Inhibition of Mutated KRAS Protein as a New Option for Targeted Treatment of Non-Small Cell Lung Cancer
RAS proteins are molecular switches for several intracellular signaling pathways. Their dysfunction due to mutation leads to the development and progression of malignant diseases such as colon or lung cancers. At the beginning of 2022, the inhibitor of the mutated KRAS protein, sotorasib, was approved. The following article outlines the effect of this first representative of a new drug group and its potential in the treatment of non-small cell lung cancer (NSCLC).
How to Fix a Broken Molecular Switch
Membrane RAS proteins transmit signals in intracellular signaling cascades responsible for regulating cell proliferation and differentiation. The protein activates upon binding to guanosine triphosphate (GTP) and subsequently remains in an active conformation, allowing the initiation of an intracellular signaling pathway. RAS terminates its activity by cleaving phosphate from GTP, resulting in guanosine diphosphate (GDP). GDP remains bound to the RAS protein for a certain period, stabilizing it in an inactive form.
Genes encoding RAS proteins are known proto-oncogenes. KRAS gene mutations, for example, are present in approximately 23% of NSCLC patients. Nearly half of these cases are due to a specific point mutation in codon 12 (G12C), causing a glycine-to-cysteine substitution in the resulting protein. This pathological change in the primary structure keeps KRAS in a permanent GTP-bound state, i.e., in an active conformation that independently maintains subsequent signaling pathways in the cell.
Covalent, irreversible binding to cysteine can "turn off" the dysfunctional KRAS protein by bringing it to an inactive state bound to GDP. This mechanism of action is exhibited by the first KRAS inhibitor, sotorasib. Currently, it is approved for monotherapy in adult patients with advanced NSCLC with mutated KRASG12C, who have progressed after at least one prior line of systemic therapy.
Efficacy of Sotorasib
Registration of the drug containing sotorasib was granted based on the results of ongoing clinical evaluations (CE) from the CodeBreaK program.
The pivotal results came from the CodeBreaK 100 study, particularly its phase II clinical trial. This included patients with advanced or metastatic NSCLC with mutated KRASG12C who had progressed after prior immunotherapy and/or platinum-based chemotherapy. Participants received 960 mg of sotorasib daily until progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR), defined as achieving complete or partial remission confirmed after ≥ 4 weeks. The last interim analysis was conducted on data from 124 patients after a median follow-up of 15.3 months and a median treatment duration of 5.5 months, yielding the following results:
- ORR: 37.1% (28.6–46.2)
- Disease control rate: 80.6% (72.6–87.2)
- Median duration of treatment response: 11.1 months (6.9 – not evaluable)
- Median progression-free survival: 6.8 months (5.1–8.2)
- Median overall survival: 12.5 months (10.0 – not evaluable)
Similar treatment responses were achieved by patients with accompanying mutations, such as in the TP53 or STK11 genes, and varying levels of programmed death-ligand 1 (PD-L1) expression. Key results from the subsequent phase III CodeBreaK 200 clinical trial are summarized in one of the previous articles.
Safety and Tolerability of the Therapy
Patients treated with sotorasib in clinical trials frequently experienced diarrhea (34% of participants), nausea (25%), and fatigue (21%). Severe adverse events primarily included elevations in hepatic transaminases and diarrhea, which were the most common reasons for dose reduction or discontinuation of sotorasib. Hepatotoxicity manifested after approximately 8 weeks of treatment and was transient, with about a quarter of patients successfully treated with corticosteroids. Severe interstitial lung processes or pneumonitis were rarer (0.8%), occurring approximately 2 weeks after therapy initiation. Patient-reported quality of life assessments during treatment remained stable or improved.
Conclusion
Sotorasib is a new oral inhibitor of the KRAS protein with a G12C mutation. It has demonstrated significant efficacy in treating NSCLC in clinical trials, accompanied by manageable adverse effects. This new drug expands the options for second and subsequent lines of treatment for patients with advanced or metastatic NSCLC with mutated KRASG12C.
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Sources:
1. Lee A. Sotorasib: a review in KRAS G12C mutation-positive non-small cell lung cancer. Target Oncol 2022; 17 (6): 727–733, doi: 10.1007/s11523-022-00922-w.
2. SPC Lumykras. Available at: www.ema.europa.eu/en/documents/product-information/lumykras-epar-product-information_cs.pdf
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