P1, N=27, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Aug 2025 --> Jun 2027 | Trial primary completion date: Aug 2025 --> Jun 2027

These results indicate that targeting the NF-κB pathway may represent a promising therapeutic strategy to attenuate HGF- induced resistance to KRAS G12C inhibitors in lung adenocarcinoma.

In this study, we evaluated the efficacy, in terms of cell viability and volumetric reduction, of adding KRAS inhibitors (KRASi) sequentially or concurrently to CT in both parental (PR) and gemcitabine-resistant (GR) KRAS mutated NSCLC cell lines (SW1573 and H23)...Interestingly, in the 3D model, the concomitant use of KRASi+CT reduced spheroid volume in both PR and GR spheroids. Our results indicate that KRASi enhances the efficacy of CT in both NSCLC PR and GR cells, suggesting a potential therapeutic strategy to overcome chemoresistance in the adjuvant setting of NSCLC.

These findings establish VEGFA-VEGFR2 signaling by PI3Kγ activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers. VEGFA-VEGFR2 signaling activation is a common feature of MRTX1133 resistance in KRAS G12D cancer cells Nuclear translocation of SP1 by AKT activation promotes VEGFA transcription in MRTX1133-resistant modelsInteraction of p110γ-p101 with KRAS activates PI3Kγ in the resistant models VEGFA-VEGFR2 inhibition reverses MRTX1133 resistance in vitro and in vivo.

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.

Additionally, secretagogue stimulation improved treatment responses and delayed recurrence in both treatment models. These findings suggest that SSZS MRI could significantly enhance PDAC diagnosis and management, providing an imaging modality that can help to optimize patient outcomes.

P1, N=25, Completed, Elicio Therapeutics | Active, not recruiting --> Completed | Trial completion date: Mar 2026 --> Sep 2024

The anticancer activities of SS-3091 and SS-30125 have been validated against the KRas G12D, G12C, G12V, and G12S mutants in various cancer cells. All findings underscore the potential of SS-3091 and SS-30125 as very promising active pan-KRas inhibitors.

P1, N=47, Active, not recruiting, Boehringer Ingelheim | Trial completion date: May 2027 --> Dec 2025 | Trial primary completion date: May 2027 --> Dec 2025

Most patients with metastatic KRAS G12C-mutated NSCLC are excluded from trials. There is significant potential to refine trial entry criteria to better balance generalizability, safety, speed, and success.

We present the final results of the phase 1 AMPLIFY-201 trial, in which patients who completed standard locoregional treatment, with minimal residual mKRAS disease (n = 25, 20 pancreatic cancer and 5 colorectal cancer), received monotherapy vaccination with lymph node-targeting ELI-002 2P, including mutant KRAS (mKRAS) amphiphile-peptide antigens (G12D, G12R) and amphiphile-adjuvant CpG-7909. Therefore, lymph node-targeting amphiphile vaccination induces persistent T cell responses targeting oncogenic driver KRAS mutations, alongside personalized, tumor antigen-specific T cells, which may correlate to clinical outcomes in pancreatic and colorectal cancer. ClinicalTrials.gov registration: NCT04853017 .

Additionally, human lung cancer xenograft and patient-derived xenograft models with a mesenchymal phenotype and high FGFR1 expression were sensitive to the combination of G12C inhibitors and pemigatinib. In short, we demonstrate that pemigatinib and KRAS G12C inhibitors are promising agents for combination therapy in non-small cell lung cancer with a mesenchymal-like phenotype harboring high FGFR1 expression and KRAS G12C mutations to broaden patient response.