Tumor heterogeneity and its impact on sotorasib response in a patient with non-small cell lung cancer

Abstract

Mutations in the Kirsten rat sarcoma virus (KRAS) gene are the most common mutations in NSCLC, and they occur in 25-40% of patients with lung adenocarcinoma. Sotorasib, a selective KRAS inhibitor, is an anticancer drug used in NSCLC patients with a G12C mutation in the KRAS gene. In previously treated patients, this therapy was safer and more effective than docetaxel chemotherapy. Heterogeneity refers to differences between tumor cells within a single tumor as well as in primary and metastatic lesions. It may influence the response to targeted therapies and the development of acquired resistance to these therapies. It is assumed that sotorasib efficacy is lower in patients with known tumor molecular heterogeneity, which may be common in patients exposed to tobacco smoke. This case report presents a 63-year-old woman with advanced NSCLC and a confirmed G12C mutation in the KRAS gene detected with the real-time PCR technique. A later next-generation sequencing (NGS) examination did not show the presence of this mutation. However, the NGS study was performed on material from a different metastatic lesion. The negative NGS result from this material was confirmed by the real-time PCR technique. The patient had a short-term benefit from first-line chemotherapy and second-line nivolumab immunotherapy (disease stabilization). Due to progression (progression of measurable lesions and new metastases to the CNS), the patient received brain radiotherapy and then sotorasib in the third line of treatment. However, the effectiveness of KRAS inhibition was limited. Regression of the lesion with a detected mutation in the KRAS gene and progression of lesions without this mutation were observed. Sotorasib therapy was terminated. The woman died two years after diagnosis, not benefiting from subsequent lines of therapy. NSCLC heterogeneity (presence of mutations in only some clones of cancer cells) may be responsible for primary and acquired resistance to molecularly targeted therapies, including KRAS inhibitors.