An Open-Label, Phase 1/1b Study of ORIC-114 in Patients with Advanced Solid Tumors Harboring an EGFR or HER2 Alteration

The purpose of this study is to establish the recommended Phase 2 dose (RP2D) and/or maximum
tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor
activity of ORIC-114 as a Single Agent or in Combination with Chemotherapy when administered
to patients with advanced solid tumors harboring an EGFR or HER2 alteration.

Inclusion Criteria:

- Histologically or cytologically confirmed locally advanced or metastatic solid tumor
with a documented EGFR or HER2 exon 20 insertion mutation or atypical EGFR mutation as
determined by any nucleic acid-based diagnostic testing method, or HER2
amplification/overexpression as determined by an immunohistochemistry (IHC) or an in
situ hybridization (ISH) test

- Previously received and progressed on or after available standard therapies and for
whom additional standard therapy is considered unsuitable or intolerable

- In Parts I and II NSCLC patients must have received platinum-based chemotherapy
or other chemotherapy regimen if platinum-based chemotherapy is contraindicated

- Part II Dose Optimization Cohort IIA: patients must either be naïve to an EGFR
exon 20 targeted agent or only have received prior amivantamab, Cohort IIB:
patients must be naïve to a HER2 targeted TKI, Cohort IIC: patients may have
received a prior EGFR TKI

- In Part III, patients may have received any number of prior treatments

- Agreement and ability to undergo pretreatment biopsy

- Measurable disease according to RECIST 1.1

- CNS involvement, which is either previously treated and controlled, or untreated and
asymptomatic

- ECOG performance status of 0 or 1

- Adequate organ function

Exclusion Criteria:

- Known EGFR T790M mutation

- Leptomeningeal disease and spinal cord compression

-- Except if LMD has been reported radiographically on baseline MRI, but is not
suspected clinically by the Investigator; the subject must be free of neurological
symptoms of LMD

- History of class III or IV congestive heart failure or severe non-ischemic
cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or
ventricular arrhythmia within the previous 6 months

- Past medical history of interstitial lung disease (ILD), drug induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active ILD

- Known, symptomatic human immunodeficiency virus (HIV) infection

- Known active infection requiring treatment or history of hepatitis B virus (HBV) or
hepatitis C virus (HCV). Patients positive for HBsAg but normal HBV DNA level are
allowed.

- Active gastrointestinal disease (eg, Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes

- Any other concurrent serious uncontrolled medical, psychological, or addictive
conditions