Adagrasib in KRYSTAL-12 has Broken the KRASG12C Enigma Code in Non-Small Cell Lung Carcinoma

Faustine X Luo,1,2 Zhaohui Liao Arter1,2 1University of California Irvine School of Medicine, Orange, CA, 92868, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, 92868, USACorrespondence: Zhaohui Liao Arter, Department of Medicine, Division of Hematology/Oncology, UC Irvine, Orange, CA, 92602, USA, Email [email protected]: Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10– 13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRASG12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45– 0.76; P< 0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRASG12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRASG12C enigma code in NSCLC.Keywords: non-small-cell lung cancer, KRASG12C mutations, adagrasib, sotorasib, KRYSTAL, targeted therapy, intracranial efficacy