KRAS G12C

P1, N=7, Terminated, Mirati Therapeutics Inc. | Completed --> Terminated; The decision was made to terminate this study to further enrollment, as of 08 March 2022. The decision was made primarily due to a change in development strategy.

The lack of association between molecular alteration status and recurrence risk prevailed after multivariable adjustment for tumor stage and perioperative treatment (P=0.82 for KRAS G12C mutation and P=0.43 for any other molecular alteration). NSCLC patients with resected tumors that harbor molecular alterations have the same recurrence risk as patients with tumors without molecular alterations if treated with surgery plus chemotherapy when indicated.

In this perspective we discuss the use of PET radioligands in central nervous system (CNS) drug discovery and development, with a focus on recent applications in psychiatry (e.g. 5-HT2A, 11β-HSD1), neuro-oncology (e.g. KRASG12C, ATM, ALK2), and neurodegeneration (e.g. amyloid beta plaques, MAPK p38), while exploring the intricacies associated with developing novel radiotracers for CNS targets. Examples highlight the preclinical and clinical uses of PET for studying biomarker function, drug candidate PK/PD, target occupancy/engagement, dosing regimen determination, clinical trial patient selection, and quantifying biomarker changes in response to treatments.

We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the "inactive" conformation and prevents binding of effector RAS-binding domain (RBD) at physiological concentrations, by signaling through an allosteric network.

P1, N=72, Terminated, Navire Pharma Inc., a BridgeBio company | N=130 --> 72 | Trial completion date: Feb 2025 --> Jul 2024 | Active, not recruiting --> Terminated; Business decision

P1, N=28, Terminated, Navire Pharma Inc., a BridgeBio company | N=85 --> 28 | Trial completion date: Jun 2025 --> Aug 2024 | Recruiting --> Terminated; Business Reasons

SRC inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying KRAS-G12C mutations. Thus, SRC inhibitors amplify the therapeutic utility of G12Ci.

Additionally, Sotorasib increased TXNIP expression by regulating the RAS/RAF/ERK axis. This study uncovers the mechanism by which Sotorasib inhibits glucose metabolism in KRASG12C mutant bladder cancer cells and suggests a potential therapeutic benefit for the treatment of KRASG12C mutant bladder cancer.

Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the Sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies.

Although once thought to be "undruggable", KRAS p.G12C inhibitors such as sotorasib and adagrasib have been developed. This paper focuses on adagrasib, the second KRAS p.G12C inhibitor to obtain regulatory approval by the FDA and describes the details on its study design, development and current place in therapy.

We tested this hypothesis in multiple preclinical PDAC models receiving MRTX1133, an investigational new drug specific for KRAS G12D mutation...Our data demonstrate the abilities of DWI, DCE and MTR derived imaging markers to detect the early (48h) cell death, pronounced stromal changes and development of resistance to KRASi. This study has high translational relevance by testing clinically ready MRI methods, an IND and a genetic engineered mouse model that recapitulates saline features of human PDAC.

P1, N=498, Recruiting, Genentech, Inc. | Trial completion date: Nov 2024 --> Mar 2026 | Trial primary completion date: Nov 2024 --> Mar 2025

In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in Phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer (NSCLC).

P1, N=100, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2024 --> Apr 2025

P2, N=40, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Jul 2026 --> Jun 2027 | Trial primary completion date: May 2023 --> Dec 2024

P1, N=36, Recruiting, Transgene | Trial completion date: Mar 2025 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

In the overall population, moderate-to-extreme problems were reported in all EQ-5D-5L dimensions (range: overall population, 15.5-39.6%; KRAS G12C, 15.6-46.6%; non-G12C, 7.8-23.1%; WT, 21.1-44.2%). HRQoL was broadly similar across KRAS G12C, non-G12C, and WT subpopulations.

Importantly, treatment of mice with FGTI-2734 inhibited sotorasib-induced ERK reactivation in KRAS G12C PDX, and treatment of mice with the combination of FGTI-2734 and sotorasib were also significantly more effective at suppressing in vivo the levels of P-ERK in sotorasib-resistant human KRAS G12C lung cancer xenografts as well as a PDX. Our findings provide a foundation for overcoming sotorasib resistance and potentially improving the treatment outcomes of KRAS G12C lung cancer.

P1/2, N=450, Recruiting, DualityBio Inc. | N=280 --> 450 | Trial completion date: Apr 2025 --> Sep 2026 | Trial primary completion date: Apr 2025 --> Sep 2026

The PBPK model well-described the single and multiple-dose adagrasib PK data as well as DDI data with itraconazole, rifampin, midazolam, warfarin, dextromethorphan, and digoxin, with model predictions within 1.5-fold of the observed clinical data. is predicted to be a strong inhibitor of CYP3A4, a moderate inhibitor of CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). These results successfully supported regulatory interactions with the United States Food and Drug Administration regarding dosing recommendations for when adagrasib is used concomitantly with other medications, supporting a range of label claims in lieu of clinical trials.

This conditional approval was based on the positive results of a single-arm, phase II study. This article summarizes the milestones in the development of fulzerasib leading to this first approval for KRAS G12C-mutated advanced NSCLC.

This study presents the first results of ipilimumab-nivolumab in invasive mucinous or non-mucinous lepidic adenocarcinoma (invasive mucinous adenocarcinoma (IMA) or invasive non-mucinous lepidic adenocarcinomas (INLA), respectively) of the lung. Expanded prospective studies are warranted. ClinicalTrials.gov registry: NCT02834013.

Some of these targeted therapies have already been approved by the Food and Drug Administration (FDA), and many others are currently undergoing clinical trials. This review summarizes recent advances in NSCLC treatment with molecular targets, highlighting progress, challenges, and their impact on patient prognosis.

P2, N=42, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Active, not recruiting

This review aims to introduce classical and emerging methods for screening small-molecule compounds in targeted cancer therapy. It includes classification, principles, advantages, disadvantages, and successful applications, serving as valuable references for subsequent researchers.

This study provides data on the molecular epidemiology of lung adenocarcinoma in Brazil, confirming high prevalence of EGFR mutations, ALK fusions, and MET exon 14 skipping alteration. Biomarker detection is largely affected by biospecimen collection and processing, with one third of the patients eligible for non-NGS testing only, which presents reduced coverage and sensitivity for actionable drivers.

Our study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRASG12Ci-AcR tumors.

The development of KRAS-targeted drugs like sotorasib and adagrasib has generated significant excitement in the clinical arena, offering new therapeutic options. However, the efficacy of immune checkpoint inhibitors in this context still requires comprehensive evaluation. The response to anti-Programmed Cell Death Protein 1/Programmed Cell Death Protein 1 Ligand (anti-PD-1/PD-L1) drugs in NSCLC may be significantly influenced by co-occurring mutations, underscoring the need for a personalized approach to treatment based on the specific genetic profile of each tumor.

This Patent Highlight explores recent cancer treatment and monitoring advancements, focusing on selective KRAS inhibitors targeting mutations like G12C and G12D alongside germline epitope burden analysis. These innovations offer enhanced therapeutic precision and personalized monitoring, improving the prediction of cancer relapse and tailoring treatment strategies to individual patient profiles, significantly advancing the field of precision oncology.

Our study provides a comprehensive characterization of the genomic landscape and clonal evolution in OCCC within a substantial cohort. These findings unveil potentially actionable molecular alterations that could be leveraged to develop targeted therapies.

Treatment with the KRasG12C-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRasG12C-mutant H358 cell line...Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade.

KRAS mutation status did not significantly influence ICI efficacy, although a non-significant trend towards better survival was observed in KRAS-MT patients treated with first-line ICI. These findings contribute to the ongoing research in this field.

METamp occurred more frequently in responders; but Teliso-V activity wasn’t restricted to these pts: most responders weren’t METamplified. Specific genomic alts beyond MET may influence clinical response. The current analysis demonstrated numeric differences between pts with identified drivers who did or didn’t respond to Teliso-V.

Our study provides an example of implementation of molecular profiling in an academic pre-screening program. Further analysis will investigate treatment matching rates, drug access schemes, and their impact on treatment efficacy and survival.

Blood-based LB performed by NGS is a non-invasive viable alternative tool for molecular genotyping and identifiy tumor-derived somatic alterations to increase the number of pts elegible to target therapy and guide personalized medicine.

Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other.

P2, N=96, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Nov 2026 --> Nov 2024

Subsequently, large numbers of electro-active monomers N-acryloxysuccinimide (NAS) were successfully grafted to the electrode surface via PET-RAFT reaction, which provided plenty of junction sites for doxorubicin-polycaprolactone (Dox-PCL) synthesized by ROP...Under optimized conditions, the biosensor has a wide linear detection range of 0.1 pM to 1 μM, with a detection limit of 86.9 fM. Attribute to its high sensitivity, specificity, reproducibility and stability, this biosensor possesses considerable potential in early diagnosis of disease and biomedical research.

Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.

Symptoms resolved after treatment with prednisone and therapy interruption of adagrasib followed by a permanent dose reduction. After the dose reduction, there was an ongoing effective tumor response at follow-up, and serum concentrations of adagrasib remained within the therapeutic index. Through this case report, we aim to bring attention to the possibility of this side effect, as we believe it is important to be aware of it for future patients undergoing treatment with adagrasib.

P1, N=12, Active, not recruiting, Amgen | Trial completion date: Dec 2024 --> Jun 2025