Abstract CT029: Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation

作者：Jayesh Desai, Sae‐Won Han, Jong‐Seok Lee, Einat Shacham‐Shmueli, Erminia Massarelli, Andrés Cervantes, Elena Garralda, Alejandro Falcón, Wilson H. Miller, Eelke Gort, Thomas B. Karasic, Salvatore Siena, Rafał Stec, Laura Medina, Luis Paz-Arez, Angelo Delmonte, Adrian G. Sacher, Hans Prenen, Martin Förster, Tae Won Kim, Matthew Krebs, Rasha Cosman, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Kenneth K. Yau, Julie Chang, Stephanie Royer‐Joo, Neekesh V. Dharia, Jennifer L. Schutzman, Manish Patel · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/1538-7445.am2023-ct029 · 被引用次数：10 · 研究领域：Colorectal Cancer Treatments and Studies、Cancer Treatment and Pharmacology、HER2/EGFR in Cancer Research

Abstract Background: GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor that demonstrated anti-tumor activity in patients with KRAS G12C-positive advanced solid tumors, including CRC. In a previously reported single-agent cohort, GDC-6036 achieved a best response of partial response or complete response in 35% (19/55) of patients, with a confirmed overall response rate (ORR) of 24% (13/55 patients) in KRAS G12C-positive CRC patients (Desai et. al., ESMO 2022). EGFR blockade may sensitize tumors to KRAS G12C inhibition and the combination of an anti-EGFR antibody (cetuximab) with a KRAS G12C inhibitor showed greater anti-tumor activity than single-agent KRAS G12C inhibition in preclinical models (Amodio et. al., 2020). Methods: In an ongoing Phase I study (NCT04449874), patients with advanced or metastatic KRAS G12C-positive CRC were administered GDC-6036 (200-400 mg orally once a day) with cetuximab (400 mg/m2 intravenously initially, then 250 mg/m2 weekly) until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1). Results: As of the clinical data cut-off date of 21 Nov 2022, 29 patients (enrolled by 07 Oct 2022) had received GDC-6036 and cetuximab. The median lines of prior metastatic therapy was 2 (range 1-8) and the median time on study treatment was 5.2 (range 1.4-11.2) months. All patients experienced at least one treatment-related adverse event (...