ORIC-114 in Combination With Subcutaneous Amivantamab in Patients With EGFR Exon20 Insertion Mutant NSCLC

Phase 1b Study of ORIC-114 in Combination With Amivantamab in Patients With EGFR Exon20 Insertion Mutant NSCLC

The purpose of this study is to establish the recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of ORIC-114 in combination with subcutaneous (SC) amivantamab in patients with advanced or metastatic NSCLC harboring an EGFR exon 20 insertion mutation.

Study Overview

• Status: Recruiting
• Conditions: NSCLC; Solid Tumors; EGFR-mutated NSCLC; EGFR Exon 20 Insertion Mutations
• Intervention / Treatment: Drug: ORIC-114 Dose 1 + amivantamab; Drug: ORIC-114 Dose 2 + amivantamab; Drug: ORIC-114 Dose 3 + amivantamab

Detailed Description

ORIC-114, is a brain penetrant, selective, orally bioavailable, irreversible small molecule inhibitor designed to target EGFR exon 20 insertion mutations, making it a promising therapeutic candidate for development in patients whose tumors harbor these alterations, including those with CNS metastases.

Amivantamab is a bispecific EGFR-directed and MET receptor-directed antibody indicated in combination with carboplatin and pemetrexed for the first line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations and also as a single agent in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

This is an open-label, single arm, multicenter, dose escalation followed by dose expansion study to assess the safety and preliminary antitumor activity of ORIC-114 in combination with SC amivantamab, in patients with locally advanced or metastatic NSCLC harboring an EGFR exon 20 insertion mutations.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: ORIC Clinical; Phone Number: 650-388-5600; Email: clinical@oricpharma.com

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 03000
      • Not yet recruiting
      • Peter Maccallum Cancer Centre
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Not yet recruiting
      • The Princess Margaret Hospital
• United States
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • NYU Langone Health
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic NSCLC with a documented EGFR exon 20 insertion mutation as determined locally by any nucleic acid-based diagnostic testing method; all tests should be performed in a CLIA certified or equivalently accredited laboratory

• Prior Therapies:

  1. Dose Escalation: Patients may have previously received and progressed on or after platinum-based chemotherapy or may be treatment naïve
  2. Dose Expansion: Patients must not have received any prior therapy; at time of enrollment, patients must decline, or be ineligible for all available standard of care therapies with proven benefit
• Agreement and ability to undergo a pretreatment biopsy, provided the procedure is clinically feasible and not deemed unsafe by the investigator
• Measurable disease according to RECIST 1.1
• Patients with asymptomatic CNS metastases are eligible
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate organ function

Exclusion Criteria:

• Known small cell lung cancer transformation
• Leptomeningeal disease
• Spinal cord compression not definitively treated with surgery or radiation
• Prior immunotherapy
• Past medical history of interstitial lung disease (ILD), drug induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
• Active gastrointestinal disease (eg, Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact absorption of ORIC-114

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Dose Escalation level 1; ORIC-114 + amivantamab	Drug: ORIC-114 Dose 1 + amivantamab; ORIC-114 oral daily, amivantamab subcutaneous weekly for 4 weeks followed by every 4 week injection
Experimental: Part 1 Dose Escalation level 2; ORIC-114 + amivantamab	Drug: ORIC-114 Dose 2 + amivantamab; ORIC-114 oral daily, amivantamab subcutaneous weekly for 4 weeks followed by every 4 week injection
Experimental: Part 1 Dose Escalation level 3; ORIC-114 + amivantamab	Drug: ORIC-114 Dose 3 + amivantamab; ORIC-114 oral daily, amivantamab subcutaneous weekly for 4 weeks followed by every 4 week injection
Experimental: Part 2 Dose Expansion; Two potential ORIC-114 dose levels + amivantamab	Drug: ORIC-114 Dose 2 + amivantamab; ORIC-114 oral daily, amivantamab subcutaneous weekly for 4 weeks followed by every 4 week injection; Drug: ORIC-114 Dose 3 + amivantamab; ORIC-114 oral daily, amivantamab subcutaneous weekly for 4 weeks followed by every 4 week injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D)	RP2D of ORIC-114 in combination with amivantamab by interval 3+3 dose escalation design	12 months
Objective response rate (ORR)	Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	12 months
Duration of response (DOR)	Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	12 months
Progression-free survival (PFS)	Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma PK parameters	Peak Plasma Concentration (Cmax)	28 Days
Plasma PK parameters	Time of maximal plasma concentration (Tmax)	28 Days
Plasma PK parameters	Area under the plasma concentration vs time curve (AUC)	28 Days
Plasma PK parameters	Apparent plasma terminal elimination half-life (t1/2)	28 Days
BICR-Objective response rate (ORR)	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM	12 months
BICR-Duration of response (DOR)	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM	12 months
BICR-Progression-free survival (PFS)	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM	12 months
Intracranial Objective response rate (ORR)	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM	12 months
Intracranial Progression-free survival (PFS)	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM	12 months

Collaborators and Investigators

• Sponsor: ORIC Pharmaceuticals
• Collaborators: Janssen Research and Development LLC
• Investigators: Study Director: Pratik S. Multani, MD, MS, ORIC Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: February 3, 2025
• First Submitted That Met QC Criteria: February 6, 2025
• First Posted (Actual): February 10, 2025

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; EGFR mutations; Amivantamab; ORIC-114; EGFR exon 20 insertion mutations; EGFR exon20
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Antineoplastic Agents; amivantamab
• Other Study ID Numbers: ORIC-114-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No