KRAS G12C

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.

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.

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.

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.

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

P3, N=95, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Sep 2024 --> May 2025

Genomic profiling yields clinically actionable information for approved therapies and evidence of resistance, and it may uncover rational therapeutic opportunities regardless of tumor type.

Given the importance of timely, comprehensive molecular test results to inform appropriate treatment decisions in NSCLC and CRC, these results suggest that the rapid in-house GeneXus NGS system can reduce TAT with comparable failure rates and alteration detection rates compared to other testing methods. Further studies evaluating the impact of the rapid OPA compared to other methods on patient care, as well as the economics of different molecular tests, are ongoing.

P1/2, N=28, Not yet recruiting, HenanCancerHospital; HenanCancerHospital

P1, N=388, Recruiting, Shanghai Chest Hospital; CSPC Megalith Biopharmaceutical Co., Ltd

P2, N=42, Active, not recruiting, Amgen | Trial completion date: Nov 2024 --> Jan 2026 | Trial primary completion date: Nov 2024 --> Jan 2026

No abstract available

The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45-0.76; P<0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRAS G12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.

Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.

AXL and PIM-1 expression detected in CTCs during treatment suggesting new possible therapeutic strategies. Our results reveal that comprehensive liquid biopsy analysis can efficiently represent the heterogeneous molecular landscape and provide prominent information on subsequent treatments for NSCLC patients at PD since druggable molecular alterations were detected in CTCs.

P1, N=830, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Aug 2026 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Aug 2027

Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

P2, N=117, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P=N/A, N=5000, Completed, QIAGEN Gaithersburg, Inc | Active, not recruiting --> Completed

The KRAS mutation and KRAS G12C mutation confer benefits that impact OS and PFS in NSCLC patients treated with immunotherapy. However, the KRAS G12D mutation negatively impacts OS compared to the KRAS non-G12D mutation. Furthermore, KRAS co-mutations involving STK11 and KEAP1/NFE2L2 are associated with a negative impact on the efficacy of immunotherapy in NSCLC patients.

P1, N=30, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

This case emphasizes the poor prognosis of patients with PSC due to a lack of therapeutic response to chemotherapy, radiation, and, as seen in this case, current targeted therapy as well. Our case emphasizes the need to further evaluate therapeutic responses of targeted therapy in this rare subtype of NSCLC.

P1, N=74, Terminated, Amgen | Completed --> Terminated; Business decision not due to safety concerns

In total, 40% of patients had druggable molecular alterations, but only 1.1% received genomically guided treatment, suggesting limited application in standard practice. Despite this, expanded gene panel testing can identify actionable mutations, aiding personalized treatment strategies in metastatic CRC, although current eligibility for biomarker-guided trials remains limited.

ARMS-HRMA is a rapid and cost-effective method for detecting KRAS mutations in PDAC patients, offering the potential for stratifying prognosis and guiding treatment decisions. The presence of G12D and G12C mutations in both tumor and plasma is associated with a poorer prognosis.

Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.

It is well known in the literature that false negative liquid biopsies are possible, but a significant finding this case highlights is the clinical importance of tumor fraction in a liquid biopsy report. We conclude that patients with a liquid biopsy with low tumor fraction need further testing with tumor NGS to determine the presence of driver genomic alterations.

IBI351 and its metabolites were primarily excreted through feces. Taken together, this is the first study on the metabolism and safety of IBI351 in Chinese subjects, and these findings may guide future clinical development of IBI351 as a novel anti-tumor drug.

These methods have been applied as a proof-of-concept to KRAS and have shown they can predict known cryptic binding sites. Furthermore, we performed ligand-binding simulations of a known inhibitor (MRTX1133) to shed light on the nature of cryptic pockets in KRASG12D and the role of conformational selection vs induced-fit mechanism in the formation of these cryptic pockets.

We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.

P1, N=1200, Recruiting, Amgen | Trial completion date: Jun 2029 --> Mar 2028 | Trial primary completion date: Jan 2027 --> Apr 2026

Investigation of the response of KRASG12C PDOs to sotorasib demonstrates that the model can examine the efficacy of treatments to suppress metastasis and identify mechanisms of drug resistance. Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD.

P1, N=1200, Recruiting, Amgen | Trial completion date: Mar 2028 --> Jun 2029 | Trial primary completion date: Sep 2025 --> Jan 2027

P1/2, N=22, Terminated, InventisBio Co., Ltd | Phase classification: P1b/2 --> P1/2 | N=144 --> 22 | Trial completion date: Dec 2024 --> Jun 2024 | Recruiting --> Terminated; Adjustment of drug development strategy.

P1/2, N=225, Completed, InventisBio Co., Ltd | Active, not recruiting --> Completed

P1/2, N=92, Recruiting, InventisBio Co., Ltd | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Jun 2025