Krazati (adagrasib)

It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.

Although covalent KRAS^G12C inhibitorsi such as sotorasib and adagrasib have demonstrated clinical activity, pooled analyses indicate only modest response rates and short progression-free survival, with no effective options for non-G12C subtypes...Cell viability, colony formation, and cell cycle distribution were assessed, and the involvement of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling axis was examined by western blot...SP09 exerts potent and selective antiproliferative effects in KRAS-mutant NSCLC through dual regulation of cell cycle and metabolic signaling pathways. Given the restricted efficacy and rapid resistance associated with current KRAS-targeted therapies, our data highlight SP09 as a promising candidate for further preclinical development with potential translational value in KRAS-driven NSCLC.

Amid rising cancer care costs and growing demand for effective therapies, evaluating new treatments' cost-effectiveness is critical. Policymakers must weigh upfront treatment costs against long-term impacts on patient outcomes and healthcare system sustainability.

In targeted therapies, KRASG12C targeted drugs, including Sotorasib, Adagrasib, Fulzerasib, Garsorasib, and Glecirasib, have demonstrated certain therapeutic efficacies in clinical trials and have obtained marketing approval. To tackle drug resistance and enhance patient's prognoses, combination therapeutic strategies that integrate targeted agents with chemotherapy, immune checkpoint inhibitors, Src homology region 2 domain-containing phosphatase 2 (SHP2) inhibitors, and epidermal growth factor receptor (EGFR) monoclonal antibodies have emerged. This paper systematically reviews the advancements in the diagnosis and targeted therapy of NSCLC with KRASG12C mutation, aiming to offer a reference for the selection of clinical treatment regimens and subsequent research..

These findings highlight the need for continued monitoring and understanding of Adagrasib potential risks. Further research is necessary to confirm these associations and address any previously unrecognized safety concerns.

P1/2, N=731, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting

P1/2, N=228, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting

The development of KRAS G12C inhibitors, such as sotorasib and adagrasib, has changed the treatment landscape for patients with KRAS-mutant NSCLC, overcoming the long-standing challenge of targeting KRAS. However, acquired resistance remains a major hurdle, along with the need for effective therapies for non-G12C KRAS mutations. Ongoing research into next-generation inhibitors and combination strategies aim to improve the clinical outcomes of KRAS-mutant NSCLC patients.

P3, N=320, Recruiting, Hoffmann-La Roche | Trial primary completion date: Sep 2026 --> Sep 2027

P2, N=0, Withdrawn, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=42 --> 0 | Trial completion date: Feb 2029 --> Sep 2025 | Active, not recruiting --> Withdrawn | Trial primary completion date: Nov 2025 --> Jun 2025

The first targeted therapies for KRAS G12C-mutant cancers comprise sotorasib and adagrasib, both of which have been authorized for use in patients with previously treated NSCLC and CRC. In this review, we summarize recent advances in KRASG12C tumor biology and pharmacological targeting. We also provide additional insights to guide future efforts to overcome the limitations of the current approaches and implement the treatment of KRASG12C-mutant cancers.

Docking results showed strong EGFR-Gefitinib affinity (-5.94 kcal/mol, Kd 4.38 × 10-5 M), while KRAS inhibitors Adagrasib and Sotorasib demonstrated moderate binding (-3.94 and -3.72 kcal/mol, respectively). This integrative study combining structural modeling, molecular interaction analysis, and transcriptomic validation confirms EGFR, ALK, KRAS, and PD-1 supports their relevance as clinically actionable and structurally druggable biomarkers in NSCLC. These findings support their continued use in targeted therapy design and precision diagnostics, highlighting nanomaterials as ideal carriers due to their ability to enhance immune checkpoint blockade and drug bioavailability in NSCLC.