Online first
Case report
Published online: 2023-12-05

open access

Page views 210
Article views/downloads 104
Get Citation

Connect on Social Media

Connect on Social Media

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

Karolina P. Nalewaj1, Izabela Chmielewska1, Paweł Krawczyk1, Anna Grenda1, Luiza Grzycka-Kowalik2, Iwona Paśnik3, Janusz Milanowski1


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. 

Article available in PDF format

View PDF Download PDF file


  1. Thandra KC, Barsouk A, Saginala K, et al. Epidemiology of lung cancer. Współczesna Onkologia. 2021; 25(1): 45–52.
  2. Zhang SS, Nagasaka M. Spotlight on Sotorasib (AMG 510) for Positive Non-Small Cell Lung Cancer. Lung Cancer (Auckl). 2021; 12: 115–122.
  3. Hofmann MH, Gerlach D, Misale S, et al. Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants. Cancer Discov. 2022; 12(4): 924–937.
  4. Ruiz-Patiño A, Rodríguez J, Cardona AF, et al. ONCOLGroup, CLICaP. p.G12C KRAS mutation prevalence in non-small cell lung cancer: Contribution from interregional variability and population substructures among Hispanics. Transl Oncol. 2022; 15(1): 101276.
  5. Hong DS, Fakih MG, Strickler JH, et al. KRAS Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020; 383(13): 1207–1217.
  6. Reita D, Pabst L, Pencreach E, et al. Direct Targeting Mutation in Non-Small Cell Lung Cancer: Focus on Resistance. Cancers (Basel). 2022; 14(5).
  7. Spinelli M, Du Parcq P, Gupta N, et al. Coexistence of two missense mutations in the KRAS gene in adenocarcinoma of the lung: a possible indicator of poor prognosis. Pathologica. 2022; 114(3): 221–227.
  8. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for Lung Cancers with p.G12C Mutation. N Engl J Med. 2021; 384(25): 2371–2381.
  9. Gregorc V, Lazzari C, Mandalá M, et al. Intratumoral Cellular Heterogeneity: Implications for Drug Resistance in Patients with Non-Small Cell Lung Cancer. Cancers (Basel). 2021; 13(9).
  10. Del Re M, Tiseo M, Bordi P, et al. Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA. Oncotarget. 2017; 8(8): 13611–13619.
  11. Sakata S, Otsubo K, Yoshida H, et al. Real-world data on NGS using the Oncomine DxTT for detecting genetic alterations in non-small-cell lung cancer: WJOG13019L. Cancer Sci. 2022; 113(1): 221–228.
  12. Aran V, Zalis M, Montella T, et al. Evaluation of KRAS Concomitant Mutations in Advanced Lung Adenocarcinoma Patients. Medicina (Kaunas). 2021; 57(10).
  13. Pirlog R, Piton N, Lamy A, et al. Morphological and Molecular Characterization of KRAS G12C-Mutated Lung Adenocarcinomas. Cancers (Basel). 2022; 14(4).
  14. Rivera-Concepcion J, Uprety D, Adjei AA. Challenges in the Use of Targeted Therapies in Non-Small Cell Lung Cancer. Cancer Res Treat. 2022; 54(2): 315–329.
  15. Dy GK, Govindan R, Velcheti V, et al. Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100. J Clin Oncol. 2023; 41(18): 3311–3317.
  16. de Langen AJ, Johnson ML, Mazieres J, et al. CodeBreaK 200 Investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS mutation: a randomised, open-label, phase 3 trial. Lancet. 2023; 401(10378): 733–746.
  17. Iska S, Alley EW. Sotorasib as First-Line Treatment for Advanced KRAS G12C-Mutated Non-Small Cell Lung Carcinoma: A Case Report. Case Rep Oncol. 2023; 16(1): 177–181.
  18. Jamal-Hanjani M, Wilson GA, McGranahan N, et al. TRACERx Consortium. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 376(22): 2109–2121.
  19. Shu CL, Liu YL. The Path to Personalized Treatment in KRAS-Mutant Non-Small Cell Lung Cancer: A Review of Targeted Therapies and Immunotherapy. Cancer Manag Res. 2022; 14: 3485–3492.
  20. Zhang W, Han W, Yu Bo, et al. Clinical features and prognosis according to genomic mutations in primary and metastatic lesions of non-small-cell lung cancer. Thorac Cancer. 2022; 13(11): 1642–1650.
  21. Ottaiano A, Ianniello M, Santorsola M, et al. From Chaos to Opportunity: Decoding Cancer Heterogeneity for Enhanced Treatment Strategies. Biology (Basel). 2023; 12(9).