A Phase 1/2 Study Targeting Acquired Resistance Mechanisms in Patients with EGFR Mutant Non-Small Cell Lung Cancer

1. >=18 years of age at the time of signing the informed consent.
2. Pathologically confirmed, definitively diagnosed, metastatic NSCLC harboring
an activating EGFR mutation.
3. Previously received at least 1 prior EGFR-targeted TKI with activity against
the T790M mutation, such as osimertinib.
a. Phase 1 Part 1B and Phase 2 Group 4: Patients must have experienced
progressive disease while on osimertinib, were able to tolerate prior
osimertinib 80 mg QD dose, and continuing on osimertinib is deemed to be in the
patient*s best interests in the opinion of the Investigator. Patients who have
discontinued osimertinib may be eligible if no more than 6 weeks elapse between
the discontinuation of prior osimertinib and resumption of osimertinib on study.
4. Tumor mutation profile determined locally via a Sponsor-approved testing
methodology (NGS is preferred and will be required for Phase 2), using tumor
tissue (ideally from a progressing lesion) and/or ctDNA in plasma. For Phase 1,
it is preferable that samples used for analysis be obtained during or after
disease progression on the last EGFR-targeted TKI received. For Phase 2,
pre-treatment tumor sample must be obtained during or after disease progression
on the last EGFR-targeted TKI received.
a. Dose Escalation (Phase 1 Part 1A and Part 1B): At each dose level, slots may
be reserved for patients with the mutations of interest.
b. BLU-945 Monotherapy Expansion (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).
c. BLU-945 with Osimertinib Expansion (Phase 2 Group 4): Slots may be reserved
for patients with mutations of interest, but at least 12 slots will be
allocated to patients with NSCLC harboring EGFR T790M and C797S mutation.
5. Pretreatment tumor sample (either an archival sample or a sample obtained by
pretreatment biopsy) submitted for central analysis. For Phase 1, it is
preferable that pretreatment tumor samples be obtained from a progressing
lesion, during or after disease progression on the last EGFR-targeted TKI
received. For Phase 2, pre-treatment tumor sample must be obtained during or
after disease progression on the last EGFR-targeted TKI received. Patients
without appropriate archival tissue available, where biopsy is not considered
safe and/or medically feasible, may be discussed with the study medical monitor
and may be approved for enrollment on a case-by-case basis.
6. Patients enrolled in Phase 1 Part 1A at doses expected to result in
efficacious exposure levels (anticipated to be >=100 mg QD, but may be modified
by the Sponsor based on emerging PK and clinical data) must consent to undergo
on-treatment biopsy for central submission of tumor sample. Following approval
from the Sponsor, on-treatment biopsy may be omitted for patients for whom the
investigator does not feel that biopsy would be safe and/or feasible.
Collection of these tumor samples may be discontinued for particular
dose-escalation cohorts or expansion groups, if the Sponsor determines that
adequate data have been obtained.
7. Phase 2 Expansion Groups: Patient has at least 1 measurable target lesion
evaluable by RECIST 1.1 as assessed by the investigator.
8. Able to swallow an oral medication.
9. Eastern Cooperative Oncology Group (ECOG) performance status is 0-1.
10. Agrees to use contraception consistent with the protocol and local
regulations, as outlined in Section 5.4.2.
11. Patient or legal guardian provides informed consent to participate in the
study.

1. Tumor harbors any additional known driver alterations (including but not
limited to EGFR 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 to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition).
3. Received the following anticancer therapy:
a. EGFR-targeted TKI within 7 days prior to the first dose of study drug. Note:
patients in Phase 1 Part 1B and Phase 2 Group 4 do not require a wash-out
period for osimertinib.
b. Any immunotherapy or other antibody therapy (including EGFR-targeted
antibodies or 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
starting BLU 945).
c. Any other systemic anticancer therapy within 14 days or 5 half-lives prior
to the 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 washout
periods if considered by the Investigator to be safe and within the best
interest of the patient, with prior Sponsor approval.
d. Radiotherapy to a large field or including a vital organ (including whole
brain radiotherapy or stereotactic radiosurgery to brain) within 14 days before
the first dose of study drug. Participant received radiotherapy to a focal site
of disease that did not include a vital organ (such as a limb) within 7 days
before the first dose of study drug.
4. CNS metastases or spinal cord compression that is associated with
progressive neurological symptoms or requires increasing doses of
corticosteroids to control the CNS disease. If a patient requires
corticosteroids for management of CNS disease, the dose must have been stable
for the 2 weeks preceding treatment. Asymptomatic CNS and leptomeningeal
disease is allowed and, when measurable, should be captured as target lesions.
5. Any of the following abnormalities on the most recent laboratory test prior
to the first dose of study drug (ie, Cycle 1 Day 1 [C1D1] or screening):
a. Absolute neutrophil count (ANC) <1.0×109/L.
b. Platelet count <75×109/L.
c. Hemoglobin <=8.0 g/dL (red blood cell transfusion and erythropoietin may be
used to reach at least 8.0 g/dL, but must have been administered at least 2
weeks prior to the first dose of study drug).
d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3× the
upper limit of normal (ULN) if no hepatic metastases are present; >5× ULN if
hepatic metastases are present.
e. Total bilirubin >1.5× ULN; >3× ULN in presence of Gilbert*s disease.
f. Estimated (Cockroft-Gault formula, Appendix 1) or measured creatinine
clearance <40 mL/min.
g. International normalized ratio (INR) >2.3 or prothrombin time (PT) >6
seconds above control or a patient-specific INR or PT abnormality that the
treating investigator considers clinically relevant and/or increases the risk
for hemorrhage in that individual patient.
6. Known intracranial hemorrhage and/or bleeding diatheses.
7. Clinically active ongoing interstitial lung disease (ILD) of any etiology,
including drug-induced ILD, and radiation pneumonitis within 28 days prior to
initiation of study treatment. Patients with prior ILD associated with
clinically resolved COVID 19 infection may be enrolled upon discussion with,
and approval by, the Medical Monitor.
8. Any unresolved toxicities from prior therapy greater than Common Terminology
Criteria for Adverse Events (CTCAE) Grade 1 or that have not resolved to
baseline at the time of starting the study. Exceptions include alopecia and
fatigue, and, upon discussion with and approval by the Medical Monitor, other
toxicities that are not thought to present a risk to patient safety.
9. Mean resting QT interval corrected using Fridericia*s formula (QTcF) >450
msec, a history of prolonged QT syndrome or Torsades de pointes, or a familial
history of prolonged QT syndrome.
10. Clinically significant, uncontrolled, cardiovascular disease including
congestive heart failure Grade III or IV according to the New York Heart
Association classification; myocardial infarction or unstable angina within the
previous 6 months, uncontrolled hypertension, or clinically significant,
uncontrolled arrhythmias, including bradyarrhythmia that may cause QT
prolongation (eg, Type II second degree heart block or third-degree heart
block).
11. History of another primary malignancy (other than completely resected
carcinomas in situ) that has been diagnosed or required therapy within 2 years
prior to initiation of study treatment. However, upon discussion with the
Sponsor, the following categories of patients with prior malignancy are
eligible to participate:
a. Patients with a previous malignancy that completed all anticancer treatment
at least 2 years before and with no evidence of residual disease from the prior
malignancy at registration
b. Patients who have another concurrent malignancy (not lung cancer) that is
clinically stable and does not require tumor-directed treatment. (Examples
include, but are not limited to, completely resected basal cell carcinoma and
squamous cell carcinoma of skin, curatively treated prostate cancer, breast
cancer and early gastric cancer cured by endoscopic mucosal resection or
endoscopic submucosal dissection.
12. 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, no evidence of systemic inflammatory response syndrome) that are
stable on antiviral treatment may be eligible if benefit/risk is justified and
permission is granted from the Sponsor.
13. Dose-escalation (Parts 1A and 1B): Received neutrophil or platelet growth
factor support within 14 days of the first dose of study drug.
14. Requires treatment with a prohibited medication or herbal remedy (as
specified in Section 6.9.1 and Appendix 2) that cannot be discontinued at least
2 weeks before the start of study drug administration. BLU 945 may be started
within 14 days or 5 half-lives of these therapies if considered by the
Investigator to be safe and within the best interest of the patient, with prior
Sponsor approval.
15. Major surgical procedure within 14 days of the first dose of study drug
(procedures such as central venous catheter placement, tumor needle biopsy, and
feeding tube placement are not considered major surgical procedures).
16. Unwilling or unable to comply with scheduled visits, drug administration
plan, laboratory tests, or other study procedures and study restrictions.
17. Patient is a women who is not postmenopausal or surgically sterile, and is
unwilling to abstain from sexual intercourse or employ highly effective
contraception during the study drug administration period and for at least 30
days after the last dose of study drug OR is a man who is not surgically
sterile, and is unwilling to abstain from sexual intercourse or employ highly
effective contraception during the study drug administration period and for at
least 90 days after the last dose of study drug. Refer to Section 5.4.2 for
acceptable methods of contraception.
18. Patient is a pregnant female, as documented by a serum beta human chorionic
gonadotropin (β hCG) pregnancy test consistent with pregnancy, obtained within
7 days prior to the first dose of study drug. Females with β hCG values that
are within the range for pregnancy but are not pregnant (false-positives) may
be enrolled with written consent of the Sponsor, after pregnancy has been ruled
out. Females of non-childbearing potential (as defined in Section 5.4.2) do not
require a serum β hCG test.
19. Patient is breastfeeding.
20. Known hypersensitivity to BLU 945 or any of its ingredients.
21. Any prior or ongoing clinically significant illness, medical condition,
surgical history, physical finding, or laboratory abnormality that, in the
Investigator*s or Sponsor*s opinion, could affect the safety of the patient;
alter the absorption, distribution, metabolism, or excretion of the study drug;
or impair the assessment of study results.