2023 World Conference on Lung Cancer (Posters)-P2.11. A Phase 1B Trial of Tarloxotinib and Sotorasib in Lung Cancer Patients with KRAS G12C Mutations

P2.11. A Phase 1B Trial of Tarloxotinib and Sotorasib in Lung Cancer Patients with KRAS G12C Mutations - PDF(Abstract)

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This document provides information about a phase 1B clinical trial investigating the combination of tarloxotinib and sotorasib in patients with non-small cell lung cancer (NSCLC) who have KRAS G12C mutations. KRAS G12C mutations are found in 13% of lung adenocarcinoma patients. Sotorasib is the first approved KRAS G12C inhibitor, but many patients with this mutation do not respond to therapy and have a high rate of relapse. Tarloxotinib is a prodrug that releases a potent inhibitor of the ERBB tyrosine kinase, targeting both normal and mutant forms of the ERBB family. Preclinical experiments have shown that the combination of tarloxotinib and sotorasib is superior to either agent alone in KRAS G12C models. <br /><br />The study is a non-randomized, single cohort phase 1B trial involving NSCLC patients with a KRAS G12C mutation who have progressed on a KRAS G12C inhibitor. A safety lead-in cohort of 6 to 18 patients is being enrolled to assess the safety of the combination. Sotorasib is administered at a fixed approved dose of 960 mg daily, while the starting dose of tarloxotinib is 150 mg/m2 weekly intravenously. The study uses a dose de-escalation design to determine the recommended phase 2 dose (RP2Dc), which is defined as the highest dose level at which at most 1 out of 6 patients experiences a dose limiting toxicity. Once the RP2Dc is determined, an expansion cohort of up to 12 patients will be enrolled.<br /><br />The primary objectives of the trial are to evaluate the safety and tolerability of the tarloxotinib-sotorasib combination and to assess the tumor objective response rate. Secondary objectives include evaluating the RP2D of the combination, progression-free survival, overall survival, duration of response, and disease control rate in patients with response or stable disease for at least 8 weeks. Biomarker analysis is also being conducted to understand resistance mechanisms. The trial began in April 2022 and is currently enrolling patients.

Asset Subtitle

Mariam Alexander

Meta Tag

Speaker Mariam Alexander

Topic Metastatic NSCLC: Targeted Therapy - KRAS/MET

Keywords

phase 1B clinical trial

tarloxotinib

sotorasib

non-small cell lung cancer

NSCLC

KRAS G12C mutations

lung adenocarcinoma

KRAS G12C inhibitor

ERBB tyrosine kinase

dose de-escalation design