Orelabrutinib Improves Progression-Free Survival in Treatment-Naive CLL/SLL

Orelabrutinib significantly prolonged progression-free survival (PFS) compared with chemoimmunotherapy in patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), according to findings from a randomized phase 3 trial (NCT04578613) published in Signal Transduction and Targeted Therapy.¹

What did the phase 3 trial show?

At a median follow-up of 21.4 months (range, 0.03-40.3), the primary end point of PFS by independent review committee (IRC) evaluation was not reached (NR; 95% CI, not estimable [NE]-NE) with orelabrutinib vs 19.4 months (95% CI, 16.6-NE) with chlorambucil (Leukeran) plus rituximab (HR, 0.32; 95% CI, 0.18-0.58; P <.0001), crossing the prespecified efficacy boundary. The benefit was consistent across all prespecified subgroups, including patients of advanced age; those with Rai stage III/IV disease; and those with high-risk features such as del(11q), unmutated IGHV, or bulky disease.

The IRC-assessed overall response rate (ORR) was 90.1% (95% CI, 82.1%-95.4%) with orelabrutinib vs 79.2% (95% CI, 70.0%-86.6%) with chemoimmunotherapy (P = .041). Additionally, duration of response (DOR) also favored orelabrutinib (HR, 0.30; 95% CI, 0.15-0.60; P = .0003). A post-hoc analysis at 30 months showed a complete response rate of 12.1% in the orelabrutinib group.

What was the safety profile?

Treatment-related adverse events (TRAEs) occurred in 90.1% (n = 82/91) of patients receiving orelabrutinib and 90.8% (n = 89/98) of those receiving chlorambucil plus rituximab, with grade 3 or higher events seen in 35.2% (n = 32/91) and 60.2% (n = 59/98), respectively. Comparable any-grade TRAE rates occurred despite a median treatment duration of 19.3 months (IQR, 11.6-27.6) with orelabrutinib being longer than the 5.2 months (IQR, 5.1-5.9) for chlorambucil and 4.7 months (IQR, 4.6-5.3) for rituximab in the control group.

Most TRAEs with orelabrutinib were grade 1 or 2, and no treatment-related atrial fibrillation, major bleeding, or second primary malignancies were reported. Patient-reported outcomes were maintained or improved with orelabrutinib relative to chemoimmunotherapy.

“[O]relabrutinib provided significantly greater benefits than chlorambucil plus rituximab in terms of PFS and tumor response in patients with previously untreated CLL/SLL, particularly among those with high-risk features. The safety profile of orelabrutinib was manageable and consistent with its known profile,” lead study author Fei Li, a professor from the First Affiliated Hospital of Nanchang University, wrote with coauthors in the publication.¹ “The clinically meaningful benefit, along with favorable safety and maintained [quality of life] indicate a favorable benefit-risk profile of orelabrutinib, establishing it as an effective and safe option for this population. Based on the positive findings of this phase 3 trial, orelabrutinib has been approved in China for the first-line treatment of CLL/SLL.”

What was the trial design?

The randomized, phase 3 study compared orelabrutinib with chemoimmunotherapy in patients with treatment-naive CLL/SLL. From February 20, 2021, to July 8, 2024, 192 eligible patients were randomly assigned 1:1 to orelabrutinib at 150 mg once daily (n = 91) or chlorambucil plus rituximab (n = 101) in the intention-to-treat population.

The primary end point was PFS by IRC assessment. Secondary end points included ORR and DOR by IRC and investigator assessment, as well as safety.

The median patient age was 68.0 years (IQR, 60.0-73.0) in the orelabrutinib arm and 67.0 years (IQR, 62.0-70.0) in the chlorambucil/rituximab arm, and most patients from each arm were male (69.2% vs 60.4%). Additionally, most patients in each respective arm had an ECOG performance status of 1 (64.8% vs 58.4%), CLL (86.8% vs 85.1%), and Rai stage III/IV disease (61.5% vs 59.4%).

Orelabrutinib is a potent, irreversible, and highly selective BTK inhibitor; it has been approved for the first-line treatment of CLL/SLL in China and was added to the country’s National Reimbursement Drug List in 2025.²

References

1. Li F, Zhou K, Xu W, et al. Orelabrutinib versus chemoimmunotherapy in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: a randomized, phase 3 trial. Signal Transduct Target Ther. Published online July 6, 2026. doi:10.1038/s41392-026-02818-x
2. InnoCare announces publication in STTT (IF=81.2) of phase 3 results showing orelabrutinib significantly prolonged progression-free survival in treatment-naïve CLL/SLL. News release. InnoCare Pharma. July 14, 2026. Accessed July 14, 2026. https://tinyurl.com/46wsxmxj