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

Activating EGFR driver mutations are common in NSCLC and have also been
identified at lower frequency in other malignancies. Classical EGFR alterations
account for ~88% of all EGFR mutations in NSCLC. The additional 12% of EGFR
mutations include exon 20 insertions, uncommon point mutations (e.g., G719X,
L861X, S768I/V and E709X), and other alterations (Harrison et al. 2020, Remon
et al. 2020). The overall frequency of driver EGFR mutations in NSCLC is 10-15%
in Caucasians and 40-45% in Asians. EGFR ex20ins mutations occur in 2-3% of all
NSCLC irrespective of ethnicity and are found more often in women, nonsmokers,
and in tumors with adenocarcinoma histology. NSCLCpatients with EGFR ex20ins
have a worse prognosis compared to those with classical EGFR mutations (median
OS: 16.5 versus 33.0 months) or some of the rare EGFR driver mutations (median
OS 16.8 versus 22.5 months) (Yasuda et al. 2013). EGFR ex20ins mutations have
been identified at low frequency (<1%) in cancers other than NSCLC (e.g.,
bladder and endometrial cancer) (Consortium 2020). There are currently only two
approved targeted therapies for NSCLC harboring an EGFR ex20ins mutation.
Amivantamab (EGFR/MET bispecific antibody) received accelerated approval from
the FDA on 21 MAY 2021. In addition to amivantamab, mobocertinib (EGFR TKI)
received accelerated approval from the FDA on 15 SEP 2021. There are also a
variety of other investigational agents targeting EGFR ex20ins in earlier
phases of clinical development (Harrison et al. 2020, Remon et al. 2020). Exon
20 insertion mutations confer primary resistance to the targeted therapies that
have been approved for use on other EGFR driver mutations, and correlate with a
very poor prognosis (Vyse and Huang 2019). These mutations are located in the
tyrosine kinase domain and occur as heterogeneous in-frame insertions or
duplications of between 3 and 21 bp clustered between amino acids 762 and 774.
Unlike classical EGFR mutations, EGFR ex20ins mutations do not affect the
ATP-binding pocket that is required for kinase activity, but rather form a
wedge at the end of the C-helix to promote an active kinase conformation
without increasing affinity for EGFR TKIs (Arcila et al. 2013, Robichaux et al.
2018, Yasuda et al. 2013). Activating driver mutations in HER2 are found in
2-4% of advanced NSCLC in Caucasian and Asian populations, with the vast
majority being HER2 ex20ins (96%) and a minority consisting of point mutations
(Remon et al. 2020). IIn addition, HER2 ex20ins mutations have been detected at
low frequency (<1%) in other cancer types (e.g., breast, ovarian, and bladder
cancer)(Consortium 2020). Recently, FDA granted accelerated approval to
fam-trastuzumab deruxtecan-nxki (Enhertu) in August 2022 for adult patients
with unresectable or metastatic NSCLC whose tumors have activating human
epidermal growth factor receptor 2 HER2 (ERBB2) mutations, as detected by an
FDA-approved test, and who have received a prior systemic therapy. Targeted
therapies have been approved by the FDA for first-line treatment of patients
with NSCLC harboring EGFR classical mutations and some of the rare EGFR driver
point mutations. The preferred first-line treatment for patients with NSCLC
harboring a classical mutation is osimertinib, which demonstrated superior
overall survival (OS) and a similar safety profile compared to erlotinib or
gefitinib (median OS of 38.6 months for osimertinib and 31.8 months for
erlotinib/gefitinib) (Ramalingam et al. 2019). Afatinib is FDA-approved for
first-line treatment of patients with NSCLC harboring specific EGFR driver
point mutations (i.e., G719X, S768I, and L861Q) (Harrison et al. 2020).
Although tumors harboring EGFR mutations often exhibit an initial response to
approved targeted therapy, resistance invariably develops. Resistance may be
due to the acquisition of additional alterations not directly related to EGFR
(e.g., amplification of MET or an activating mutation in HER2), or to the
acquisition of a secondary EGFR mutation (e.g., EGFR T790M or EGFR C797X
following treatment with EGFR TKIs such as erlotinib or osimertinib,
respectively) (Leonetti et al. 2019). When resistance is due to an acquired
secondary EGFR mutation, the initial driver EGFR mutation is retained.
Subsequent treatment with an alternative EGFR TKI that remains active in the
presence of the secondary mutation may successfully overcome the acquired
resistance. For example, tumors that develop resistance to erlotinib via the
acquisition of the EGFR T790M secondary mutation are responsive to osimertinib
(Jänne et al. 2015).Initial clinical development for BAY 2927088 will focus on
patients with advanced NSCLC (i.e., those harboring an ex20ins driver mutation
in EGFR or HER2), and those who have developed resistance to other targeted
therapies via acquisition of an EGFR secondary
mutation to which BAY 2927088 retains activity (e.g., EGFR C797X), or via
acquisition of an activating HER2 mutation.The broad activity of BAY 2927088
against a wide repertoire of EGFR and HER2 driver mutations, the retention of
activity in the presence of some of the known secondary EGFR resistance
mutations, and the anticipated wide therapeutic window in the clinic due to
relatively weak activity against the wildtype EGFR, offer BAY 2927088 the
potential to benefit a variety of patients with NSCLC who are naïve to other
targeted therapies or have acquired resistance to these agents.

This study has been transitioned to CTIS with ID 2023-503795-24-00 check the CTIS register for the current data.

Primairy objectives:
- Determine the safety and tolerability of orally administered BAY 2927088
- Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD)
of BAY 2927088
- Characterize pharmacokinetics (PK) of BAY 2927088

Secondary objectives:
- Assess the preliminary anti-tumor activity of BAY 2927088
- Determine the recommended Phase II dose (RP2D) of BAY 2927088

This is a non-randomized, open-label, single-arm, multicenter Phase 1 FiH trial
to determine the MTD or MAD and determine the RP2D of BAY 2927088. The study is
comprised of Dose Escalation, Backfill, and Dose Expansion parts.

BAY 2927088 will be administered in 21-day cycles with continual daily oral
administration and no treatment pause between cycles. Alternative dosing
schedules may be explored.

Visits: 21-day treatment cycles, see Schedule of Activities (SoA) in the
protocol.

Measurements:
- Vital signs and physical examination - No risks. Possible discomfort around
the arm due to the blood pressure cuff.
- ECOG-PS questionnaire - No risks.
- Blood draw - risks: Pain, Bruising, Feeling faint or dizzy, Infection.
- Urinalysis - No risks.
- Electrocardiogram (ECG) - Risk: Skin irritation.
- Diary - No risks.
- Echocardiogram - No risks.
- Imaging using magnetic resonance imaging (MRI). Risks: discomfort in small
spaces; nausea, headache and/or allergic reaction to contrast medium.
- Computed tomography scan (CT scan) / Positron emission tomography computed
tomography (PET-CT scan) - Risks: radiation exposure; discomfort in small
spaces; contrast dye: flushing, nausea or allergic reaction. The injection may
also cause pain, bleeding, bruising, hives, or itching.
- Bone scintigraphy - Risks: radiation exposure; The injection may also cause
pain, bruising, swelling at the injection site, bleeding, leakage of fluid
around the vein, as well as infection or an allergic reaction.
- Tumor tissue (archived) - No risks.
- Surgical biopsy or core needle biopsy - Risks: Pain, bleeding, bruising,
infection, nerve damage, scarring. If the correct tissue is not collected, the
procedure may need to be repeated. Anesthetics (local or general): rash, severe
allergic reaction (difficulty breathing or drop in blood pressure), nausea,
vomiting.
- Visual acuity - No risks.
- Slit lamp - Risks: Allergic reaction to eye drops, Temporary blurred vision,
Increased pressure in the eye (very rare), Mild and momentary discomfort caused
by the strong light of the device (this will not last or cause no damage)

BAY 2927088 may have a therapeutic benefit, however this cannot be guaranteed.
Patients are at risk of side effects.