Mechanism of Action and Target
Target: KRAS G12C Mutation
KRAS mutation is one of the most common driver mutations in cancer.KRAS G12C is a frequent subtype in tumors including NSCLC and colorectal cancer (CRC).This mutation causes persistent activation of the KRAS protein, promoting cancer cell proliferation and survival.
Mechanism of Action
Adagrasib selectively binds to the switch‑II pocket of the KRAS G12C protein, locking it in an inactive conformation.This blocks downstream signaling pathways such as the MAPK pathway and inhibits tumor growth.
Indications and Clinical Efficacy
Non‑Small Cell Lung Cancer (NSCLC)
For patients with advanced or metastatic KRAS G12C‑mutated NSCLC:
Objective response rate (ORR) with single‑agent adagrasib: approximately 40%–50%
Median progression‑free survival (PFS): approximately 6.5 months
Colorectal Cancer (CRC)
In patients with KRAS G12C‑mutated colorectal cancer:
ORR of adagrasib plus cetuximab (anti‑EGFR agent): up to 46%, which is significantly higher than monotherapy.
Other Solid Tumors
Exploratory studies have shown promising activity in other KRAS G12C‑mutated tumors, including pancreatic cancer and cholangiocarcinoma.
Use in Special Populations
Pregnancy
There are no available human data on the use of adagrasib in pregnant women.In animal reproductive studies, oral administration during organogenesis in pregnant rats and rabbits did not cause adverse developmental effects or embryo‑fetal death at exposures below the human clinical exposure (600 mg twice daily).
Lactation
No data exist on the presence of adagrasib or its metabolites in human milk, or its effects on breastfed infants or milk production.Due to the potential for serious adverse reactions in breastfed children, women are advised not to breastfeed during treatment and for 1 week after the last dose.
Females and Males of Reproductive Potential
Based on animal studies, adagrasib may impair fertility in females and males of reproductive potential.
Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
Geriatric Use
In the KRYSTAL‑1 trial, among 116 patients receiving adagrasib 600 mg orally twice daily, 49% (57 patients) were aged ≥ 65 years.No overall differences in safety or effectiveness were observed between elderly and younger patients.
