한빛사논문
- 조회1,015
Jayesh Desai 1,*, Guzman Alonso 2, Se Hyun Kim 3, Andres Cervantes 4, Thomas Karasic 5, Laura Medina 6, Einat Shacham-Shmueli 7, Rasha Cosman 8, Alejandro Falcon 9, Eelke Gort 10, Tormod Guren 11, Erminia Massarelli 12, Wilson H Miller Jr 13, Luis Paz-Ares 14, Hans Prenen 15, Alessio Amatu 16, Chiara Cremolini 17, Tae Won Kim 18, Victor Moreno 19, Sai-Hong I Ou 20, Alessandro Passardi 21, Adrian Sacher 22, Armando Santoro 23, Rafal Stec 24 25, Susanna Ulahannan 26 27, Kathryn Arbour 28, Patricia Lorusso 29, Jia Luo 30, Manish R Patel 31, Yoonha Choi 32, Zhen Shi 32, Sandhya Mandlekar 32, Mark T Lin 32, Stephanie Royer-Joo 32, Julie Chang 32, Tomi Jun 32, Neekesh V Dharia 32, Jennifer L Schutzman 32, GO42144 Investigator and Study Group, Sae-Won Han 33,*
1Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
2Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.
3Seoul National University Bundang Hospital, Seongnam, South Korea.
4Hospital Clinico Universitario De Valencia, Valencia, Spain.
5Abramson Cancer Center, University Of Pennsylvania, Philadelphia, PA, USA.
6Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga, Spain.
7Sheba Medical Center, Sackler School of Medicineó, Tel Aviv University, Tel Aviv, Israel.
8The Kinghorn Cancer Centre, St. Vincent's Hospital and School of Medicine, University of New South Wales, Sydney, Australia.
9Hospital Universitario Virgen del Rocio, Sevilla, Spain.
10Universitair Medisch Centrum Utrecht, Utrecht, Netherlands.
11Oslo University Hospital Radiumhospitalet, Oslo, Norway.
12City of Hope - Comprehensive Cancer Center, Duarte, CA, USA.
13Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
14Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain.
15University Hospital Antwerp, Edegem, Belgium.
16Haematology and Oncology Division, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
17University of Pisa, Pisa, Italy.
18Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South Korea.
19START MADRID-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.
20University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA.
21Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy.
22Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, Department of Medicine & Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
23Humanitas University and IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.
24Biokinetica, Przychodnia Jozefow, Józefów, Poland.
25Warsaw Medical University, Warsaw, Poland.
26Stephenson Cancer Center, Oklahoma City, OK, USA.
27Sarah Cannon Research Institute, Nashville, TN, USA.
28Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
29Yale Cancer Center, Yale University, New Haven, CT, USA.
30Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
31Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA.
32Genentech, South San Francisco, CA, USA.
33Seoul National University Hospital and Seoul National University Cancer Research Institute, Seoul, South Korea.
*Corresponding authors: correspondence to Jayesh Desai or Sae-Won Han
Abstract
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.ClinicalTrials.gov identifier: NCT04449874.
논문정보
- Research article
- 2023년 12월 (BRIC 등록일 2023-12-07)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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