Breakthrough Clinical Results
Eli Lilly and Company announced positive topline results from the Phase 3 BRUIN CLL-314 clinical trial of Jaypirca (pirtobrutinib), a non-covalent BTK inhibitor, compared to Imbruvica (ibrutinib) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). The trial met its primary endpoint of non-inferiority on overall response rate (ORR) in both pre-treated and intent-to-treat populations, with ORR favoring pirtobrutinib. Progression-free survival (PFS) data was immature but trending favorably for pirtobrutinib. BRUIN CLL-314 is the first head-to-head Phase 3 study versus a covalent BTK inhibitor to include treatment-naïve patients, a subpopulation showing a particularly strong PFS benefit for pirtobrutinib. Detailed results will be presented at a future medical congress. This builds on positive results from previous BRUIN trials and will support global regulatory submissions.
Key Highlights
- Jaypirca (pirtobrutinib) met the primary endpoint of non-inferiority in overall response rate (ORR) compared to ibrutinib in a Phase 3 trial.
- ORR favored pirtobrutinib with a nominal P-value for superiority (p<0.05).
- Progression-free survival (PFS) data was immature but trending in favor of pirtobrutinib.
- The trial included treatment-naïve patients, a key subpopulation showing a pronounced PFS effect size favoring pirtobrutinib.
Drug used in other indications
Pirtobrutinib Clinical Trials Beyond CLL
Based on a thorough review of the available information, there is insufficient data to determine which indications beyond Chronic lymphocytic leukemia (CLL) pirtobrutinib is being trialed for.
The only relevant information found indicates that pirtobrutinib is considered one of the next-generation BTK inhibitors that have been developed to address issues with earlier inhibitors, offering "improved specificity and reduced toxicity profiles." It is mentioned alongside other BTK inhibitors including acalabrutinib, orelabrutinib, and zanubrutinib.
However, no specific details are available regarding: - Non-CLL indications for pirtobrutinib trials - Intervention models for these trials - Study designs being utilized - Treatment protocols in clinical settings - Combination therapies with other agents - Monotherapy approaches - Dosing regimens for different patient populations
While BTK inhibitors as a class have shown promise in various hematological malignancies, the specific indications being explored for pirtobrutinib beyond CLL cannot be determined from the available information.
For patients and clinicians interested in pirtobrutinib trials for non-CLL indications, consulting clinical trial registries such as ClinicalTrials.gov or contacting the drug developer would be necessary to obtain current and accurate information about ongoing studies.
Incidence and Prevalence
Global Estimates of Chronic Lymphocytic Leukemia Incidence and Prevalence
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the United States and western countries. The disease is more common in developed world than in developing countries and typically occurs in elderly patients with a highly variable clinical course.
Regional Incidence Patterns
In Taiwan, according to data published in 2021, the age-standardized incidence rates of CLL/small lymphocytic lymphoma (SLL) increased from 0.36 per 100,000 persons in 2006 to 0.54 per 100,000 persons in 2015. The incidence of CLL/SLL appears to be increasing over time based on this data.
In the United States, based on Surveillance, Epidemiology and End Results (SEER) data from 13 registries (published in 2012), 30,622 cases of CLL/SLL were recorded from 1992 to 2007. CLL is the most prevalent leukemia in the United States with almost 4390 attributable deaths per year.
The incidence of CLL is lower among African Americans than among Caucasians (4.6 and 6.2 per 100,000 men, respectively). However, African American patients are almost twice as likely to die from a CLL-related complication in the first 5 years after diagnosis compared to Caucasian patients.
Demographic Patterns
A consistent finding across regions is male predominance. In Taiwan, the sex ratio ranged from 1.21 to 2.63 with male predominance during 2006 and 2015. In the United States, males had higher incidence than females with a male-to-female incidence rate ratio of 1.89 (95% confidence interval 1.85-1.94).
Age at diagnosis varies by region and ethnicity. In the US, black patients were diagnosed at a younger age compared to white patients (mean age at diagnosis 70 versus 67 years, P < .001). In Pakistan (published in 2015), CLL is seen in a relatively young population with a mean age of 59.0±9.2 years (range 40-82) and a male to female ratio of 2.1:1. The peak age group in Pakistan was 60-70 years (38.3%) with 18.3% under 50 years old.
Geographic Variations
CLL is less frequent in the Orient, Asia and Middle Eastern Arabic speaking countries compared to Western nations. There are few studies regarding CLL epidemiology and treatment patterns in Asian countries.
In Senegal, patients may present with CLL at a younger age (mean age 61 years, range 48-85), with 82.5% classified as having advanced Binet stages B or C at diagnosis, suggesting CLL in Senegal may be more aggressive than in Western populations.
Geographic variations in CLL incidence persist in migrants to other countries, continuing into subsequent generations. The absence of an association between place of birth and the occurrence of CLL suggests a genetic basis for geographic variations in incidence, supported by documented familial aggregation with an increased frequency of 8.5-fold among first-degree relatives of patients with CLL.
While comprehensive global prevalence figures are limited, the 5-year overall survival (OS) rate was reported as 61% in the Taiwan study.
Study Design Parameters
Study Design Parameters and Endpoints in Key CLL Trials
Patient Stratification and Risk Assessment
Risk stratification in CLL trials has evolved with advances in understanding disease biology. Key prognostic factors include Immunoglobulin V(H) gene mutation status, CD38 expression, ZAP-70 expression, clinical staging, cytogenetic status, and lymphocyte doubling time. The IGHV3-23 gene usage is associated with shorter time-to-treatment even in mutated CLL. Modern trials stratify patients according to these prognostic markers to determine optimal treatment approaches.
Trial Design Evolution
Multicenter prospective trials now commonly stratify patients according to prognostic risk. Recent trial designs investigate whether early and aggressive treatment improves survival in poor-prognosis patients. The goal is developing targeted treatment algorithms based on clinical and biological characteristics. Trials for high-risk CLL patients (characterized by Ig V(H) unmutated or high-risk interphase cytogenetics including del(17p) or del(11q)) evaluate more aggressive therapies, including hematopoietic cell transplantation.
Treatment Approaches in Trials
Key trials have established chemoimmunotherapy (combination of chemotherapy with anti-CD20 antibodies) as standard first-line treatment. For younger patients without comorbidities, trials have shown that fludarabine, cyclophosphamide, and rituximab prolongs survival. For patients with comorbidities, studies evaluate chlorambucil and obinutuzumab. Recent trials focus on targeted therapies including BTK inhibitors (ibrutinib, acalabrutinib), Idelalisib, and Venetoclax (Bcl2 inhibitor).
Novel Therapeutic Approaches
Emerging trials investigate novel agents such as Zilovertamab vedotin (ZV), an antibody-drug conjugate targeting ROR1. A Phase 1 first-in-human dose-escalation study enrolled patients who had received a median of four previous therapies, testing dose levels from 0.5 to 2.5 mg/kg every 3 weeks. Other innovative approaches include Chimeric antigen receptor therapy (CAR) based on autologous T-lymphocytes.
Endpoints in CLL Trials
Key endpoints in CLL trials include: - Response rates including molecular remissions - Time-to-treatment - Progression-free survival (PFS) - Overall survival (OS) - Treatment-related toxicities
The CALGB 9712 study demonstrated that PFS and OS were significantly shorter among Ig V(H) unmutated patients compared to Ig V(H) mutated patients. Using the hierarchical classification of Döhner, both PFS and OS were significantly longer as the classification moved from high risk to low risk.
Current chemoimmunotherapy can achieve progression-free survival of more than eight years in certain genetically defined subgroups, giving hope that CLL may soon be a controllable disease. The evolution of trial design in CLL reflects the growing understanding of disease heterogeneity and the need for personalized treatment approaches based on biological and clinical risk factors.