HS-10365 is a small molecular, oral potent, selective RET inhibitor. The purpose of this study is to investigate the efficacy and safety of HS-10365 in Chinese advanced RET fusion-positive non-small cell lung cancer patients without any systemic therapy.

This is an open-label, single arm, multi-center Phase 2 study in participants with treatment-naïve locally advanced or metastatic RET fusion-positive non-small cell lung cancer, which is designed to investigate the anti-tumor activity, safety and pharmacokinetics (PK) of HS-10365 at the recommended phase 2 dose (RP2D). HS-10365 will be administered orally twice daily until the occurrence of disease progression, unacceptable adverse events, withdrawal of consent, death or the end of the study. Primary endpoint is objective response rate (ORR) by Independent Reading Committee (IRC). Secondary and exploratory objectives include evaluation of secondary efficacy endpoints, safety and PK in the study population.

Inclusion Criteria:

1. Men or women aged more than or equal to (≥) 18 years.
2. Histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC with RET fusion-positive, including recurrent or initial diagnosed Stage IIIB-IIIC/IV NSCLC that is not suitable for radical surgery.
3. A RET gene fusion is required by using tumor tissue for central testing.
4. At least one measurable lesion in accordance with RECIST 1.1
5. Eastern Cooperative Oncology Group (ECOG) performance status: 0~1.
6. Estimated life expectancy >12 weeks.
7. Reproductive-age women agree to use adequate contraception and cannot breastfeed while participating in this study and for a period of 6 months after the last dose. Likewise, men also consent to use adequate contraceptive method within the same time limit.
8. Females must have evidence of non-childbearing potential.
9. Signed and dated Informed Consent Form.

Exclusion Criteria:

1. Treatment with any of the following:

   Additional validated oncogenic drivers in NSCLC if known. Previous or current treatment with selective RET inhibitors or multi-kinase Inhibitor of RET.

   Prior systemic therapy for metastatic disease. Treatment (including chemotherapy or immunotherapy) in the adjuvant/neoadjuvant setting is permitted if it was completed at least 6 months prior to relapse.

   Local radiotherapy for palliation within 2 weeks of the first dose of study drug, or patients received more than 30% of the bone marrow irradiation, or large-scale radiotherapy within 4 weeks of the first dose.

   Major surgery (including craniotomy, thoracotomy, or laparotomy, etc.) within 4 weeks of the first dose of study drug.

2. Inadequate bone marrow reserve or serious organ dysfunction.

3. Uncontrolled pleural effusion or ascites or pericardial effusion.

4. Known and untreated, or active central nervous system metastases.

5. Active autoimmune diseases or active infectious disease

6. Refractory nausea, vomiting, or chronic gastrointestinal diseases, or inability to swallow oral medications.

7. History of severe allergic reaction, hypersensitivity to any active or inactive ingredient of HS-10365 or to drugs with a similar chemical structure or class to HS-10365.

8. The subject who is unlikely to comply with study procedures, restrictions, or requirements judged by the investigator.

9. The subject whose safety cannot be ensured or study assessments would be interfered judged by the investigator.

10. Pregnant women, breastfeeding women or woman who has a child-bearing plan during the study.

11. History of neuropathy or mental disorders, including epilepsy and dementia