Study of Avutometinib (VS-6766) + Adagrasib in KRAS G12C NSCLC Patients

Phase 1

Active, not recruiting

• Conditions: Non Small Cell Lung Cancer; KRAS Activating Mutation; Advanced Cancer; Metastatic Cancer; Malignant Neoplastic Disease; Malignant Neoplasm of Lung
• Interventions: Drug: avutometinib (VS-6766) and adagrasib

• Registration Number: NCT05375994
• Lead Sponsor: Verastem, Inc.

Brief Summary

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with adagrasib in patients with G12C Non-Small Cell Lung Cancer (NSCLC) who have been exposed to prior G12C inhibitor and experienced progressive disease.

Detailed Description

This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety, tolerability and efficacy of avutometinib (VS-6766) in combination with adagrasib in patients with KRAS G12C mutant NSCLC who have been exposed to prior G12C inhibitor and experienced progressive disease.

Study Timeline

• Study First Submitted: 2022-05-02
• Study First Submitted QC: 2022-05-10
• Study First Posted: 2022-05-17
• Study Start: 2022-08-01
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-13
• Last Update Posted: 2025-05-18
• Primary Completion: 2025-12-24
• Study Completion: 2026-01-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 85

Inclusion Criteria

• Male or female subjects ≥ 18 years of age
• Histologic or cytologic evidence of NSCLC
• Known KRAS G12C mutation
• The subject must have received prior therapy with a KRAS G12C inhibitor and experienced progression
• Must have received appropriate treatment with at least one prior systemic regimen, but no more than 3 prior regimens, for Stage 3B-C or 4 NSCLC
• Measurable disease according to RECIST 1.1
• An Eastern Cooperative Group (ECOG) performance status ≤ 1
• Adequate organ function
• Adequate recovery from toxicities related to prior treatments
• Agreement to use highly effective method of contraceptive

Exclusion Criteria

• Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy or treatment with an investigational agent within 14 days of receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 for chest radiation > 30Gy)
• History of prior malignancy, with the exception of curatively treated malignancies
• Major surgery within 4 weeks (excluding placement of vascular access)
• Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy
• Exposure to strong inhibitors of breast cancer resistance protein (BCRP) within 14 days prior to the first dose and during the course of therapy
• Symptomatic brain metastases requiring steroids or other local interventions within the 2 weeks prior to initiation of therapy
• Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy
• Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active
• Active skin disorder that has required systemic therapy within the past 1 year
• History of rhabdomyolysis or interstitial lung disease
• Concurrent ocular disorders
• Concurrent heart disease or severe obstructive pulmonary disease
• Subjects with the inability to swallow oral medications

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
avutometinib(VS-6766)+adagrasib	avutometinib (VS-6766) and adagrasib	To determine the recommended phase 2 dose (RP2D) for VS-6766 in combination with adagrasib in G12C inhibitor exposed patients
avutometinib (VS-6766)+adagrasib RP2D	avutometinib (VS-6766) and adagrasib	To determine the efficacy of the RP2D identified from Part A in G12C inhibitor exposed patients

Primary Outcome Measures

Name	Time	Method
Part A: To determine RP2D for avutometinib(VS-6766) in combination with adagrasib	From start of treatment to confirmation of RP2D; 28 days	Assessment of Dose-limiting toxicities (DLTs)
To determine the efficacy of the optimal regimen identified from Part A	From start of treatment to confirmation of response; 16 weeks	Confirmed overall response rate per RECIST 1.1

Secondary Outcome Measures

Name	Time	Method
ECG QT Interval	24 months	Corrected ECG QT interval by Fredericia (QTcF)
Duration of Response (DOR)	Time from the first documentation of response to first documentation of progressive disease or death due to any cause, greater than or equal to 6 months	Time of first response to PD as assessed per RECIST 1.1
To characterize the safety and toxicity profile:	24 Months	* Incidence of Adverse events (AEs) and Serious Adverse Events (SAEs) assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0); * Severity of Adverse events (AEs) and Serious Adverse Events (SAEs) by toxicity grade assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0); * Duration of Adverse events (AEs) and Serious Adverse Events (SAEs); * Incidence of clinically significant changes in lab parameters; * Incidence of abnormal vital signs (including systolic and diastolic blood pressure in mmHg)
Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Tmax	10 weeks	time of Maximum concentration (Tmax)
Disease Control Rate (DCR)	Greater than or equal to 8 weeks	CR and PR stable disease as assessed per RECIST 1.1
Progression Free Survival (PFS)	24 months	From the time of first dose of study intervention to PD or death from any cause
Overall Survival (OS)	Up to 5 years	From time of first dose of study intervention to death
Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - AUC	10 weeks	Area under plasma Concentration (AUC) 0 to t
Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Half-life	10 weeks	concentration Half-life (T1/2)
Clinical Benefit Rate	≥ 6 months	defined as Complete Response+Partial Response +Stable Disease

Trial Locations

Locations (7)

UCSF Thoracic Oncology; 🇺🇸 San Francisco, California, United States

University of Colorado Hospital Anschutz Cancer Pavllion; 🇺🇸 Aurora, Colorado, United States

Mayo Clinic Cancer Center; 🇺🇸 Rochester, Minnesota, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

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

Medical College Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States