FDA Grants Breakthrough Therapy Designation to Orelabrutinib for Relapsed/Refractory MCL

The FDA has granted a breakthrough therapy designation orelabrutinib for the treatment of patients with relapsed/refractory mantle cell lymphoma.

The FDA has granted a breakthrough therapy designation orelabrutinib (ICP-022) for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL).1

The novel, potent, highly selective BTK inhibitor was designed to target B-cell lymphomas and autoimmune indications.2 The agent was developed to have stronger target selectivity vs ibrutinib (Imbruvica) and acalabrutinib (Calquence), which should result in improved safety.

With a proprietary formulation, the agent achieves high bioavailability vs other BTK inhibitors.

“We are very proud that orelabrutinib was granted breakthrough therapy designation after obtaining orphan drug designation,” Jasmine Cui, PhD, cofounder, chairwoman, and chief executive officer of InnoCare Pharma, stated in a press release. “We will continue to uphold the concept of ‘science drives innovation for the benefit of patients’ and accelerate clinical trials for multiple indications of orelabrutinib in China and the rest of the world to benefit patients worldwide.”

In an open-label, multicenter, phase 2 trial, investigators set out to examine the safety, tolerability, and efficacy of orelabrutinib, following oral administration, in Chinese patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small cell leukemia (SLL).2 The primary end point of the study was objective response rate (ORR), and key secondary end points comprised duration of response (DOR), progression-free survival (PFS), and safety. Response was evaluated in accordance with 2008 International Workshop on Chronic Lymphocytic Leukemia criteria with modification for partial response (PR) with lymphocytosis (PR-L).

The study was comprised of 2 stages. In the first stage, investigators evaluated the safety and tolerability of the BTK inhibitor given orally at a dose of 150 mg in patients with relapsed/refractory CLL/SLL. In the second stage of the research, investigators examined the clinical benefits of orelabrutinib, when given at the same dose (n = 80).

Eighty patients with relapsed/refractory CLL were enrolled to the trial; of these patients, 70 had CLL and 10 patients had SLL. At a data cutoff of May 31, 2019, half of patients (n = 40) completed 6 cycles of treatment.

At a median follow-up of 6.3 months (range, 0.4-13.7), 78 patients were determined to be evaluable for response. Results indicated that orelabrutinib elicited an ORR of 88.5% (n = 69), with 1 patient achieving a complete response, 39 experiencing a PR, and 29 reporting a PR-L. Moreover, 7.7% of patients experienced disease stability. The median DOR had not yet been reached, and the 6-month DOR rate was 89.8%. The disease control rate achieved with the BTK inhibitor was 96.2%.

No significant differences in benefit were observed with orelabrutinib across different subgroups analyzed, including age, disease stage, prior treatment, 17p deletion, 11q deletion, and IGHV mutation.

The most common adverse effects (AEs) of any cause reported with the BTK inhibitor were hematologic toxicities that were well characterized; these effects included thrombocytopenia, neutropenia, and anemia. Patients also reported respiratory system infections and purpura. Notably, no patients experienced atrial fibrillation or secondary malignancy. The most common any-grade grade 3 or higher AEs comprised neutropenia, thrombocytopenia, and lung infections.

A total of 25 patients reported at least 1 serious toxicity with the BTK inhibitor; 13 of these effects were determined to be associated with the agent and included decreased platelet count (n = 3), pneumonitis (n = 2), pyrexia (n = 2), and herpes zoster (n = 1).

In December 2020, China’s National Medical Products Administration (NMPA) approved the agent for use in the following indications: patients with relapsed/refractory CLL/SLL and those with relapsed/refractory MCL.

In February 2021, the NMPA approved a phase 3 clinical trial examining the use of orelabrutinib in combination with R-CHOP in previously untreated patients with MCL.3 The primary end point of this study is PFS, and secondary end points include ORR, DOR, and overall survival.


  1. InnoCare announces breakthrough therapy designation of orelabrutinib by US FDA for treatment of R/R MCL. News release. InnoCare Pharma. June 28, 2021. Accessed June 28, 2021. https://prn.to/35VpN4Z
  2. Xu W, Song Y, Li Z, et al. Safety, tolerability and efficacy of orelabrutinib, once a day, to treat Chinese patients with relapsed or refractory chronic lymphocytic leukemia/small cell leukemia. Blood. 2019;134(suppl 1):4319. doi:10.1182/blood-2019-123331
  3. InnoCare announces approval of orelabrutinib in combination with R-CHOP as first-line therapy for mantle cell lymphoma in China. News release. InnoCare Pharma. February 5, 2021. Accessed June 28, 2021. https://bit.ly/3hv3vMT