KRAS G12C

DFT and MEP analysis highlighted the nucleophilic and electrophilic zones of best-docked flavonoids. A novel avenue for the control of KRAS G12C and G12D mutations is made possible by flavonoids.

The first successes occurred with allele-specific targeting of KRAS p.Gly12Cys (G12C) in non-small cell lung cancer, resulting in regulatory approval of two agents-sotorasib and adagrasib. Herein, we outline RAS pathobiology with a focus on KRAS, illustrate therapeutic approaches across a variety of malignancies, including emphasis on the 'on' and 'off' switch allele-specific and 'pan' RAS inhibitors, and review immunotherapeutic and other key combination RAS targeting strategies. We summarize mechanistic understanding of de novo and acquired resistance, review combination approaches, emerging technologies and drug development paradigms and outline a blueprint for the future of KRAS therapeutics with anticipated profound clinical impact.

P1, N=830, Recruiting, Merck Sharp & Dohme LLC | N=450 --> 830

Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation...Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1...Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

Sotorasib and adagrasib, direct KRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRASG12C-mutated NSCLC, and these advances have become practice changing. New KRASG12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRASG12C-mutated NSCLC.

In the first-line treatment, combination regimen has advantages over single regimen. Among them, chemotherapy combined with immunotherapy plus antiangiogenic therapy can achieve significant efficacy benefits.

This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRASG12C-dependent lung cancer. Insights from successful KRASG12C targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.

P=N/A; Our data suggest detectable pre-treatment KRASG12C ctDNA as a marker for poor prognosis, and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.

In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded.

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

P1/2, N=822, Recruiting, Mirati Therapeutics Inc. | Trial completion date: Sep 2024 --> Jan 2026 | Trial primary completion date: Dec 2023 --> Jul 2025

P2, N=80, Recruiting, ImaginAb, Inc. | Phase classification: P2b --> P2 | Trial completion date: Dec 2025 --> Jul 2025 | Trial primary completion date: Dec 2024 --> Jul 2025

Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRASG12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

P2, N=0, Withdrawn, ETOP IBCSG Partners Foundation | N=47 --> 0 | Not yet recruiting --> Withdrawn

Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer.

To do this, we have exploited the use of monobody (Mb) technology to develop specific protein-based inhibitors of selected RAS isoforms and mutants (Spencer-Smith et al., Nat Chem Biol 13:62-68, 2017; Khan et al., Cell Rep 38:110322, 2022; Wallon et al., Proc Natl Acad Sci USA 119:e2204481119, 2022; Khan et al., Small GTPases 13:114-127, 2021; Khan et al., Oncogene 38:2984-2993, 2019). Herein, we describe our combined use of Mbs and NanoLuc Binary Technology (NanoBiT) to analyze RAS protein-protein interactions and to screen for RAS-binding small molecules in live-cell, high-throughput assays.

Given that mutations in KRAS occur early in PDAC tumorigenesis, an understanding of its pleiotropic effects is key to progress in this disease. Herein, we review current perspectives on targeting KRAS with a focus on PDAC.

Advances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.

P1/2, N=352, Recruiting, D3 Bio (Wuxi) Co., Ltd | Phase classification: P1 --> P1/2 | N=168 --> 352 | Trial completion date: May 2025 --> Sep 2026 | Trial primary completion date: May 2025 --> Sep 2026

Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both...These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy...However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRASG12C or HER2 amplification) and in non-oncogenic driven patients.

P1/2, N=410, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting | Trial completion date: Jul 2029 --> May 2024 | Trial primary completion date: Aug 2027 --> May 2024

Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation...In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

The identification of both a KRAS p.G12C mutation and an ANK3::RET fusion in the same CRC patient adds a new layer to the oncogenic landscape and treatment considerations for CRC. It highlights the intricate decision-making required in the era of precision medicine, where targeted therapies must be carefully chosen and potentially combined to combat complex genetic profiles. The case emphasizes the urgency of investigating the clinical effects of concurrent or sequential use of KRAS p.G12C and RET inhibitors to inform future therapeutic guidelines and improve patient outcomes in similar cases.

There have been two treatment-related deaths, one due to cardiac arrest and one due to pneumonitis. Ten additional participants have experienced Grade 4 treatment-related adverse events, nine of which are non-hematologic toxicities.

P1, N=40, Recruiting, NYU Langone Health | Phase classification: P1/2 --> P1

The sotorasib and adagrasib are the recently approved drugs that selectively target KRASG12C, and offer new treatment approaches to enhance patient outcomes however drug resistance frequently arises. These new hits have the potential to inhibit KRASG12C and may help to prevent KRAS-associated lung cancer. All the datasets used in this study can be freely available at ( https://github.com/Amar-Ajmal/Datasets-for-KRAS ).

KRAS G12V mutation was associated with aggressive clinical-pathological phenotype and early recurrence. To note, this mutation exhibited significantly worse prognosis in part-solid and stage Ⅰ lung adenocarcinoma patients. Meanwhile, the prognostic significance of KRAS G12C and G12V variants were comparable.

Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.

P1, N=12, Active, not recruiting, Amgen | Trial completion date: Mar 2023 --> Jul 2024

P2, N=146, Recruiting, Genentech, Inc. | N=85 --> 146

Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.

In this preliminary prospective study, sotorasib after PD-(L)1 blockade was associated with severe hepatotoxicity, especially in patients with a short interval between treatments, prior immune-related hepatitis and higher anti-PD-1 plasma concentrations. Our results suggest a minimum interval of 6 weeks between anti-PD-(L)1 and sotorasib to minimize the risk of hepatotoxicity.

For patients with NSCLC, initial use of SGT increases subsequent CGP test cancellations, turnaround time, and the likelihood of incomplete molecular profiling for guideline-recommended biomarkers due to tissue insufficiency.

Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.

P1, N=130, Active, not recruiting, Navire Pharma Inc., a BridgeBio company | Recruiting --> Active, not recruiting

We present two applications to demonstrate the capabilities of our assay: maleimide-biotin labeling of a KRAS4BG12D cysteine mutant panel and treatment of three KRAS4B proteins (WT, G12C, and G13C) with small molecule compounds. Our results show the time- or concentration-dependence of KRAS4B-compound engagement in context of the intact protein molecule while directly mapping the compound binding site.

No abstract available

Accordingly, we have tested FTIs (tipifarnib and lonafarnib) in G12C mutant human cancer cell lines in vitro and in vivo. At last, we have also tested FTIs on G12V mutant human cancer cells and again we have detected antitumoral effects. We suggest that FTIs may have clinical relevance outside the HRAS mutant cancers.

The EGFR exon 19 deletion mutation was more common in both MIA (50%; n = 6/12) and ADC (41%; n = 149/363), whereas p.L858R was more prevalent in AIS (75%; n = 3/4). In contrast to pulmonary advanced ADC, KRAS driver mutations are less common, whereas mutations in EGFR are more common, in detectable AIS and MIA.

Consequently, there has been a growing interest in biomarkers that may help guide targeted therapy in pancreatic cancer. Therefore, this review aims to offer an updated perspective on biomarkers with therapeutic potential in pancreatic cancer.