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

Phase 1

Recruiting

• Conditions: EGFR Exon 20 Insertion Mutations; NSCLC; Solid Tumors; EGFR-mutated NSCLC
• Interventions: Drug: ORIC-114 Dose 1 + amivantamab; Drug: ORIC-114 Dose 2 + amivantamab; Drug: ORIC-114 Dose 3 + amivantamab

• Registration Number: NCT06816992
• Lead Sponsor: ORIC Pharmaceuticals

Brief Summary

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.

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 Timeline

• Status Verified: 2025-02
• Study First Submitted: 2025-02-03
• Study First Submitted QC: 2025-02-06
• Study First Posted: 2025-02-10
• Study Start: 2025-02-27
• Last Update Submitted: 2025-03-17
• Last Update Posted: 2025-03-20
• Primary Completion: 2026-05
• Study Completion: 2027-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 76

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1 Dose Escalation level 1	ORIC-114 Dose 1 + amivantamab	ORIC-114 + amivantamab
Part 1 Dose Escalation level 2	ORIC-114 Dose 2 + amivantamab	ORIC-114 + amivantamab
Part 1 Dose Escalation level 3	ORIC-114 Dose 3 + amivantamab	ORIC-114 + amivantamab
Part 2 Dose Expansion	ORIC-114 Dose 2 + amivantamab	Two potential ORIC-114 dose levels + amivantamab
Part 2 Dose Expansion	ORIC-114 Dose 3 + amivantamab	Two potential ORIC-114 dose levels + amivantamab

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Plasma PK parameters	28 Days	Apparent plasma terminal elimination half-life (t1/2)
Intracranial Objective response rate (ORR)	12 months	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM
BICR-Duration of response (DOR)	12 months	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM
BICR-Objective response rate (ORR)	12 months	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM
BICR-Progression-free survival (PFS)	12 months	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM
Intracranial Progression-free survival (PFS)	12 months	Blinded independent central review (BICR) according to RECIST 1.1 and RANO-BM

Trial Locations

Locations (4)

NYU Langone Health; 🇺🇸 New York, New York, United States

Virginia Cancer Specialists; 🇺🇸 Fairfax, Virginia, United States

Peter MacCallum Cancer Centre; 🇦🇺 Melbourne, Victoria, Australia

The Princess Margaret Hospital; 🇨🇦 Toronto, Ontario, Canada