A Phase II Study of Neoadjuvant Opnurasib KRAS G12C Inhibitor in Patients With Surgically Resectable Non-Small Cell
Abstract:
Molecularly targeted agents are increasingly being studied in the treatment of early-stage non-small cell lung cancer (NSCLC) to try and improve cure. However, phase 3 data on neoadjuvant therapy have largely been conducted in a biomarker agnostic manner with inconsistent exclusion of EGFR and ALK alterations. Our objective was to develop IND.242 as a large-scale neoadjuvant platform trial to introduce novel agents into the preoperative window for molecularly-defined NSCLC patient populations. Given that KRAS G12C mutations are common in the overall NSCLC patient population, ranging from 9.4% to 13% of cases across different cohorts, and may be associated to worse prognosis, the initial IND.242A Substudy was designed to test neoadjuvant JDQ443 (opnurasib), a selective KRAS G12C inhibitor. This current trial report describes the multicenter, Canadian Cancer Trials Group (CCTG)-led IND.242 neoadjuvant phase 2 platform master protocol and its first Substudy (IND.242A) of neoadjuvant opnurasib KRAS G12C inhibitor for patients with surgically resectable NSCLC (AJCC 8th edition stage IA2 to IIIA). In IND.242A, a maximum of 27 patients will be accrued in participating Canadian sites. The primary objective is the rate of major pathological response (MPR) following neoadjuvant opnurasib. Secondary objectives include safety and tolerability of the treatment regimen, objective response rate (ORR) by RECIST 1.1 for the neoadjuvant treatment period, pathological complete response (pCR) rate, event-free survival (EFS) at 2 years, and surgical outcomes. Exploratory objectives are to explore patient related outcomes (PROs) and identify potential predictive biomarkers of response and mechanisms of resistance on tissue and peripheral blood samples.
Insights
This study introduces a new neoadjuvant therapy for early-stage non-small cell lung cancer (NSCLC) targeting KRAS G12C mutations. The IND.242A trial investigates opnurasib, a selective KRAS G12C inhibitor, to improve treatment outcomes in molecularly-defined NSCLC patients.
Area of Science:
- Oncology
- Translational Research
- Clinical Trials
Background:
- Neoadjuvant therapy for early-stage non-small cell lung cancer (NSCLC) is evolving, with a need for molecularly-defined patient populations.
- Previous trials often lacked specific molecular targeting, leading to inconsistent outcomes.
- KRAS G12C mutations are prevalent in NSCLC and associated with poorer prognosis, necessitating targeted therapeutic strategies.
Purpose of the Study:
- To establish the IND.242 as a large-scale neoadjuvant platform trial for novel agents in molecularly-defined NSCLC.
- To evaluate the efficacy and safety of neoadjuvant opnurasib (JDQ443), a selective KRAS G12C inhibitor, in patients with surgically resectable NSCLC.
- To assess the rate of major pathological response (MPR) as the primary endpoint in the IND.242A substudy.
Main Methods:
- A multicenter, Canadian Cancer Trials Group (CCTG)-led, phase 2 platform master protocol (IND.242) with its first substudy (IND.242A).
- Accrual of up to 27 patients with surgically resectable NSCLC (AJCC 8th edition stage IA2 to IIIA) in Canadian sites.
- Administration of neoadjuvant opnurasib, with assessment of primary endpoint (MPR) and secondary objectives including safety, objective response rate (ORR), pathological complete response (pCR), event-free survival (EFS), and surgical outcomes.
Main Results:
- The report details the design and objectives of the IND.242 neoadjuvant platform trial and its first substudy (IND.242A).
- The primary objective is to determine the rate of major pathological response (MPR) following neoadjuvant opnurasib treatment.
- Secondary and exploratory objectives focus on safety, response rates, survival, surgical outcomes, patient-reported outcomes, and predictive biomarkers.
Conclusions:
- The IND.242 platform trial aims to accelerate the introduction of novel molecularly targeted agents into the neoadjuvant setting for NSCLC.
- The IND.242A substudy specifically targets KRAS G12C-mutated NSCLC with opnurasib, addressing a common and prognostically significant molecular alteration.
- This approach facilitates the development of personalized neoadjuvant therapies for NSCLC based on specific molecular profiles.
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