A Study of FWD1509 in Adults With Non-Small Cell Lung Cancer

Key Inclusion Criteria: Study-Wide Eligibility (Across All Study Parts): A subject will be eligible for inclusion in this study only if all of the followingcriteria apply.

1. Have histologically or cytologically confirmed locally advanced or metastatic NSCLC (Stage IIIB/IIIC or IV) [JACC edition 8], and inclusion of Stage IIIB only if not acandidate for curative therapy
2. Must have sufficient tumor tissue (either archived sample or recent biopsy) availablefor analysis:
3. Phase 1 Dose-escalation part: EGFR and HER2 mutations (including but not limitedtoL858R, exon 19 deletion, T790M, ex20ins, 21exon, G719X, S768I, L861Q, etc. forEGFR and A775YVMG, C776insVC, P780ins GSP etc. for HER2) should be confirmed bypreviously documented evidence or central lab
4. Patients with both EGFR and HER2 mutations may be included in the dose escalationphase
5. Phase 1 Dose-expansion part and Phase 2: Have an EGFR in-frame exon 20 insertiontest by any central lab
6. Must have at least one measurable lesion as defined by response evaluation criteria insolid tumors (RECIST v1.1)
7. Prior anti-cancer therapies:
8. Previously treated with one or more regimens of systemic therapy for locallyadvanced or metastatic disease
9. Disease progressed or intolerant to at least one line of systematic therapiesincluding but not limited to any EGFR-target therapies or immunotherapies, formetastatic / local relapsed settings
10. Male or female adult participants (aged 18 years or older, or as defined per localregulations)
11. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
12. Minimum life expectancy of 3 months or more
13. Adequate organ function at baseline
14. Bone marrow function

• Absolute neutrophil count (ANC)≥1.5 x 10^9/L
• Platelets ≥100 x 10^9/L
• Hemoglobin ≥9 g/dL, criteria must be met without a transfusion within 2weeks of the blood draw

2. Hepatic function

• AST and ALT ≤3 x upper limit of normal (ULN); if liver metastases, then ≤ 5x ULN
• Bilirubin ≤1.5 x ULN or ≤3 x ULN in the presence of documented Gilbert'sSyndrome

3. Renal function

• Creatinine clearance ≥50 ml/min (calculated by Cockcroft and Gault equation (Cockcroft DW, 1976) (Appendix 3)

9. Willingness and ability to comply with scheduled visits and study procedures

Exclusion Criteria: A subject will be not eligible for inclusion in this study if any of the following criteriaapply:

1. Received anticancer therapy including cytotoxic chemotherapy, biological products andinvestigational agents, ≤ 21 days prior to first dose of FWD1509 MsOH; or receivedprior EGFR TKIs (e.g., gefitinib, erlotinib or osimertinib) ≤7 days prior to the firstdose FWD1509 MsOH
2. Have been diagnosed with another primary malignancy other than NSCLC except forpatients with adequately treated non-melanoma skin cancer, cervical cancer in situ ordefinitively treated non-metastatic prostate cancer, or participants with anotherprimary malignancy who are definitively relapse-free with at least 3 years elapsedsince the diagnosis of the other primary malignancy
3. Received radiotherapy ≤14 days prior to the first dose of FWD1509 MsOH or have notrecovered from radiotherapy-related toxicities; palliative radiation administeredoutside the chest and brain, stereotactic radiosurgery (SRS), and stereotactic bodyradiotherapy are allowed up to 7 days prior to the first dose of FWD1509 MsOH
4. Received strong CYP3A inhibitors and inducers within 2 weeks prior to the first doseof FWD1509 MsOH; they should be discontinued at least 2 weeks prior to the first doseof FWD1509 MsOH and avoided throughout the study duration (see Appendix 6)
5. Received concomitant medications (e.g., statins) which are substrates of BCRP,p-glycoprotein or OATP1B1/1B3 (dose escalation part of phase 1 study)
6. Have undergone major surgery within 28 days prior to first dose of FWD1509 MsOH. Minorsurgical procedures, such as catheter placement or minimally invasive biopsy, areallowed
7. Brain Metastasis: Have known active brain metastases (have either previously untreatedintracranial CNS metastases or previously treated intracranial CNS metastases withradiologically documented new or progressing CNS lesions), except for the followingconditions
8. Brain metastases are allowed if they have been treated with surgery and/orradiation and have been stable without requiring corticosteroids to controlsymptoms within 7 days before the first dose of FWD1509 MsOH and have no evidenceof new or enlarging brain metastases
9. Requiring corticosteroids to control symptoms within 7 days prior to the firstdose of FWD1509 MsOH or during study period; patients previously treated for CNSmetastases who are clinically stable, have no new lesions, and who do not needtreatment with a corticosteroid within the 7 days before the first dose ofFWD1509 MsOH and during study period are allowed to be enrolled
10. Have current spinal cord compression (symptomatic or asymptomatic and detected byradiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic)
11. Have significant, uncontrolled, or active cardiovascular disease
12. QCc-related criteria:
13. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstrationof a QTc interval >480 milliseconds (ms) (CTCAE grade 1) using Fredericia's QTcorrection formula
14. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heartfailure, hypokalemia, family history of Long QT Syndrome
15. Have significant, uncontrolled, or active renal disease
16. Have a known history of uncontrolled hypertension (per institution practice);participants with hypertension should be under treatment on study entry to controlblood pressure
17. Have any abnormal changes in the cornea or retina that may increase the risk of oculartoxicity during screening
18. Have an ongoing or active infection, including but not limited to, the requirement forintravenous (IV) antibiotics, or a known history of human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Testing is not required inthe absence of history
19. Currently have or have a history of interstitial lung disease, radiation pneumonitisthat required steroid treatment, or drug-related pneumonitis
20. Female participants who are lactating and breastfeeding or have a positive urine orserum pregnancy test during the screening period
21. Have gastrointestinal illness or disorder that could affect oral absorption of FWD1509MsOH
22. Have any condition or illness that, in the opinion of the investigator, mightcompromise participant safety or interfere with the evaluation of the safety of thedrug