P1, N=191, Completed, Eli Lilly and Company | Recruiting --> Completed

P1, N=16, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P1/2, N=42, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

P1/2, N=29, Completed, Jacobio Pharmaceuticals Co., Ltd. | Recruiting --> Completed | N=100 --> 29 | Trial completion date: Jul 2025 --> Feb 2025 | Trial primary completion date: Jan 2024 --> Feb 2025

With further research, recently, targeted drugs targeting the KRASG12C gene mutation have achieved significant breakthroughs in clinical trials, especially the application of KRASG12C-specific inhibitors adagrasib and sotorasib, which has changed the treatment landscape for NSCLC patients. To address challenges such as tumor heterogeneity, the complexity of the tumor microenvironment, interpatient variability, and acquired drug resistance mechanisms, combination therapy strategies involving KRASG12C inhibitors have emerged sequentially. This article systematically reviews the progress of targeted therapy for KRASG12C-mutant NSCLC and the results of related clinical trials, while exploring novel therapeutic strategies for patients with KRASG12C mutations, aiming to provide a reference for the selection of clinical treatment regimens.

Notably, co-targeting ERBB and AURK effectively overcame resistance in afatinib- and sotorasib-refractory models, wherein bypass activation of EGFR, ERK, and AURK was observed. Given the limited survival benefit associated with KRAS-targeted therapies and rapid emergence of resistance in clinical settings, our findings establish ERBB/AURK co-inhibition as a promising therapeutic strategy to improve durability of response and combat acquired resistance in KRAS driven LUAD.

Recently, selective small-molecule inhibitors of KRAS G12C, including sotorasib and adagrasib, have shown encouraging activity in early clinical trials, indicating potential clinical benefits for this subset of patients. Future studies should focus on developing more potent next-generation inhibitors, exploring and optimizing rational combination strategies with other targeted agents or immunotherapies, investigating innovative therapeutic methods, and systematically identifying and validating predictive biomarkers. Collectively, with these efforts, we aim to enhance the efficacy, overcome resistance, and advance precision therapy for patients with KRAS G12C-mutant CRC.

While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849)...To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways...Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC.

However, the development of selective KRAS G12C inhibitors, such as sotorasib and adagrasib, together with progress in immunotherapy, have demonstrated potential clinical activity. Although there has been notable progress, concerns regarding optimal therapy combinations, resistance management and early treatment strategies remain. The present review demonstrated the need for continued research to address these challenges and improve outcomes for patients with KRAS‑mutated NSCLC.

P1, N=30, Active, not recruiting, Jian Li | Recruiting --> Active, not recruiting | Phase classification: P2 --> P1 | Trial primary completion date: Jun 2026 --> Mar 2026

P2, N=130, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

MAIC-based comparative effectiveness was used in the absence of head-to-head trial data; conclusions informed by MAIC should be interpreted with caution; long-term projections are limited without mature OS data; published data sources may be based on different populations. Sotorasib was more cost-effective than adagrasib in the second- and subsequent-line treatment of KRAS G12C NSCLC, based on current efficacy and safety data.