Sistema de Salut de Catalunya
Institut Català de la Salut
[Desai J] Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia. [Alonso G] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Kim SH] Seoul National University Bundang Hospital, Seongnam, South Korea. [Cervantes A] Hospital Clinico Universitario De Valencia, Valencia, Spain. [Karasic T] Abramson Cancer Center, University Of Pennsylvania, Philadelphia, PA, USA. [Medina L] Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga, Spain
Vall d'Hebron Barcelona Hospital Campus
2024-02-01T11:30:39Z
2024-02-01T11:30:39Z
2024-01
Divarasib; Colorectal cancer; Drug development
Divarasib; Càncer colorectal; Desenvolupament de medicaments
Divarasib; Cáncer colorrectal; Desarrollo de medicamentos
KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS–MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.
This study was sponsored by Genentech. We thank the patients and family members that were involved in this trial, as well as the clinical study teams. Writing assistance was provided by A. Occiano and S. Diaz of Genentech.
Article
Published version
English
Anomalies cromosòmiques; Còlon - Càncer - Tractament; Medicaments antineoplàstics - Ús terapèutic; Recte - Càncer - Tractament; PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation; DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols; FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada
Nature Portfolio
Nature Medicine;30
https://doi.org/10.1038/s41591-023-02696-8
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Articles científics - HVH [3440]
