BTKi therapy has significantly transformed the treatment landscape for several indolent non-Hodgkin lymphomas (iNHLs), including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). These inhibitors work by targeting Bruton's tyrosine kinase (BTK), a critical enzyme in the B-cell receptor signaling pathway that promotes the growth and survival of malignant B-cells. BTK inhibitors, such as ibrutinib, acalabrutinib, zanubrutinib and others, are typically administered continuously over the long term. This sustained treatment is essential to maintain disease control and prolong survival. Despite their efficacy, BTK inhibitors can cause adverse events (AEs) that lead to treatment discontinuation in some patients. Interrupting BTKi therapy can have significant consequences, including early disease progression and shorter overall survival. Patients who discontinue BTKi therapy due to intolerance but have an ongoing response represent an unmet medical need. These patients require alternative treatments that can provide effective disease control without the adverse effects associated with their previous BTKi therapy. 

Orelabrutinib, a second-generation, irreversible BTKi, offers enhanced BTK selectivity and better tolerability. Orelabrutinib has been engineered to selectively target BTK with minimal off-target activity. This selectivity is intended to reduce the incidence of off-target adverse effects, which are a significant cause of intolerance with first-generation BTK inhibitors.

Orelabrutinib received first approval from the China National Medical Products Administration (NMPA) in December 2020 in two indications: relapsed/refractory CLL/SLL and relapsed/refractory MCL. Later, in April 2023, the drug also received approval for the treatment relapsed/refractory MZL in China.

Preliminary results from a Phase II study (ChiCTR2400080207) being conducted to assess the safety and activity of orelabrutinib in prior BTKi intolerant iNHL were presented at the EHA 2024 Congress. Patients were eligible if they aged ≥18 years, had histologically confirmed CLL/SLL, WM, MCL, MZL, or follicular lymphoma (FL), and were intolerant to prior BTKi therapy.

As of February 26, 2024 data cutoff, a total of 47 patients (30 with CLL/SLL, 9 with LPL, 5 with MZL, and 3 with MCL) were treated. These patients experienced 110 adverse events (AEs) leading to discontinuation of previous BTKi therapy, with a median of 2 AEs per patient. Common AEs included anemia (43%), decreased platelet count (38%), and hypertension (32%), with 15 patients (32%) experiencing AEs of grade 3 or higher. Upon switching to orelabrutinib, 46% of these AEs resolved, and 18% showed improvement. Resolved or improved adverse events of special interest (AESIs) included hypertension, cardiac events, renal dysfunction, liver dysfunction, infectious events, and subcutaneous hemorrhage. The outcomes for AEs intolerant to ibrutinib or zanubrutinib were similar. Following treatment with orelabrutinib, 15 patients (32%) experienced AEs of any grade, and two patients (3%) experienced grade 3 or higher AEs. Most AEs were hematologic toxicities, such as decreased white blood cell count, hypoalbuminemia, decreased neutrophil count, and anemia. No treatment-related serious AEs or deaths were reported. 

Regarding efficacy, of the 38 evaluated patients, the hematologic response rate (HRR) was 58%. 5 out of 13 responders showed improvement in two or more criteria. No patients experienced disease progression by the data cutoff.

KOL insights

“Orelabrutinib has shown promising efficacy and safety in patients intolerant to previous BTK inhibitors, particularly by improving off-target toxicities such as cardiac and infectious adverse events. These preliminary results suggest a significant advancement for patients with prior BTKi intolerance.” – MD, United States

Conclusion 

Currently, Orelabrutinib is the flagship brand of Innocare. With the help of Orelabrutinib's coverage of the National Reimbursement Drug List (NRDL) for R/R MCL and the expansion of R/R MZL's indications in China, product revenue in 2023 was RMB 670.7 million, up 18.5% from RMB 565.9 million in 2022. The Chinese Society of Clinical Oncology (CSCO) Diagnosis and Treatment Guidelines for Malignant Lymphoma, expansion in additional indications, and seamless adoption of the revised NRDL were the primary factors driving the sales growth.

Innocare is hoping to extend the use of orelabrutinib as a first-line treatment for several B-cell malignancies in China, such as MCL, CLL/SLL, and the MCD subtype of DLBCL. In order to optimize the benefit of orelabrutinib's better clinical profile in NHL markets outside of China, Inncare is also aggressively exploring possible combination treatment partners and advancing its efforts to secure orelabrutinib's speedy approval in the United States for R/R MCL.

This Phase II study is the first study to demonstrate the safety and efficacy of orelabrutinib in patients with iNHL who were intolerant to previous BTK inhibitors such as ibrutinib and zanubrutinib. Indolent non-Hodgkin lymphomas (iNHLs) are a subset of lymphomas characterized by their slow progression and often asymptomatic nature and are one of the most common cancers worldwide. Indolent subtypes, such as FL and MZL, account for approximately 35-40% of all NHL cases. 

Preliminary results indicate that orelabrutinib offers promising efficacy and safety for iNHL patients previously intolerant to BTKi therapy. Specifically, orelabrutinib improved outcomes for patients experiencing adverse events from previous BTKi treatments, particularly those related to off-target toxicities, with 64% of these adverse events resolving or alleviating after the switch. The drug exhibited a favorable safety profile and achieved a high hematologic response rate among these patients. No treatment-related serious adverse events or deaths were reported. Further data from this ongoing study will be presented in future updates.

Research is also exploring the potential of combining orelabrutinib with other targeted therapies, such as anti-CD20 monoclonal antibodies and BCL-2 inhibitors, to enhance its therapeutic efficacy and overcome resistance mechanisms.