Study of ORIC-114 in Patients with Advanced Solid Tumors Harboring an EGFR or HER2 Alteration

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced or metastatic solid tumorwith a documented EGFR or HER2 exon 20 insertion mutation or atypical EGFR mutationas determined by any nucleic acid-based diagnostic testing method, or HER2amplification/overexpression as determined by an immunohistochemistry (IHC) or an insitu hybridization (ISH) test

1. Part I Dose Escalation (CLOSED) Any solid tumor with

• EGFR exon 20 insertion mutation
• HER2 exon 20 insertion mutation
• Atypical EGFR mutations (NSCLC only) (Appendix 8)
• HER2 amplification or overexpression (HER2+)
• Previously received and progressed on or after available standardtherapies and for whom additional standard therapy is consideredunsuitable or intolerable

2. Part I Extension (ONGOING)

• Cohort IA: Patients with HER2+ breast cancer previously received andprogressed on or after available standard therapies and for whomadditional standard therapy is considered unsuitable or intolerable
• Cohort IB: NSCLC patients with EGFR exon 20 insertion mutation previouslytreated with chemotherapy and amivantamab
• Cohort IC: Treatment-naïve NSCLC patients with EGFR exon 20 insertionmutation

3. Part II Dose Optimization (ONGOING): NSCLC patients with

• Cohort IIA: EGFR exon 20 insertion mutation, patients must have receivedplatinum-based chemotherapy or other chemotherapy regimen if platinum-based chemotherapy was contraindicated. Additionally, patients must benaïve to an EGFR exon 20 targeted agent, ie, must have declined or beineligible for all available exon 20 targeted therapies with provenbenefit

• Cohort IIB: HER2 exon 20 insertion mutation, patients must have receivedplatinum-based chemotherapy or other chemotherapy regimen if platinum-based chemotherapy was contraindicated. Additionally, patients must benaïve to a HER2 exon 20 targeted TKI

• Cohort IIC: Atypical EGFR mutation, patients may have received a priorEGFR TKI

• 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 andasymptomatic

• 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 notsuspected clinically by the Investigator; the subject must be free of neurologicalsymptoms of LMD

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

• Past medical history of interstitial lung disease (ILD), drug induced ILD, radiationpneumonitis which required steroid treatment, or any evidence of clinically activeILD

• Known, symptomatic human immunodeficiency virus (HIV) infection

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

• Active gastrointestinal disease (eg, Crohn's disease, ulcerative colitis, or shortgut syndrome) or other malabsorption syndromes

• Any other concurrent serious uncontrolled medical, psychological, or addictiveconditions