Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.
Клиническое исследование I фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Desai Jayesh, Alonso Guzman, Kim Se Hyun, Cervantes Andres, Karasic Thomas, Medina Laura, Shacham-Shmueli Einat, Cosman Rasha, Falcon Alejandro, Gort Eelke, Guren Tormod, Massarelli Erminia, Miller Wilson H, Paz-Ares Luis, Prenen Hans, Amatu Alessio, Cremolini Chiara, Kim Tae Won, Moreno Victor, Ou Sai-Hong I, Passardi Alessandro, Sacher Adrian, Santoro Armando, Stec Rafal, Ulahannan Susanna, Arbour Kathryn, Lorusso Patricia, Luo Jia, Patel Manish R, Choi Yoonha, Shi Zhen, Mandlekar Sandhya, Lin Mark T, Royer-Joo Stephanie, Chang Julie, Jun Tomi, Dharia Neekesh V, Schutzman Jennifer L, GO42144 Investigator and Study Group, Han Sae-Won
Аннотация
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.