Zanubrutinib sNDA for Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Accepted in China

The China National Medical Products Administration (NMPA) has accepted a supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) as a treatment option for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹ The BTK inhibitor was also granted a breakthrough therapy designation.¹

The application was supported by findings from the phase 3 SEQUOIA trial (NCT03336333), which found that zanubrutinib improved progression-free survival (PFS) vs bendamustine plus rituximab (Rituxan; BR) in this patient population.²

At a median follow-up of 26.15 months, the 24-month PFS rates in the investigative and control arms were 85.5% (95% CI, 80.1%-89.6%) and 69.5% (95% CI, 62.4%-75.5%), respectively, per independent review committee (IRC) assessment (HR, 0.42; 95% CI, 0.27-0.63; P < .0001).

“This is [zanubrutinib’s] first filing in treatment-naïve CLL supported by the positive global phase 3 SEQUOIA trial, a remarkable step forward in its global registration program,” Jane Huang, MD, chief medical officer of hematology at BeiGene, stated in a press release. “As presented at [the 2021] ASH [Annual Meeting, zanubrutinib] significantly prolonged PFS and was generally well tolerated in these patients, with demonstrated superiority over chemoimmunotherapy in the SEQUOIA trial.”

SEQUOIA enrolled patients who were at least 65 years of age or who were not fit to receive treatment with fludarabine, cyclophosphamide, and rituximab. Central verification of del(17p) status via fluorescence in situ hybridization was required.

Patients with treatment-naïve CLL/SLL without del(17p) compried cohort 1 of the trial. These patients were randomized to receive either zanubrutinib at a twice-daily dose of 160 mg until disease progression or intolerable toxicity, or bendamustine at 90 mg/m² on days 1 and 2 in combination with rituximab at 375 mg/m² in cycle 1 and 500 mg/m² in cycles 2 through 6 for six 28-day cycles.

Those in cohort 2 of the trial had tumors that had del(17p) and were given zanubrutinib, and those in cohort 3 had tumors that harbored del(17p) and TP53 mutations and were administered zanubrutinib in combination with venetoclax (Venclexta).

Between October 31, 2017, and July 22, 2019, a total of 479 patients without del(17p) underwent randomization to the BTK inhibitor arm (n = 241) and the BR arm (n = 238); 240 and 227 patients, respectively, ended up receiving treatment and were included in the safety analysis.

Across the arms, the median age of participants was 70.0 years. In the investigative and control arms, most patients had unmutated IGHV, at 53.4% (n = 125/234) and 52.4% (n = 121/231), respectively; 17.8% and 19.3% of patients, respectively, had del(11q).

Stratification factors included age (younger than 65 years vs 65 years or older), Binet Stage (C vs A/B), IGHV mutational status (mutated vs not), and geographic region.

The primary end point of the trial was PFS per IRC assessment, and key secondary end points comprised investigator-assessed PFS, IRC- and investigator-assessed overall response rate (ORR), overall survival (OS), and safety.

Additional data presented during the 2021 ASH Annual Meeting indicated that zanubrutinib was also found to prolong PFS compared with BR per investigator assessment (HR, 0.42; 95% CI, 0.27-0.66; P < .0001; 2-sided P = .0001). The PFS benefit derived with the BTK inhibitor was observed across key subsets, irrespective of age, Binet stage, bulky disease, and del(11q) status. Notably, benefit with zanubrutinib was also noted in those with unmutated IGHV (HR, 0.24), but not for mutated IGHV (HR, 0.67).

Moreover, zanubrutinib elicited an ORR of 97.5% (95% CI, 94.7%-99.1%) per investigator assessment, vs 88.7% (95% CI, 83.9%-92.4%) with BR. The estimated OS rates at 24 months in the investigative and control groups were 94.3% (95% CI, 90.4%-96.7%) and 94.6% (95% CI, 90.6%-96.9%), respectively.

At the time of the data cutoff, a total of 206 patients in the investigative arm were still receiving treatment with zanubrutinib. Moreover, 188 patients in the BR arm had completed treatment, and 15 patients had crossed over from the control arm to the investigative arm following the confirmation of progressive disease.

Any-grade toxicities of interest with the BTK inhibitor vs BR included atrial fibrillation (2.2% vs 2.6%, respectively), bleeding (45.0% vs 11.0%), hypertension (14.2%-10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Grade 3 or higher adverse effects in the investigative and control arms, respectively, included bleeding (3.8% vs 1.8%), infection (16.3% vs 18.9%), and neutropenia (11.7% vs 51.1%).

Moreover, 8.3% of patients who received zanubrutinib discontinued treatment because of toxicities vs 13.7% of those who were given BR. Notably, 85.5% of patients remain on treatment with the BTK inhibitor.

Toxicities resulted in death in 4.6% of those who received zanubrutinib and 5.3% of those who were administered BR. No sudden deaths were reported.

In January 2022, the China NMPA also accepted a sNDA for zanubrutinib as a treatment for patients with Waldenström macroglobulinemia based on findings from the phase 3 ASPEN trial (BGB-3111-302; NCT03053400), which showed that zanubrutinib resulted in a combined complete response and very good partial response rate of 28% (95% CI, 20%-38%) per IRC assessment in the overall intent-to-treat population compared with 19% (95% CI, 12%-28%) with ibrutinib (Imbruvica).³

“Together with the filing in Waldenström macroglobulinemia, we are hoping to expand the clinical use of this potential best-in-class BTK inhibitor from [the] relapsed or refractory setting to frontline care for the blood cancer community in China,” Huang added in the press release.

References

1. BeiGene announces acceptance of supplemental new drug application in China for BRUKINSA (zanubrutinib) in chronic lymphocytic leukemia with breakthrough therapy designation. News release. BeiGene; January 28, 2022. Accessed February 1, 2022. https://bit.ly/3ufpU8M
2. Tam CS, Giannopoulos K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab (BR) in patients with treatment-naïve (TN) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Blood. 2021;138(suppl 1):396. doi:10.1182/blood-2021-148457
3. BeiGene announces acceptance of a supplemental new drug application in China for BRUKINSA (zanubrutinib) in Waldenström’s macroglobulinemia. News release. BeiGene, Ltd.; January 20, 2022. Accessed February 1, 2022. https://bit.ly/33Y40eV