An open label, first-in-human study of BAY 2927088 in participants with advanced non-small cell lung cancer (NSCLC) harboring an EGFR and/or HER2 mutation

Researchers are looking for a better way to treat people who have advanced non-small cell
lung cancer (NSCLC), a group of lung cancers that have spread to nearby tissues or to other
parts of the body.

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)
are proteins that help cells to grow and divide. A damage (also called mutation) to the
building plans (genes) for these proteins in cancer cells leads to a production of abnormal
EGFR and/or HER2. These abnormal proteins drive the growth and the spread of the cancer.

Several EGFR and/or HER2 mutations exist in the cancer cells. Two mutations observed in NSCLC
are called EGFR- or HER2exon20ins and EGFR C797X. The study treatment, BAY2927088, works by
blocking the mutated EGFR protein and also its ex20ins version which are present in NSCLC. It
is also believed to work against HER2 and HER2ex20ins mutations. Researchers think this may
help stop the further spread of NSCLC cancer.

This is the first time that researchers will study BAY2927088 in humans. In this study, the
researchers want to learn more about using BAY2927088 in participants who have NSCLC with
EGFR and/or HER2 mutations including EGFRex20ins and/or HER2ex20ins mutations.

The main aims of this study are to find for BAY2927088

- how safe BAY2927088 is

- how it affects the body (also referred to as tolerability)

- how BAY2927088 moves into, through and out of the body

- the maximum amount of BAY2927088 that the participants can take without too many side
effects.

The researchers will also study the action of BAY2927088 against the cancer. The study will
have three parts: Dose Escalation, Backfill, and Dose Expansion. Each participant of the
first, so called dose escalation part, will be assigned to one of specific sequential dose
groups for BAY2927088. The amount of BAY2927088 that is given increases stepwise from one
group to the next.

The second may be initiated at any dose that has already been tested during the first part
and found to be safe and to have either reached a predicted efficacious exposure range or to
have induced an objective response. The first part and second part will run concurrently.

The participants of the third, so called dose expansion part, will receive the most
appropriate dose of BAY2927088 found in the first and second parts. The third part may be
initiated in parallel with the first and second part based on emerging data.

During the study, the participants will take the study treatment in 3 week periods called
"cycles". They will in general take BAY2927088 once daily until their cancer gets worse,
until they have medical problems, until they leave the study or until the study is
terminated. Participants will have around 5 visits in each cycle.

During the study, the study team will:

- take blood and urine samples

- take regular CT or MRI scans to check if the participants' cancer has gotten better or
worse

- check the participants' overall health and heart health

- ask the participants questions about how they are feeling and what adverse events they
are having.

An adverse event is any medical problem that a participant has during a study. Doctors keep
track of all adverse events that happen in studies, even if they do not think the adverse
events might be related to the study treatments.

Inclusion Criteria:

- Documented histologically or cytologically confirmed locally advanced NSCLC, not
suitable for definitive therapy or recurrent or metastatic NSCLC at screening (small
cell or mixed histologies are excluded).

- Documented disease progression after treatment with at least one prior systemic
therapy for advanced disease. Participants who do not have standard of care access due
to any reason, are intolerant to, or are not eligible for standard treatments, may
also be eligible.

- Adequate archival tumor tissue (ideally taken after last targeted treatment and not
older than 6 months) has to be available, either from primary or metastatic sites. If
archival material is not available, a fresh tumor biopsy should be performed if
feasible and if the procedure poses no significant risk for the participant.

- Measurable disease by RECIST v1.1 with at least one lesion not chosen for biopsy
during the screening period (if a biopsy is taken during screening) that can be
accurately measured at baseline with computed tomography (CT) or magnetic resonance
imaging (MRI) and that is suitable for accurate repeated measurements. A biopsied
lesion should not be used as a target lesion for RECIST 1.1 tumor assessments.
Previously irradiated lesions must have shown progression to be considered measurable.

- Documented activating EGFR and/or HER2 mutation assessed by a Clinical Laboratory
Improvement Amendments (CLIA)-certified (United States [US] sites) or an equally
accredited (outside of the US) local laboratory

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

- Minimum life expectancy of 12 weeks.

- Adequate bone marrow function as assessed by the following laboratory tests to be
conducted within 7 days before the first dose of study treatment:

1. Hemoglobin ≥ 9.0 g/dL. Criteria must be met without erythropoietin dependency and
without packed red blood cell (pRBC) transfusion within 2 weeks prior to testing.

2. Platelets ≥ 100 × 10^9 cells/L.

3. Absolute neutrophil count ≥ 1.5 ×10^9 cells/L. Criteria must be met without the
use of hematopoietic growth factors (e.g., G-CSF) within 2 weeks prior to
testing.

- Adequate kidney function as assessed by following laboratory test to be conducted
within 7 days before the first dose of study treatment:

a. Estimated glomerular filtration rate (eGFR) > 60 mL/min per 1.73 m^2 according to
the Modification of Diet in renal Disease Study Group (MDRD) formula.

- Adequate liver function as assessed by following laboratory tests to be conducted
within 7 days before the first dose of study treatment:

1. Total bilirubin ≤ 1.5 × ULN (or ≤ 3 X ULN for participants with documented
Gilbert-Meulengracht Syndrome, or for participants with hyperbilirubinemia
considered due to liver metastasis).

2. Aspartate transaminase and alanine transaminase ≤ 2.5 × ULN (or ≤ 5 × ULN if due
to liver involvement by tumor).

Exclusion Criteria:

- Treatment with an EGFR tyrosine kinase inhibitor (TKI) ≤ 8 days or 5x the terminal
phase, elimination half-lives, whichever is shorter, prior to the first dose of study
drug.

- Treatment with a systemic anti-cancer treatment (excluding EGFR TKIs as described
above) ≤ 14 days prior to the first dose of study drug.

- Radiation therapy, stereotactic radiosurgery (SRS) and palliative radiation ≤ 14 days
prior to the first dose of study drug.

- Treatment with immunotherapy ≤ 28 days prior to the first dose of study drug.

- Have any unresolved toxicity of Grade ≥ 2 from previous anti-cancer treatment, except
for alopecia and skin pigmentation. Participants with chronic, but stable Grade 2
toxicities may be allowed to enroll after agreement between the Investigator and
Sponsor.

- Any history of primary brain or leptomeningeal disease (symptomatic or asymptomatic),
presence of symptomatic central nervous system (CNS) metastases, or CNS metastases
that require local treatment (such as radiotherapy or surgery).

- History of spinal cord compression or brain metastases with the following exceptions:

1. Participants with treated brain metastases that are asymptomatic at screening and
who are off or receiving low-dose of corticosteroids (≤10 mg prednisone or
equivalent) for at least 7 days prior to first dose of BAY 2927088 are eligible
to enroll in Dose Escalation and Backfill.

2. Participants with treated brain metastases that are asymptomatic at screening are
eligible in Dose Expansion if all of the following criteria are met:

- there is no evidence of progression (new or enlarging brain metastases) for
at least 4 weeks after CNS-directed treatment, as ascertained by clinical
examination and brain imaging (MRI or CT) during the screening period.

- Participants must be off or receiving low-dose of corticosteroids (≤10 mg
prednisone or equivalent) for 7 days prior to first dose of BAY2927088.

3. Participants with history of spinal cord compression >3 months from definitive
therapy and stable by imaging (MRI or CT) during the screening period and
clinically asymptomatic.

- History of congestive heart failure (CHF) Class >II according to the New York Heart
Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring
treatment (e.g. ventricular arrhythmias, atrial fibrillation) or any clinically
important abnormalities in rhythm, conduction or morphology or resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval >250 msec)

- Participants with:

1. Known human immunodeficiency virus (HIV), except as noted below: Participants
with history of HIV infection are eligible at the Investigator's discretion
provided that: • CD4+ T-cell (CD4+) counts are ≥ 350 cells/uL • The participant
has been on established antiretroviral therapy (ART) for at least 4 weeks prior
to the start of study drug and has an HIV viral load less than 400 copies/mL
prior to start of the study treatment • The ART being used does not contain
strong inducers or inhibitors of CYP3A4, and is not anticipated to cause
overlapping toxicities with study drug • The participant has not had an
opportunistic infection within the past 12 months

2. Active Hepatitis B infection (positive for Hepatitis B surface antigen [HbsAg])
and Hepatitis B virus [HBV] DNA).

3. Active Hepatitis C infection (positive anti-HCV Antibody and quantitative HCV RNA
results greater than the lower limits of detection of the assay).

NOTE: Participants with history of chronic HBV or HCV infection are eligible at
the Investigator's discretion provided that the disease is stable and
sufficiently controlled under treatment.

- Use of strong CYP3A4 inhibitors and inducers from 14 days prior to first
administration of study drug. Strong CYP3A4 inhibitors and inducers are prohibited
during the study and until Safety FU (follow up) visit.