The purpose of this study is to establish the recommended dose, safety, and anti-cancer effect of a targeted therapy called ORIC-114 by itself, or in combination with chemotherapy, when given to people with advanced solid cancers with EGFR or HER2 alterationsAn Open-Label, Phase 1/2 Study of ORIC-114 As a Single Agent or in Combination with Chemotherapy, in Patients with Advanced Solid Tumors Harboring an EGFR or HER2 Alteration

Inclusion

• 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

  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 standard therapies and for whom additional standard therapy is considered unsuitable or intolerable

  2. Part I Extension (ONGOING)

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

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

     • Cohort IIA: EGFR exon 20 insertion mutation, patients must have received platinum-based chemotherapy or other chemotherapy regimen if platinum- based chemotherapy was contraindicated. Additionally, patients must be naïve to an EGFR exon 20 targeted agent, ie, must have declined or be ineligible for all available exon 20 targeted therapies with proven benefit
     • Cohort IIB: HER2 exon 20 insertion mutation, patients must have received platinum-based chemotherapy or other chemotherapy regimen if platinum- based chemotherapy was contraindicated. Additionally, patients must be naïve to a HER2 exon 20 targeted TKI
     • Cohort IIC: Atypical EGFR mutation, patients may have received a prior EGFR 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 and asymptomatic
• ECOG performance status of 0 or 1
• Adequate organ function