Phase II Study Investigating the Combination of Encorafenib and Binimetinib in BRAF V600E Mutated Chinese Patients With Metastatic Non-Small Cell Lung Cancer

Multicenter, Open-label, Phase II Study With a Safety Lead-in Part Investigating the Efficacy, Safety and Pharmacokinetics of Encorafenib and Binimetinib Combination in BRAF V600E Mutated Chinese Patients With Metastatic Non-Small Cell Lung Cancer Who Are BRAF- and MEK Inhibitor Treatment-naïve

This is a phase 2, multicenter, single-arm study with a safety lead-in to investigate the efficacy, safety and pharmacokinetics of encorafenib 450 mg once daily (QD) in combination with binimetinib 45 mg twice daily (BID) (Combo450) in adult Chinese participants with metastatic unresectable stage IV BRAF V600E mutant NSCLC, who are BRAF- and MEK-inhibitor treatment-naïve and are either previously untreated or have had one line of prior therapy in metastatic setting.

Inclusion Criteria:

If a participant has a BRAF V600E mutational status confirmed as per local assessment, the participant might enter the main screening directly.

All the following inclusion criteria must be met for a participant to be eligible to be included in this study:

1. Provide a signed and dated screening Informed Consent Form (ICF).
2. Chinese male or female with age ≥ 18 years old for China mainland and ≥ 20 years old for Taiwan at the time of the screening informed consent.
3. Documented histology- and/or cytology-confirmed metastatic unresectable Non-small cell lung cancer (NSCLC (i.e. Adenocarcinoma (ADC), large cell carcinoma, squamous cell carcinoma (SCC)).
4. Presence of B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) V600E mutation in tumor tissue previously determined by a local assay at any time prior to screening or by the central laboratory.
5. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archived or newly obtained) for central prospective laboratory testing of BRAF mutation status and comparison of central BRAF V600E testing in the clinical study to BRAF V600E testing with a candidate companion diagnostic.
6. BRAF- and Mitogen-activated protein kinase kinase (MEK)-inhibitor treatment-naïve participants and previously untreated or have had one line of prior therapy in metastatic setting.
7. At least one measurable disease as per investigator assessment, as defined by RECIST v1.1, which has neither been irradiated nor biopsied during the screening period.
8. Life expectancy ≥ 3 months.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
10. Adequate hematologic function at screening and baseline.
11. Adequate hepatic function at screening and baseline.
12. Adequate renal function at screening and baseline.
13. Able to comply with the study protocol as per investigator assessment including oral drug intake, complying scheduled visits, treatment plan, laboratory tests and other study procedures.
14. Women are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or child-bearing potential women must agree to take appropriate precautions to avoid pregnancy.
15. Men must agree not to father child until 90 days after the last dose of the study treatment.

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible to be included in this study:

1. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs (encorafenib and binimetinib), or their excipients.

2. Documented Anaplastic lymphoma kinase (ALK) fusion oncogene, Reactive oxygen species (ROS) rearrangement or Epidermal growth factor receptor (EGFR) sensitizing or driver mutation.

3. Participants who have received more than one prior line of systemic therapy.

4. Receipt of anti-cancer medications or investigational drugs within the specified intervals before the first administration of study treatment.

5. Symptomatic brain metastases or other active Central nervous system (CNS) metastases.

6. Leptomeningeal disease.

7. Participant has not recovered to ≤ Grade 1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study treatment.

8. Current use of prohibited medication ≤ 1 week prior to start of the study treatment and/or concomitantly.

9. Impairment of gastrointestinal function or disease which may significantly alter the absorption of oral study treatment.

10. Impaired cardiovascular function or clinically significant cardiovascular diseases

11. History of thromboembolic or cerebrovascular events within 3 months prior to starting the study treatments

12. History or evidence of retinal pathology considered as risk factor for Retinal vein occlusion (RVO) or neovascular macular degeneration.

13. Concurrent neuromuscular disorder associated with the potential of elevated Creatine phosphokinase (CPK)

14. Participants with active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) or any other severe viral active infection (e.g. SARS-CoV-2 infection)

15. Evidence of active, non-infectious pneumonitis, history of interstitial lung disease that required oral or intravenous glucocorticosteroids for management.

16. Known history of a positive test for Human immunodeficiency virus (HIV) or known Acquired Immunodeficiency Syndrome (AIDS). Testing for HIV must be performed at sites where mandated locally.

17. Participants who have had major surgery (e.g. inpatient procedure with regional or general anesthesia) within 6 weeks prior to start of study treatment.

18. Participants with concurrent or history of another malignancy within 2 years of study entry Except:

    1. Bowen's disease
    2. Cured basal cell or cutaneous squamous cell carcinoma (CuSCC)
    3. Gleason 6 prostate cancer
    4. Treated in-situ carcinoma of cervix

19. Participant's conditions that contraindicates the use of study treatments and may affect interpretation of results or may render the participant at high risk from treatment complications.

20. Pregnant (confirmed by positive serum beta-human chorionic gonadotropin (ß-HCG) test), lactating or breast-feeding women.

21. Is a family member of the investigator or any associate, colleague, and employee assisting in the conduct of the study (secretary, nurse, technician).

22. Is in a position likely to represent a conflict of interest.