Management of KRAS-mutated non-small cell lung cancer
Jyoti Malhotra1,2, Danny Nguyen1,2, Tingting Tan1,2
1City of Hope Orange County, Irvine, California.
Abstract:
Kirsten rat sarcoma virus (KRAS) is the most frequently mutated oncogene in human cancers, particularly in non-small cell lung cancer (NSCLC), where mutations are present in 32% of lung adenocarcinoma and 4% of squamous cell lung cancer. The most common KRAS variant is KRAS G12C, which accounts for nearly 40% of all KRAS mutations. Although it is the most common oncogenic driver in NSCLC, KRAS was considered a "nondruggable target" until recently, owing to the lack of any progress in developing targeted therapies for this oncogene. With the recent development and approval of selective KRAS G12C inhibitors such as sotorasib and adagrasib for the treatment of advanced or metastatic NSCLC in the second-line setting and beyond, the standard of care for managing these tumors has undergone a significant change. Mechanisms of resistance to KRAS G12C inhibitors are highly heterogeneous, including both on-target and off-target resistance as well as morphologic switching, thus limiting the activity of these drugs when used as monotherapy. New-generation inhibitors and different combination strategies are being developed in early-phase trials to overcome or delay the onset of resistance as well as to target non-G12C mutations. Owing to the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualized based on factors such as co-occurring mutations.
Insights
Targeted therapies for Kirsten rat sarcoma virus (KRAS) G12C-mutant non-small cell lung cancer (NSCLC) have advanced treatment. However, resistance mechanisms necessitate new combination strategies and individualized therapy for KRAS-mutant NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Kirsten rat sarcoma virus (KRAS) is a frequently mutated oncogene in human cancers, especially non-small cell lung cancer (NSCLC).
- KRAS G12C is the most common KRAS variant, driving tumor growth in a significant portion of NSCLC cases.
- KRAS was historically considered undruggable until the development of selective KRAS G12C inhibitors.
Purpose of the Study:
- To review the current landscape of KRAS G12C inhibitors in advanced or metastatic NSCLC.
- To discuss the mechanisms of resistance to KRAS G12C inhibitors.
- To highlight the development of new therapeutic strategies, including next-generation inhibitors and combination therapies, for KRAS-mutant NSCLC.
Main Methods:
- Literature review of recent clinical trials and research on KRAS G12C inhibitors.
- Analysis of resistance mechanisms to targeted KRAS G12C therapies.
- Overview of ongoing early-phase trials for novel treatment approaches.
Main Results:
- Selective KRAS G12C inhibitors like sotorasib and adagrasib have changed the standard of care for advanced NSCLC.
- Resistance to KRAS G12C inhibitors is heterogeneous, involving on-target, off-target, and morphologic switching mechanisms.
- These resistance mechanisms limit the efficacy of monotherapy, driving the need for alternative strategies.
Conclusions:
- New-generation inhibitors and combination strategies are under development to overcome or delay resistance.
- Individualized treatment approaches, considering co-occurring mutations and biological heterogeneity, are crucial for managing KRAS-mutant NSCLC.
- Targeting non-G12C KRAS mutations is also an area of active research.
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