Akale ® (ripretinib) was approved by the China National Medical Products Administration (NMPA) for the treatment of patients with ROS1-positive non-small cell lung cancer

The approval was based on the TRIDENT-1 pivotal study, in which repretinib achieved high response rates and durable responses, including intracranial responses

SHANGHAI and CAMBRIDGE, Mass. (GLOBE NEWSWIRE) -- Zai Lab (Nasdaq: ZLAB; HKEx stock code: 9688) announced that Akale ® (rippretinib) has been approved by the National Medical Products Administration (NMPA) of the People's Republic of China for the treatment of adult patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer. The approval is based on the TRIDENT-1 pivotal study, an open-label, single-arm Phase 1/2 study evaluating repretinib in TKI-naïve patients and TKI-treated patients with ROS1-positive NSCLC.

Dr. Rafael G. Amado, President and Head of Global Oncology R&D at Zai Lab, commented, "We are pleased that the NMPA has approved repretinib for the treatment of ROS1-positive NSCLC patients in China. Given the limited duration of benefit for patients with existing therapies that can lead to resistance and eventual tumor progression, there is a significant unmet need. We thank the China National Medical Products Administration for its comprehensive evaluation of repretinib and its recognition of its potential to address unmet medical needs in China." "

Prof. Shun Lu, Director of the Lung Cancer Center at Shanghai Jiao Tong University Chest Hospital, said, "Although the previous generation of ROS1 TKIs can also treat ROS1-positive non-small cell lung cancer, patients still have unmet needs and therefore need new treatment options to support important clinical goals such as durable remission. In the TRIDENT-1 study, repretinib demonstrated high response rates and good durability in patients with ROS1-positive NSCLC who were TKI-naïve, TKI-experienced, and intracranial metastasized. Based on this study, repretinib is expected to become the new standard of care for these patients. "

In June 2023, China's National Medical Products Administration (NMPA) accepted the New Drug Application (NDA) for repretinib for the treatment of adult patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer. In May 2023, repretinib was granted priority review by the NMPA.

Zai Lab participated in the TRIDENT-1 pivotal study and dosed the first patient in Greater China in May 2021. In January 2024, the findings were published in the New England Journal of Medicine. Efficacy and safety data in the Chinese subgroup were consistent with the global population, demonstrating robust response rates and durable clinical activity in patients with ROS1-positive NSCLC. Repretinib was well tolerated and had an overall manageable safety profile.

About Okal

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Akale (repretinib) is a next-generation tyrosine kinase inhibitor targeting ROS1 and NTRK oncogenic factors. Patients with solid tumors (including NSCLC) harboring ROS1 and NTRK gene fusions often develop resistance mutations that limit drug binding to the target and ultimately lead to tumor progression after receiving currently approved targeted therapies. Ripretinib is the first next-generation ROS1 and NTRK TKI uniquely designed to improve the durability of benefits, including in the brain.

In November 2023, the U.S. FDA approved repretinib for the treatment of adult patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer.

The FDA previously granted three Breakthrough Therapy Designations to repretinib in patients with ROS1-positive metastatic non-small cell lung cancer who have not received a ROS1 TKI; To treat patients with ROS1-positive metastatic non-small cell lung cancer who have received a prior first-line ROS1 TKI and have not received platinum-based chemotherapy; To treat patients with advanced solid tumors who have received one or two prior TRK TKIs, have progressed on disease with or without chemotherapy, and have no satisfactory alternative therapy. In addition, repretinib has previously received four Fast-Track designations from the FDA, including for patients with ROS1-positive advanced non-small cell lung cancer naïve with ROS1 TKIs; Patients with ROS1-positive advanced non-small cell lung cancer who have received prior treatment with one front-line platinum-based chemotherapy and one front-line ROS1 TKI; Patients with ROS1-positive advanced non-small cell lung cancer who have received a prior front-line ROS1 TKI and have not received platinum-based chemotherapy; and patients with NTRK-positive advanced solid tumors who have progressed on at least one prior chemotherapy and one or two front-line TRK TKIs and have no satisfactory alternative therapy. In 2017, repretinib was also granted orphan drug designation by the FDA.

In China, repretinib has been granted Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA): ROS1-positive patients with metastatic non-small cell lung cancer who have not been treated with a ROS1 TKI; Patients with ROS1-positive metastatic non-small cell lung cancer who have received a prior ROS1 TKI and have not received platinum-based chemotherapy or immunotherapy; Patients with ROS1-positive metastatic non-small cell lung cancer who have received one front-line ROS1 TKI and one front-line platinum-based chemotherapy; and patients with advanced solid tumors with NTRK gene fusions who have received one or two prior TRK TKIs, have progressed on disease with or without chemotherapy, and for which there is no satisfactory alternative therapy.

Zai Lab has signed an exclusive license with Turning Point Therapeutics (acquired by Bristol-Myers Squibb) to develop and commercialize repretinib in Greater China (Chinese mainland, Hong Kong, Macau and Taiwan).

concerning TRIDENT-1 study

TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical study evaluating the safety, tolerability, pharmacokinetics, and antitumor activity of repretinib in patients with advanced solid tumors, including non-small cell lung cancer[1,2]. Stage 1/2 includes patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK fusions[2]. Additional analyses for the study are ongoing; Asymptomatic central nervous system (CNS) metastases are allowed [1,2]. Among other exclusion criteria, patients with symptomatic brain metastases are excluded from the study[1]. The first phase of the study consists of determining the dose escalation of the recommended Phase II dose[2].

The primary endpoint of Phase 2 of the study is overall response rate (ORR) [1,2]. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS) as assessed by an independent, blinded center (BICR) according to RECIST v1.1 criteria, and intracranial responses in six different expansion cohorts, including tyrosine kinase inhibitor (TKI)-naïve and TKI-experienced patients with ROS1-positive locally advanced or metastatic NSCLC [1,2].

In the TRIDENT-1 study, 79 percent (95% CI: 68-88) of treatment-naïve patients responded to treatment, 6 percent achieved a complete response, and 73 percent achieved a partial response [1]. The median duration of response (mDOR) is 34.1 months[1]. Among patients previously treated with TKIs (n=56), the ORR was 38 percent (95% CI: 25 to 52), of which 5 percent achieved a complete response, 32 percent achieved a partial response, and the mDOR was 14.8 months [1]. Among patients with measurable brain metastases at baseline, an intracranial response was observed in 7 of 8 TKI-naïve patients; Intracranial responses were observed in 5 of the 12 patients who had received TKIs [1].

The FDA-approved dose of repretinib is 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or intolerable toxicity occurs[1].

About non-small cell lung cancer in China

Lung cancer is a common type of cancer in China and the leading cause of cancer death. In 2022, there were about 871,000 new cases of lung cancer and about 767,000 deaths in China [3]. Non-small cell lung cancer accounts for about 85% of lung cancers, and about 70% of non-small cell lung cancers are locally advanced or metastatic at the time of initial diagnosis. In China, ROS1 rearrangements account for approximately 2 to 3 percent of patients with advanced non-small cell lung cancer [4].

1 Augtyro Prescribing Information. Augtyro U.S. Product Information. Last updated: November 2023. Princeton, NJ: Bristol Myers Squibb Company.

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3 Changfa Xia, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants.

4 Zhang, et al. Prevalence of ROS1 fusion in Chinese patients with non-small cell lung cancer, Thoracic Cancer January 2019.