(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC

Inclusion Criteria:

1. ≥18 years of age at the time of signing the informed consent.

2. Pathologically confirmed, definitively diagnosed, metastatic NSCLC harboring anactivating EGFR mutation.

3. Previously received at least 1 prior EGFR-targeted TKI with activity against theT790M mutation, such as osimertinib. a. Phase 1 Part 1B and Phase 2 Group 4: Patients must have experienced progressivedisease while on osimertinib, and were able to tolerate prior osimertinib 80 mg QDdose.

4. Tumor mutation profile determined locally via a Sponsor-approved testingmethodology, using tumor tissue (ideally from a progressing lesion) and/or ctDNA inplasma. For Phase 1, it is preferable that samples used for analysis be obtainedduring or after disease progression on the last EGFR-targeted TKI received. ForPhase 2, pre-treatment tumor sample must be obtained during or after diseaseprogression on the last EGFR-targeted TKI received.

5. Dose Escalation (Phase 1 Part 1A and Part 1B): At each dose level, slots may bereserved for patients with the mutations of interest.

6. BLU-945 Monotherapy Expansion Groups (Phase 2 Group 1, Group 2, and Group 3):Patients must have NSCLC harboring EGFR T790M and C797S mutation (Group 1);EGFR T790M but not C797S (Group 2); or EGFR C797S but not T790M (Group 3).

7. BLU-945 with Osimertinib Expansion (Phase 2 Group 4): Slots may be reserved forpatients with mutations of interest, but at least 12 slots will be allocated topatients with NSCLC harboring EGFR T790M and C797S mutation.

8. Pretreatment tumor sample (either an archival sample or a sample obtained bypretreatment biopsy) submitted for central analysis. For Phase 1, it is preferablethat pretreatment tumor samples be obtained from a progression lesion, during orafter disease progression on the last EGFR-targeted TKI received. For Phase 2,pre-treatment tumor sample must be obtained during or after disease progression onthe last EGFR-targeted TKI received. Patients without appropriate archival tissue available, where biopsy is notconsidered safe and/or medically feasible, may be discussed with the study medicalmonitor and may be approved for enrollment on a case-by-case basis.

9. Phase 2 Expansion Groups: Patient has at least 1 measurable target lesion evaluableby RECIST 1.1 as assessed by the investigator.

10. Eastern Cooperative Oncology Group (ECOG) performance status is 0-1.

11. Agrees to use contraception consistent with the protocol and local regulations

Exclusion Criteria:

1. Tumor harbors any additional known driver alterations (including but not limited toEGFR exon 20 insertion, or pathologic abnormalities of KRAS, BRAF V600E, NTRK1/2/3,HER2, ALK, ROS1, MET, or RET).

2. NSCLC with mixed cell histology or a tumor with histologic transformation (NSCLC toSCLC, SCLC to NSCLC, or epithelial to mesenchymal transition).

3. Received the following anticancer therapy:

4. EGFR-targeted TKI within 7 days prior to the first dose of study drug.

5. Any immunotherapy or other antibody therapy (including EGFR-targeted antibodiesor bi-specific antibodies) within 28 days prior to the first dose of study drug (immune-related toxicities must have resolved to < Grade 2 prior to startingBLU 945).

6. Any other systemic anticancer therapy within 14 days or 5 half-lives prior tothe first dose of study drug, whichever is the shortest, but with a minimum of 7 days in all circumstances. BLU 945 may be started within these washoutperiods if considered by the Investigator to be safe and within the bestinterest of the patient, with prior Sponsor approval.

7. Radiotherapy to a large field or including a vital organ (including whole brainradiotherapy or stereotactic radiosurgery to brain) within 14 days before thefirst dose of study drug. Participant received radiotherapy to a focal site ofdisease that did not include a vital organ (such as a limb) within 7 daysbefore the first dose of study drug.

8. CNS metastases or spinal cord compression that is associated with progressiveneurological symptoms or requires increasing doses of corticosteroids to control theCNS disease. If a patient requires corticosteroids for management of CNS disease,the dose must have been stable for the 2 weeks preceding treatment. Asymptomatic CNSand leptomeningeal disease is allowed and, when measurable, should be captured astarget lesions.

9. Any of the following abnormalities on the most recent laboratory test prior to thefirst dose of study drug (ie, Cycle 1 Day 1 [C1D1] or screening):

10. Absolute neutrophil count (ANC) <1.0×109/L.

11. Platelet count <75×109/L.

12. Hemoglobin ≤8.0 g/dL (red blood cell transfusion and erythropoietin may be usedto reach at least 8.0 g/dL, but must have been administered at least 2 weeksprior to the first dose of study drug).

13. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3× theupper limit of normal (ULN) if no hepatic metastases are present; >5× ULN ifhepatic metastases are present.

14. Total bilirubin >1.5× ULN; >3× ULN in presence of Gilbert's disease.

15. Estimated (Cockroft-Gault formula) or measured creatinine clearance <40 mL/min.

16. International normalized ratio (INR) >2.3 or prothrombin time (PT) >6 secondsabove control or a patient-specific INR or PT abnormality that the treatinginvestigator considers clinically relevant and/or increases the risk forhemorrhage in that individual patient.

17. Known intracranial hemorrhage and/or bleeding diatheses.

18. Clinically active ongoing interstitial lung disease (ILD) of any etiology, includingdrug-induced ILD, and radiation pneumonitis within 28 days prior to initiation ofstudy treatment. Patients with prior ILD associated with clinically resolved COVID 19 infection may be enrolled upon discussion with, and approval by, the MedicalMonitor.

19. Any unresolved toxicities from prior therapy greater than Common TerminologyCriteria for Adverse Events (CTCAE) Grade 1 or that have not resolved to baseline atthe time of starting the study. Exceptions include alopecia and fatigue, and, upondiscussion with and approval by the Medical Monitor, other toxicities that are notthought to present a risk to patient safety.

20. Mean resting QT interval corrected using Fridericia's formula (QTcF) >450 msec, ahistory of prolonged QT syndrome or Torsades de pointes, or a familial history ofprolonged QT syndrome.

21. Clinically significant, uncontrolled, cardiovascular disease including congestiveheart failure Grade III or IV according to the New York Heart Associationclassification; myocardial infarction or unstable angina within the previous 6months, uncontrolled hypertension, or clinically significant, uncontrolledarrhythmias, including bradyarrhythmia that may cause QT prolongation (eg, Type IIsecond degree heart block or third-degree heart block).

22. History of another primary malignancy (other than completely resected carcinomas insitu) that has been diagnosed or required therapy within 2 years prior to initiationof study treatment. However, upon discussion with the Sponsor, the followingcategories of patients with prior malignancy are eligible to participate:

23. Patients with a previous malignancy that completed all anticancer treatment atleast 2 years before and with no evidence of residual disease from the priormalignancy at registration

24. Patients who have another concurrent malignancy (not lung cancer) that isclinically stable and does not require tumor-directed treatment. (Examplesinclude, but are not limited to, completely resected basal cell carcinoma andsquamous cell carcinoma of skin, curatively treated prostate cancer, breastcancer and early gastric cancer cured by endoscopic mucosal resection orendoscopic submucosal dissection.)

25. Active, uncontrolled infection (viral, bacterial, or fungal) or active tuberculosis,hepatitis B, hepatitis C, AIDS-related illness, or known COVID 19 infection.Controlled infections, including HIV and "cured" hepatitis C (no active fever, noevidence of systemic inflammatory response syndrome) that are stable on antiviraltreatment may be eligible if benefit/risk is justified and permission is grantedfrom the Sponsor.

26. Dose-escalation (Parts 1A and 1B): Received neutrophil or platelet growth factorsupport within 14 days of the first dose of study drug.

27. Requires treatment with a prohibited medication or herbal remedy that cannot bediscontinued at least 2 weeks before the start of study drug administration. BLU 945may be started within 14 days or 5 half-lives of these therapies if considered bythe Investigator to be safe and within the best interest of the patient, with priorSponsor approval.

28. Major surgical procedure within 14 days of the first dose of study drug (proceduressuch as central venous catheter placement, tumor needle biopsy, and feeding tubeplacement are not considered major surgical procedures).