The findings of the thematic analysis indicate that KRAS mutation in lung cancer, the prognosis following B-Raf proto-oncogene, serine/threonine kinase (BRAF) or rat sarcoma (RAS) mutations, and anti-epidermal growth factor receptor (EGFR)-related lung cancer are the significant hotspots in the given field. Considering the significant advancements made in direct targeting drugs like sotorasib, it is anticipated that interest in cancers associated with KRAS mutations will remain steadfast.

P2, N=30, Recruiting, Ryan Gentzler, MD | Not yet recruiting --> Recruiting

P3, N=600, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer...Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

P4, N=21, Completed, Radboud University Medical Center | Recruiting --> Completed | Trial completion date: Nov 2024 --> Mar 2024 | Trial primary completion date: Nov 2024 --> Mar 2024

Sotorasib and adagrasib are FDA-approved targeted agents for pre-treated patients with KRAS-G12C-mutated NSCLC. In this review, we summarize the biology of the KRAS protein and the characteristics of KRAS mutations. We then present current and emerging therapeutic approaches for targeting KRAS mutation subtypes intending to provide individualized treatment for lung cancer harboring this challenging driver mutation.

P3, N=522, Recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Not yet recruiting --> Recruiting

P1/2, N=1126, Recruiting, Amgen | Trial primary completion date: Sep 2026 --> Dec 2026

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=12, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

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

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.

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.

The experience with sotorasib might help better prevent, screen and manage sotorasib-related and other KRASG12C inhibitors-related AEs, particularly hepatotoxicity.

Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

P1, N=0, Withdrawn, Amgen | N=140 --> 0 | Trial completion date: Jun 2024 --> Sep 2024 | Initiation date: Apr 2024 --> Jul 2024 | Not yet recruiting --> Withdrawn | 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

Furthermore, GIC-20 also enhanced the sensitivity of resistant MIA-PaCa-2-AMG510R cells to AMG510, suggesting the great potential of GIC-20 in overcoming the acquired resistance of KRASG12C inhibitors. Overall, GIC-20 represents a novel dual ferroptosis/apoptosis inducer warranting further development for cancer therapeutics and overcoming drug resistance.

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.

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

P1, N=72, Not yet recruiting, Jemincare

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

P3, N=600, Not yet recruiting, Merck Sharp & Dohme LLC

P1, N=160, Recruiting, TheRas, Inc

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

P2, N=160, Recruiting, Memorial Sloan Kettering Cancer Center

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 ).

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

P1, N=15, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting | Trial completion date: Apr 2025 --> Mar 2026 | Trial primary completion date: Apr 2025 --> Mar 2026

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.

P4, N=22, Recruiting, Radboud University Medical Center

We further test whether FDA-approved KRAS inhibitors sotorasib and adagrasib successfully inhibit the E31D and E63K mutants. Based on sharp coherence in trajectories between wild KRAS and non-hotspot mutants, it is suggested that these novel mutants do not contribute to drug resistance mechanism. Overall, we provide a comprehensive understanding of the impact of non-hotspot mutations on KRAS and their potential as targets for effective cancer therapies.Communicated by Ramaswamy H. Sarma.

P3, N=461, Active, not recruiting, Mirati Therapeutics Inc. | Trial completion date: Dec 2024 --> Feb 2026 | Trial primary completion date: Apr 2024 --> Feb 2025

P1, N=18, Completed, Mirati Therapeutics Inc. | Not yet recruiting --> Completed

P1, N=16, Completed, Mirati Therapeutics Inc. | Recruiting --> Completed | Trial completion date: Aug 2024 --> Aug 2023

P2, N=42, Not yet recruiting, Maastricht University Medical Center | Initiation date: Nov 2023 --> Apr 2024

P3, N=522, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P2, N=69, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting