Lilly reports Phase III BRUIN CLL-322 trial results for Jaypirca combo

Lilly's Jaypirca Combo Reduces Disease Progression Risk in r/r CLL/SLL

Eli Lilly and Company announced positive results from its Phase III BRUIN CLL-322 trial, evaluating Jaypirca (pirtobrutinib) combined with venetoclax and rituximab (PVR) against venetoclax and rituximab alone (VR) in 639 patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma (r/r CLL/SLL). The trial met its primary endpoint, demonstrating a 45% reduction in the risk of disease progression or death for the PVR group. At a median follow-up of 27.3 months, the median progression-free survival (PFS) was not reached for PVR, compared to 39.7 months for VR.

• The BRUIN CLL-322 trial successfully met its primary endpoint, showing a statistically significant improvement in progression-free survival (PFS) for the Jaypirca combination arm. Patients receiving pirtobrutinib plus venetoclax and rituximab experienced a 45% reduction in the risk of disease progression or death, with a median PFS not reached, compared to 39.7 months for the control group.
• The clinical benefit of the Jaypirca combination was consistently observed across various challenging patient subgroups. This included individuals with prior exposure to covalent BTK inhibitors (comprising 79.8% of the study population), as well as those with high-risk genetic features such as unmutated immunoglobulin heavy chain variable region, TP53 mutations, 17p deletions, or complex karyotype, highlighting its potential in a diverse r/r CLL/SLL population.
• The safety findings from the trial indicated similar rates of Grade ≥3 adverse events between the treatment and control groups, with comparable discontinuation rates due to adverse events. Specific Grade ≥3 clinical adverse events of interest included neutropenia and tumour lysis syndrome. Eli Lilly plans to submit these positive results to global regulatory authorities, indicating a path towards potential approval and broader availability for patients.

BRUIN CLL-322: Jaypirca Combination Delivers Significant PFS Benefit

The ALPINE trial (phase 3 RCT; N=652) evaluated zanubrutinib versus ibrutinib in relapsed/refractory CLL and represents one of the most clinically informative datasets in this setting. Zanubrutinib demonstrated superior progression-free survival (PFS) compared to both ibrutinib (HR=0.67, 95% CrI: 0.52–0.87) and acalabrutinib (HR=0.57, 95% CrI: 0.34–0.95) in the general R/R CLL population, with this PFS advantage maintained in the high-risk subgroup harbouring del(17p) and/or del(11q). Overall survival was similar across BTK inhibitors in both populations, though wide credible intervals precluded definitive conclusions. From a pooled safety analysis of 508 patients, any-grade adverse events occurred in 98.5% of patients; grade ≥3 events in 67.0%; and serious adverse events in 32.2%. Treatment discontinuation due to toxicity was reported in 7.2% of patients, with adverse event-related mortality at 7.1%. The most frequent haematological toxicities were neutropenia (32.1%) and anaemia (26.7%), while notable non-haematological events included bleeding (51.9%), upper respiratory tract infections (27.2%), pneumonia (19.4%), hypertension (16.4%), and atrial fibrillation (2.9%).

The ASCEND trial (phase 3 RCT; N=310) and ELEVATE-RR trial (phase 3 RCT; N=533) served as key comparators in indirect treatment analyses for acalabrutinib in R/R CLL. A matching-adjusted indirect comparison (MAIC) using ASCEND data demonstrated that zanubrutinib was associated with significantly improved investigator-assessed PFS versus acalabrutinib (HR=0.68, 95% CI: 0.46–0.99; p=0.0448), a trend toward improved overall survival (HR=0.60, 95% CI: 0.35–1.02; p=0.0575), and a significantly higher complete response rate (OR=2.90, 95% CI: 1.13–7.43; p=0.0270). ELEVATE-RR specifically enrolled a high-risk population with del(17p) and/or del(11q) and was incorporated into multilevel network meta-regression analyses to characterise BTK inhibitor efficacy across genomic risk strata. A phase 1/2 study of acalabrutinib (NCT02029443; N=99 treatment-naive, N=134 R/R) at a median follow-up of 73.7 and 52.6 months respectively reported overall response rates of 97.0% and 94.8%, with 72-month PFS rates of 86.7% (TN) and 45.1% (R/R). Key safety signals included atrial fibrillation (6.1% TN; 9.0% R/R), hypertension (29.3% TN; 23.1% R/R), and major bleeding (~8% in both cohorts), with most common adverse events decreasing in incidence over time.

In the fixed-duration regimen space, the MURANO study (venetoclax plus rituximab), alongside CLL14 (venetoclax plus obinutuzumab), GLOW, CAPTIVATE (ibrutinib plus venetoclax), and AMPLIFY (acalabrutinib plus venetoclax ± obinutuzumab) all demonstrated extended treatment-free intervals. Cardiovascular toxicity and death remain a notable safety concern with ibrutinib-based combinations, which are also associated with elevated rates of diarrhoea and atrial fibrillation. Importantly, while fixed-duration targeted regimens outperformed chemoimmunotherapy in high-risk patients — those with unmutated IGHV or TP53/del(17p) — outcomes in this subgroup remained inferior to those seen in standard-risk patients. For patients who are double-refractory to both covalent BTK inhibitors and BCL-2 inhibitors, pirtobrutinib (non-covalent BTKi) offers rapid disease control albeit often with limited durability, while lisocabtagene maraleucel (CD19-directed CAR-T therapy) represents an FDA-approved option capable of achieving durable remissions in heavily pretreated patients.

Addressing Critical Unmet Needs in Relapsed/Refractory CLL/SLL

The relapsed/refractory (R/R) CLL/SLL landscape has evolved substantially with the advent of targeted therapies, yet significant unmet needs persist across several high-risk patient subgroups. Despite the paradigm shift driven by BTK inhibitors (BTKis) and BCL-2 inhibitors (BCL2is), disease remains incurable, and patients who exhaust both drug classes face particularly limited options with short-lasting disease control.

• Patients failing both BTKi and BCL2i therapy: This population represents the most critical unmet need, with limited subsequent treatment options offering durable disease control. Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) have emerged as newer options for R/R disease following prior BTKi- and BCL2i-containing regimens, though challenges around toxicity and resistance persist.

• TP53-aberrant and high-risk biomarker populations: Despite BTKi achieving 70% progression-free survival (PFS) at 5 years versus 15% with FCR, TP53 abnormalities continue to confer worse outcomes even in the era of novel agents. Markers including unmutated IGHV, deletion 17p, and TP53 mutation retain differential prognostic and predictive impact under targeted therapy, mandating formal risk stratification in frontline and relapsed settings. Patients with high-risk disease are encouraged to enrol in clinical trials exploring combination and novel therapeutic strategies.

• BCRi-pretreated patients: Data from the VENICE-1 trial (NCT02756611) demonstrated that venetoclax monotherapy achieved a complete remission rate of 27% (18/67; 95% CI 16.8–39.1) in BCRi-pretreated patients, compared with 35% (66/191; 95% CI 27.8–41.8) in BCRi-naïve patients, over a median follow-up of 49.7 months — underscoring the need for improved therapeutic options following BCR-associated kinase inhibitor exposure.

• Unmutated IGHV patients on finite-duration therapy: Unmutated IGHV is associated with inferior PFS with fixed-duration venetoclax plus anti-CD20 monoclonal antibody regimens, though this adverse prognostic effect is not observed with continuous BTKi treatment, highlighting the importance of treatment-sequencing decisions in this subgroup.

• Richter transformation (DLBCL-RT): Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma carries a poor prognosis. In ibrutinib-treated patients, DLBCL-RT occurred in 83 of 979 patients (8.5%), with a 7-year cumulative rate of 15.6%, median overall survival of 4.7 months, and only 32% response to chemoimmunotherapy. Molecular analysis to determine clonal relationship between CLL/SLL and transformed DLBCL is recommended to guide appropriate treatment selection. Immunotherapy approaches — including immune checkpoint blockade, CAR T-cell therapy, and bispecific antibodies — have shown promise specifically in Richter transformation but have demonstrated reduced activity in CLL itself.

• Patients requiring optimised treatment sequencing and re-treatment strategies: BTKis and BCL2is fail to provide long-term disease control in a subset of patients, representing an ongoing clinical need. Relapsed CLL arising after discontinuation of time-limited venetoclax-based regimens generally retains sensitivity to venetoclax re-treatment, whereas patients progressing on continuous venetoclax exposure may develop genetic resistance mechanisms (e.g., BCL2 mutations) and may be better served by switching to an alternative drug class. The impact of NOTCH1 mutations on combination regimens such as obinutuzumab–venetoclax or venetoclax–BTKi combinations remains to be determined.

Unpacking the BRUIN CLL-322 Trial Design and Endpoints

The BRUIN CLL-322 trial sits within a broad and rapidly evolving evidence base for R/R CLL/SLL, shaped by pivotal phase 3 registrational studies, network meta-analyses, and early-phase exploratory trials spanning more than a decade. Across this landscape, progression-free survival (PFS) has consistently served as the primary endpoint, with overall survival (OS), overall response rate (ORR), and undetectable minimal residual disease (uMRD) increasingly used to differentiate regimens. The table below consolidates key trial design parameters and endpoints from the most clinically relevant studies.

Jaypirca's Potential Impact on the r/r CLL/SLL Treatment Landscape

Across the published literature, BTK inhibitors (BTKis) have consistently demonstrated superior progression-free survival (PFS) compared with conventional combination regimens in relapsed/refractory (R/R) CLL/SLL. A meta-analysis of four randomized controlled trials (N = 1,510) found that BTKis significantly improved PFS over combination therapy (HR 0.30; 95% CI, 0.22–0.40), with a better overall response rate (RR 1.10; 95% CI, 1.04–1.16), though overall survival (OS) did not favor single-agent BTKis (HR 0.87; 95% CI, 0.67–1.15) and complete response rates were comparable between arms. A network meta-analysis of seven phase III trials (N = 2,512) further established that all novel targeted therapies were significantly more effective than ofatumumab, with venetoclax plus rituximab and ibrutinib monotherapy each reducing the risk of progression or death by approximately 90% versus ofatumumab, and both demonstrating improved OS versus that comparator. Acalabrutinib monotherapy in the ASCEND trial (N = 310) also showed substantially improved PFS over investigator's choice of idelalisib–rituximab or bendamustine–rituximab (median PFS not reached vs. 16.5 months; HR 0.31; 95% CI, 0.20–0.49; P < .0001), with a more favorable serious adverse event profile compared with idelalisib–rituximab (29% vs. 56%).

Within the BTKi class, a multilevel network meta-regression drawing on three phase III trials — ALPINE (N = 652), ELEVATE-RR (N = 533), and ASCEND (N = 310) — demonstrated that zanubrutinib confers a PFS advantage over both ibrutinib (HR 0.67; 95% CrI, 0.52–0.87) and acalabrutinib (HR 0.57; 95% CrI, 0.34–0.95) in the general R/R CLL population, with this benefit maintained in the high-risk subgroup harboring del(17p) and/or del(11q). OS remained similar across all three BTKis, with credible intervals encompassing no difference. From a safety standpoint, second-generation BTKis carried a significantly lower risk of grade ≥3 adverse events relative to combination therapy (RR 0.73; 95% CI, 0.54–0.98), whereas first-generation ibrutinib was associated with cardiovascular side effects in 25.0% and hemorrhagic events in 15.6% of patients in real-world cohorts. Real-world data further indicated that treatment discontinuation was markedly higher in R/R patients than in first-line patients (74.3% vs. 39.6%; RR 1.81; 95% CI, 1.23–2.66), with prior immunochemotherapy exposure independently increasing discontinuation risk (HR 2.15; 95% CI, 1.18–3.89).

Beyond BTKis, venetoclax-based combinations and triplet regimens have broadened the therapeutic landscape. BCL2 inhibition with venetoclax combined with anti-CD20 monoclonal antibodies offers a finite, time-limited treatment approach, and ongoing trials are evaluating BTKi plus BCL2 inhibitor combinations to deepen and extend responses. A phase II study of obinutuzumab, ibrutinib, and venetoclax in R/R CLL (n = 25) achieved an overall response rate of 88% and undetectable minimal residual disease (uMRD) in 50% of patients in both blood and marrow, with median PFS and OS not yet reached at a median follow-up of 21.5 months, though grade 3–4 neutropenia occurred in 66% of patients. Current treatment sequencing strategies reflect this evolving landscape: BTKi-naïve patients are typically offered a BTKi- or BCL2-based regimen, while prior BTKi exposure directs patients toward BCL2 inhibition and vice versa; patients who are intolerant but otherwise responding to a BTKi may be switched to an alternative agent within the class; and those who have progressed on both BTKi and BCL2 inhibitor backbones — so-called "double refractory" patients — are strongly encouraged to enroll in clinical trials, with PI3K inhibitors representing a limited option outside the trial setting given modest durability and high toxicity.

Pirtobrutinib's Triplet Breakthrough: A New Horizon for R/R CLL/SLL

The recent positive Phase III results for Eli Lilly's Jaypirca (pirtobrutinib) in combination with venetoclax and rituximab (PVR) mark a pivotal moment in the treatment of relapsed or refractory chronic lymphocytic leukaemia/small lymphocytic lymphoma (r/r CLL/SLL). Demonstrating a 45% reduction in the risk of disease progression or death compared to venetoclax and rituximab alone (VR), with a median progression-free survival not yet reached, this triplet regimen offers a compelling new option for patients facing limited durable therapies.

Historically, the treatment landscape for CLL/SLL has been transformed by targeted agents like covalent Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) and B-cell lymphoma 2 (BCL-2) inhibitors (e.g., venetoclax). While these agents have significantly improved outcomes, patients eventually relapse, and those who progress after both a BTK inhibitor and a BCL-2 inhibitor face particularly poor prognoses, representing a significant unmet medical need. Pirtobrutinib, as a non-covalent BTK inhibitor, is specifically designed to re-establish BTK inhibition, even in patients whose disease has become resistant to earlier-generation covalent BTK inhibitors. Its proven efficacy in heavily pretreated, BTK inhibitor-failed patients underscores its unique mechanism.

The success of PVR in this trial suggests a potential shift in the treatment paradigm for r/r CLL/SLL. Instead of sequential therapy, a triplet combination could offer a deeper, more sustained response earlier in the relapsed setting. However, the introduction of a third agent necessitates careful consideration of the safety profile. While pirtobrutinib has shown a lower incidence of certain adverse events like atrial fibrillation and major hemorrhage compared to covalent BTK inhibitors, the combined toxicity burden, particularly neutropenia and infections, will need close monitoring. Furthermore, the long-term durability of responses and the potential for new resistance pathways to emerge with this combination will be crucial areas for ongoing research. From a market perspective, the cost-effectiveness of this enhanced regimen will be a key determinant for broad adoption, as healthcare systems weigh the significant clinical benefits against the incremental cost of adding a novel agent to an already effective backbone. This breakthrough offers renewed hope for patients and presents a strategic opportunity for Eli Lilly to solidify Jaypirca's role as a cornerstone therapy in CLL/SLL.