Krazati (adagrasib)

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.

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.

The success of inhibitors like sotorasib and adagrasib has expanded options for targeting once 'undruggable' oncogenic drivers such as KRAS...ADCs such as EMRELIS™, Datroway, and ELAHERE™ offer precise targeting along with potent cytotoxic agents...Cancer vaccine research is progressing with licensed immunoprophylactic drugs, and AI tools like AlphaFold are speeding up drug discovery by enhancing structural biology predictions. This review covers recent cancer therapeutics advancements, including targeted inhibitors, immunotherapies, resistance strategies, epigenetic interventions, combination therapies, vaccines, and AI applications.

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.

Allele-specific inhibitors are likely to find their place in combinations that suppress adaptive bypass (e.g. SOS1/SHP2, MEK/ERK, EGFR) while leveraging immunotherapy or metabolic vulnerabilities. Prospective biomarker integration and resistance-informed trial designs will be decisive in translating early signals into durable patient benefit.

P1, N=100, Not yet recruiting, M.D. Anderson Cancer Center

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.

Here, we report a reduction-sensitive micellar system for the codelivery of a KRAS G12C inhibitor (adagrasib, KI) and a TLR7/8 agonist (R848, TA) (mKITA), aiming to synchronize direct oncogenic signaling blockade with potent immune modulation within tumor microenvironment (TME)...In orthotopic lung cancer models, combining mKITA with αPD-1 achieves complete tumor regression and long-term survival in 60% of mice. This strategy offers a clinically translatable nanomedicine to overcome resistance in KRAS-driven lung cancer.

P1, N=437, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P2, N=535, Not yet recruiting, City of Hope Medical Center

This case highlights the potential clinical utility of KRAS G12C inhibitors in EC and highlights the importance of molecular profiling in identifying actionable mutations that may guide treatment decisions. This report, contributing to the limited body of evidence that includes three prior cases evaluating the role of sotorasib and adagrasib across several solid malignancies, highlights the clinical and translational relevance of adagrasib in advancing precision-targeted therapy for KRAS G12C-mutated tumors.