Targeted Therapies for Previously “Undruggable” KRAS-Mutated Non–Small Cell Lung Cancer: A Review of Sotorasib and Adagrasib

Abstract

Objective: To evaluate the safety and efficacy of the novel KRAS-targeting agents, sotorasib and adagrasib, in treating KRAS G12C-mutated non–small cell lung cancer (NSCLC). Data Sources: A comprehensive English-based literature search of PubMed and Clinicaltrials.gov between January 2000 and July 2023 was conducted using the terms sotorasib, Lumakras, AMG 510, adagrasib, Krazati, and MRTX849. Study Selection and Data Extraction: Relevant prescribing information, clinical trials, and treatment guidelines were evaluated. Data Synthesis: Sotorasib and adagrasib received accelerated US Food and Drug Administration (FDA) approval following pivotal phase I/II clinical trials. Sotorasib, a first-in-class KRAS inhibitor, demonstrated an overall response rate (ORR) of 41% and a progression-free survival (PFS) of 6.3 months. In a phase III confirmatory trial, sotorasib showed significantly longer PFS compared with docetaxel (5.6 vs. 4.5 months; P = 0.0017). Adagrasib produced an ORR of 42.9% and a PFS of 6.5 months. Both drugs present unique safety profiles, with common toxicities, including diarrhea, musculoskeletal pain, fatigue, and hepatotoxicity. Relevance to Patient Care and Clinical Practice: With KRAS mutations being among the most common oncogenic alterations in NSCLC, sotorasib and adagrasib offer new therapeutic avenues for this previously “undruggable” target. Current treatment guidelines list sotorasib and adagrasib as second-line options in patients with confirmed KRAS G12C-mutated NSCLC. Additional studies are required to further differentiate the safety and efficacy profiles of these 2 agents and identify their optimal place in therapy. Conclusion: Sotorasib and adagrasib demonstrated promising outcomes in targeting the constitutively active KRAS G12C oncogenic driver, underscoring the need for further research to optimize their therapeutic application in this high-risk population.

Impact of KRAS mutation on the tumor microenvironment in colorectal cancer

“…Adagrasib demonstrates encouraging clinical efficacy and is well tolerated in patients pretreated with KRASG12C-mutated solid tumors [165]. Targeting the constitutively active KRAS G12C oncogenic driver with sotorasib and adagrasib has shown promising results, highlighting the need for additional studies to enhance the therapeutic use of these agents in this high-risk population [166]. Although sotorasib and adagrasib are currently approved for use in patients with advanced/ metastatic NSCLC, regular biomarker testing of KRAS G12C mutations should include testing and reporting before first-line therapy since these tests may aid in clinical decision-making in patients with KRAS G12C-mutated advanced NSCLC [167].…”

Development of PROTACS degrading KRAS and SOS1

“…Oncogenic KRAS mutations are clustered in positions 12, 13, or 61 of the gene and lock KRAS in the GTP-bound active state leading to permanent overactivation and cell growth [ 2 ]. Two small molecules targeting KRAS-G12C, namely Amgen (AMG510-Sotorasib) and Mirati (MRTX849-Adagrasib) bind to the allosteric switch-II pocket and covalently link the cysteine residue and the acrylamide group of the KRAS G12C inhibitor, were recently approved for clinical use in docetaxel-pretreated lung cancer patients [ 3 , 4 ]. Sotorasib, the first-in-class KRAS inhibitor, yielded an overall response rate (ORR) of 41%, a progression-free survival (PFS) of 6.3 months, and proved superior to docetaxel.…”