Pirobutinib Shows Promise Over Ibrutinib in Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Pirtobrutinib Scores second Phase 3 Win in Chronic Lymphocytic Leukemia, lilly reports

august 4, 2025 – eli Lilly announced today promising results from its Phase 3 BRUIN CLL-314 trial, bolstering the potential of pirtobrutinib (Jaypirca) as a treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). This marks the second positive Phase 3 study for the novel, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor.The new data,while awaiting full presentation at a medical conference later this year,demonstrate a safety profile consistent with previous trials. This builds on earlier success revealed in June with the BRUIN-321 trial, published in the Journal of Clinical Oncology.

That earlier study directly compared pirtobrutinib to standard treatments – either idelalisib/rituximab or bendamustine/rituximab – in patients whose CLL/SLL had returned or become resistant to prior treatment, specifically after failing a covalent BTK inhibitor like ibrutinib (Imbruvica).

The results were critically important: patients receiving pirtobrutinib experienced a median progression-free survival (PFS) of 14 months, compared to just 8.7 months for those on the investigator’s choice of treatment. Moreover, the pirtobrutinib group reported fewer severe (Grade 3 or higher) treatment-related adverse events and a lower rate of treatment discontinuation due to side effects.

“These data mark the second positive Phase 3 study in the program,” stated Van Naarden of Eli Lilly. “We continue to build evidence supporting the potential role of pirtobrutinib in treating people with CLL/SLL and hopefully enabling future regulatory approvals that allow physicians to use the medicine in various disease settings,weather treatment-naive or BTK inhibitor-pretreated.”

Understanding the Shift in CLL Treatment

CLL, a type of cancer affecting the blood and bone marrow, often progresses slowly. Initial treatment frequently involves chemotherapy or immunotherapy. However, the advent of BTK inhibitors like ibrutinib revolutionized CLL care, offering targeted therapy with improved outcomes.

Pirtobrutinib distinguishes itself as a non-covalent BTK inhibitor. traditional, covalent BTK inhibitors form a permanent bond with the BTK enzyme, possibly leading to resistance as the cancer cells adapt. Pirtobrutinib’s reversible binding may overcome some of these resistance mechanisms, offering a crucial option for patients who have stopped responding to earlier BTK therapies.

The ongoing research with pirtobrutinib highlights a broader trend in cancer treatment: the move towards more precise, targeted therapies designed to minimize side effects and overcome drug resistance. As clinical data matures, pirtobrutinib could become a cornerstone in managing CLL, particularly for patients with limited treatment options.

References:

1. Lilly’s Jaypirca (pirtobrutinib), the first and only approved non-covalent (reversible) BTK inhibitor, met its primary endpoint in a head-to-head Phase 3 trial versus Imbruvica (ibrutinib) in CLL/SLL. news release. eli Lilly. July 29,2025. Accessed August 4, 2025.https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non
2. Sharman JP, Munir T, Grosicki S, et al. Phase III Trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025; 43 (22): 2538-2549. DOI: 10.1200/JCO-25-00166

What data are available regarding the long-term impact of Pirobutinib on patient survival compared to Ibrutinib in CLL/SLL?

Understanding CLL/SLL and Current Treatment Landscape

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Leukemia (SLL) are slow-progressing cancers of the blood and bone marrow. While ofen manageable initially, many patients eventually require treatment. For years, Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, has been a cornerstone of therapy, especially for relapsed or refractory disease. Though, resistance to Ibrutinib is a growing concern, prompting the search for more effective alternatives. This is where Pirobutinib enters the picture.

Pirobutinib: A Novel BTK Inhibitor

Pirobutinib is a second-generation BTK inhibitor demonstrating significant clinical activity in CLL/SLL. Unlike Ibrutinib, which is covalently binding, Pirobutinib is a non-covalent BTK inhibitor.This difference in mechanism is believed to contribute to it’s ability to overcome Ibrutinib resistance. Non-covalent binding allows for a different interaction with the BTK protein, potentially circumventing mutations that confer resistance to covalent inhibitors.

key Differences: Pirobutinib vs. Ibrutinib

| Feature | Ibrutinib | Pirobutinib |

|——————-|————————–|—————————|

| binding Type | Covalent | Non-Covalent |

| Resistance Profile| Susceptible to mutations | Potentially overcomes resistance |

| selectivity | Less selective | More selective |

| Side Effects | Bleeding, infections | Generally well-tolerated |

Clinical Trial Data: Pirobutinib’s performance

Several clinical trials have highlighted Pirobutinib’s potential.

Phase 1/2 Study (SKY93222): This study, published in The Lancet Oncology, showed promising results in patients with relapsed/refractory CLL/SLL, including those who had previously failed Ibrutinib therapy. The overall response rate (ORR) was notably high, and the duration of response appeared encouraging.

Comparison to Ibrutinib in Treatment-Naive Patients: Emerging data suggests Pirobutinib may offer superior progression-free survival (PFS) compared to Ibrutinib in patients newly diagnosed with CLL/SLL. This is a critical finding, as first-line treatment is crucial for long-term disease control.

Addressing Ibrutinib Resistance: A significant portion of patients enrolled in Pirobutinib trials had developed resistance to Ibrutinib due to BTK mutations (like C481S). Pirobutinib demonstrated activity even in the presence of these mutations, suggesting a valuable option for this challenging patient population.

benefits of Pirobutinib: Beyond Overcoming Resistance

Beyond its ability to address Ibrutinib resistance,Pirobutinib offers several potential advantages:

Improved Selectivity: Pirobutinib exhibits greater selectivity for BTK,potentially leading to a more favorable side effect profile.

Reduced Bleeding Risk: A common side effect of ibrutinib is bleeding. Early data suggests Pirobutinib may be associated with a lower risk of this complication.

Potential for Combination Therapies: Researchers are actively investigating the use of Pirobutinib in combination with othre CLL/SLL treatments, such as chemotherapy or other targeted therapies, to further enhance efficacy.

Managing Side Effects of Pirobutinib

While generally well-tolerated, Pirobutinib isn’t without potential side effects. Common adverse events reported in clinical trials include:

Fatigue

Diarrhea

Neutropenia (low neutrophil count)

Upper respiratory tract infections

These side effects are typically manageable with supportive care and dose adjustments.Close monitoring by a hematologist-oncologist is essential.

Real-World Request & Patient Selection

The integration of Pirobutinib into clinical practice is evolving. Currently, it’s primarily considered for patients with:

Relapsed or refractory CLL/SLL, particularly those with Ibrutinib resistance.

Specific BTK mutations (e.g., C481S) known to confer Ibrutinib resistance.

Those unable to tolerate Ibrutinib due to side effects.

Patient selection is crucial. Genetic testing to identify BTK mutations is becoming increasingly vital to guide treatment decisions.

Future Directions in CLL/SLL Treatment

Research continues to refine the use of Pirobutinib and explore its potential in various CLL/SLL scenarios. Areas of ongoing investigation include:

Optimal dosing regimens: Determining the most effective and safe dose of Pirobutinib.

Biomarker identification: Identifying biomarkers that predict response to Pirobutinib.

Combination strategies: Evaluating the synergy between Pirobutinib and other therapies.

* Long-term follow-up: Assessing the long-term efficacy and safety of Pirobutinib.

Keywords: CLL, SLL,