What does this mean for Eli Lilly and Company’s oncology strategy?

Eli Lilly and Company’s oncology unit, led by Jacob Van Naarden, is leveraging the momentum from the Jaypirca data to deepen its hematology portfolio. In 2024, the company secured full FDA approval for Jaypirca in post-covalent BTK settings, and the latest Phase 3 success strengthens its positioning in broader patient populations.

With several blockbuster oncology assets already in the portfolio, including Verzenio and Retevmo, Eli Lilly and Company appears poised to make Jaypirca a cornerstone asset in its hematologic strategy. The consistent investment in head-to-head trials signals the drugmaker’s willingness to challenge entrenched standards and redefine treatment algorithms.

What is the market outlook and investor sentiment around Jaypirca?

Jaypirca’s success in BRUIN CLL-314 comes amid rising investor focus on differentiated oncology pipelines. Analysts tracking Eli Lilly and Company have pointed to Jaypirca’s potential to capture meaningful market share in the CLL/SLL space, particularly if PFS and OS data hold up in subsequent readouts.

In the immediate term, the stock has remained resilient, supported by a robust late-stage pipeline and expanding oncology revenue base. The BRUIN data has been flagged by several institutional investors as a positive catalyst for long-term franchise value.

As competition in the BTK space intensifies — with next-generation candidates from other biotech firms in development — Eli Lilly and Company’s first-mover advantage in head-to-head trials could yield strategic leverage in payer discussions and formulary access.

What is the future of non-covalent BTK inhibition in leukemia and lymphoma care?

The BRUIN CLL-314 trial may reshape the narrative in BTK inhibition, a space long dominated by covalent inhibitors. As more patients experience resistance or intolerance to first-generation agents, demand for flexible, safer, and more potent alternatives will rise.

If Jaypirca ultimately demonstrates superiority in future analyses, it could replace Imbruvica as a frontline therapy in many CLL/SLL treatment pathways. That would have broad implications for clinical guidelines, reimbursement policy, and oncology prescribing behavior.

Further validation in Phase 3 trials and real-world studies will be critical in cementing Jaypirca’s role, but for now, Eli Lilly and Company appears well-positioned to lead the next era of targeted therapy for B-cell malignancies.

What are the key takeaways from Eli Lilly’s Jaypirca versus Imbruvica Phase 3 trial?

• Jaypirca (pirtobrutinib) achieved a higher overall response rate (ORR) of 87.0 percent compared to 78.5 percent for Imbruvica in the Phase 3 BRUIN CLL-314 study.

• The trial met its primary endpoint of non-inferiority and demonstrated a nominal p-value of 0.0035 in favor of Jaypirca.

• In treatment-naïve patients, Jaypirca showed a 76 percent reduction in the risk of disease progression or death, the largest effect size across all subgroups.

• Progression-free survival (PFS) data are not yet mature but trended positively across ITT, treatment-naïve, and relapsed/refractory populations.

• The overall safety profile of Jaypirca was favorable, with lower rates of atrial fibrillation (2.4% vs. 13.5%) and hypertension (10.6% vs. 15.1%) compared to Imbruvica.

• Fewer patients discontinued or reduced Jaypirca dosing due to adverse events compared to those on Imbruvica.

• The BRUIN CLL-314 results were published in the Journal of Clinical Oncology and presented at ASH 2025, establishing the trial as the first randomized comparison between covalent and non-covalent BTK inhibitors in CLL/SLL.

• Eli Lilly and Company is also sharing data from the Phase 3 BRUIN CLL-313 trial comparing Jaypirca with chemoimmunotherapy in treatment-naïve patients without 17p deletion.

• Analysts believe Jaypirca’s differentiated profile positions it for frontline use and broader adoption across CLL/SLL treatment settings.

• Investor sentiment toward Eli Lilly and Company remains positive, with Jaypirca viewed as a potential blockbuster in hematologic oncology.