Glecirasib Combined With Ivonescimab for First-line Treatment of KRAS G12C-mutated NSCLC

Glecirasib Combined With Ivonescimab for First-line Treatment of KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer: A Prospective, Multi-center, Phase I/II Clinical Study

This study evaluates the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) of Glecirasib in combination with Ivonescimab in patients with previously untreated, KRAS G12C-mutated, locally advanced or metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥1%. The study includes a Phase I 3+3 dose-escalation stage followed by a Phase II Simon two-stage design to assess preliminary antitumor efficacy.

Study Overview

• Status: Not yet recruiting
• Conditions: NSCLC Stage IV; KRAS G12C
• Intervention / Treatment: Drug: Glecirasib; Drug: Ivonescimab

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Zhijie Wang, MD; Phone Number: 010-67781331; Email: wangzj@cicams.ac.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Signed written informed consent.
• Age ≥18 years.
• Newly diagnosed, unresectable, locally advanced (ineligible for curative concurrent - chemoradiotherapy) or metastatic NSCLC per AJCC 9th edition.
• KRAS G12C mutation confirmed by validated testing.
• PD-L1 TPS ≥1%.
• ≥1 measurable lesion per RECIST v1.1.
• No prior systemic therapy for advanced/metastatic NSCLC; prior adjuvant therapy allowed if completed >6 months before dosing and toxicities recovered to ≤Grade 1.
• ECOG PS 0-2.
• Life expectancy >3 months
• Adequate organ function (hematologic, hepatic, renal, coagulation per protocol thresholds)
• Negative pregnancy test for women of childbearing potential; adequate contraception for men and women through 3 months post-treatment
• Willing and able to comply with study procedures and follow-up.

Exclusion Criteria:

• History of other malignancies (exceptions: cured basal cell carcinoma, cervical carcinoma in situ)
• Predominant squamous NSCLC, small cell carcinoma, or neuroendocrine carcinoma.
• Other actionable drivers (EGFR, ALK, ROS1, RET, BRAF, NTRK, MET, etc.).
• Known hypersensitivity to study drugs.
• Prior PD-1/PD-L1 inhibitors or KRAS inhibitors.
• Active autoimmune disease or autoimmune disease history requiring systemic therapy.
• Systemic immunosuppressive therapy within 14 days prior to first dose.
• Symptomatic ascites/pleural effusion needing recurrent drainage.
• Significant cardiovascular disease (NYHA ≥2, MI within 1 year, uncontrolled arrhythmias).
• Active infection, unexplained fever >38.5°C.
• Interstitial lung disease or pneumonitis.
• HIV infection or other immunodeficiency.
• Live vaccines within 4 weeks.
• Substance abuse, alcoholism, or psychiatric disorders impairing compliance.
• Unable to swallow oral medication.
• Any condition that may interfere with study participation or interpretation as judged by investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glecirasib Combined With Ivonescimab	Drug: Glecirasib; For Phase I Dose Escalation, Glecirasib includes 2 dose cohorts: 600 mg QD and 800 mg QD, respectively, to determine the Glecirasib PR2D dose for the Phase II study.; Other Names: JAB-21822; Drug: Ivonescimab; Administered intravenously at 20 mg/kg, every 3 weeks (Q3W).; Other Names: AK112

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Maximum Tolerated Dose (MTD)	The MTD is determined using a standard 3+3 dose-escalation design. It is defined as the dose level prior to the dose at which ≥2 out of 3-6 patients experience a Dose-Limiting Toxicity (DLT) within the first 21 days of treatment	21 days after the first dose.
Phase I: Incidence of Dose-Limiting Toxicities (DLTs)	Evaluation of toxicities related to the study drugs, including hematologic and non-hematologic toxicities as defined in the protocol.	21 days after the first dose.
Phase I: Recommended Phase 2 Dose (RP2D)	The RP2D of Glecirasib in combination with Ivonescimab will be selected based on the comprehensive evaluation of the MTD, DLT occurrences, and overall safety data observed during the Phase I escalation phase. This dose will then be utilized in the Phase II Simon's two-stage expansion to further evaluate efficacy and safety.	21 days after the first dose.
Phase II: Objective Response Rate (ORR)	The proportion of patients who achieve a Complete Response (CR) or Partial Response (PR) based on RECIST v1.1.	Assessed up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR)	Proportion of patients with CR, PR, or SD.	Up to 24 months
Progression-Free Survival (PFS)	Time from the first dose to the first documented disease progression or death from any cause.	Up to 24 months
Duration of Response (DOR)	Time from the first documented response (CR or PR) to progression or death.	Up to 24 months
Overall Survival (OS)	Time from the first dose to death from any cause	Up to 24 months
Incidence of Adverse Events (AEs)	Severity of AEs graded by CTCAE v5.0	From first dose enrollment through 28 days after the last dose.

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2029

Study Registration Dates

• First Submitted: January 5, 2026
• First Submitted That Met QC Criteria: January 5, 2026
• First Posted (Actual): January 14, 2026

Study Record Updates

• Last Update Posted (Actual): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• 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
• Other Study ID Numbers: NCC5886

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: No
• Studies a U.S. FDA-regulated device product: No