2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.12H.07 A Phase I Clinical Trial of Carfilzomib in Combination with Sotorasib in Patients with KRASG12C Mutated NSCLC

EP.12H.07 A Phase I Clinical Trial of Carfilzomib in Combination with Sotorasib in Patients with KRASG12C Mutated NSCLC

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This clinical trial investigates the combination of two drugs, carfilzomib and sotorasib, in patients with non-small cell lung cancer (NSCLC) harboring the KRASG12C mutation. Despite initial promising responses to KRASG12C inhibitors like sotorasib, many patients experience disease progression within a year. Resistance is thought to be non-genetic, linked to the ITGB4/PXN pathway, making it a targetable point of intervention with carfilzomib.<br /><br />Carfilzomib was identified after a virtual screening process as potentially effective against molecules in this pathway. Preclinical tests demonstrated that when used with sotorasib, carfilzomib showed synergistic activity by down-regulating ITGB4. The study aims to test the safety and determine optimal doses (Phase I) of this drug combination in treating KRASG12C mutations.<br /><br />This single-center, investigator-initiated dose-escalation trial (NCT06249282) focuses on patients whose cancer has progressed after prior KRAS inhibitor treatment. The study’s primary objective is to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Secondary objectives include evaluating the objective response rate (ORR) and progression-free survival (PFS).<br /><br />The trial employs a structured dose-escalation strategy, starting from a defined dose of both drugs to ascertain tolerability and safety, with plans to enroll up to 18 patients over approximately 18 months. In this design, carfilzomib is administered intravenously, with increasing doses each cycle, while sotorasib is given daily at a fixed dose.<br /><br />Correlative studies will analyze factors such as KRAS G12C, paxillin, and integrin beta-4 in tumor tissue, along with pharmacokinetic and proteomic analyses, to understand the drugs’ effects and mechanisms better. Patient-derived models may also be created to facilitate more in-depth evaluations.

Asset Subtitle

Jyoti Malhotra

Meta Tag

Speaker Jyoti Malhotra

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

carfilzomib

sotorasib

non-small cell lung cancer

NSCLC

KRASG12C mutation

ITGB4/PXN pathway

dose-escalation trial

maximum tolerated dose

progression-free survival

pharmacokinetic analysis