Osimertinib in the Treatment of Patients with NSCLC with Secondary EGFR T790M Mutation – Case Study

NSCLC and EGFR Tyrosine Kinase Inhibitors

Lung cancer is the third most common malignancy in Czech men and the fourth most common in women. Approximately 80% of cases are NSCLC with a high percentage of specific mutations. Targeted therapy of these mutations significantly improves the prognosis of patients with NSCLC. Therefore, it is necessary to test newly diagnosed NSCLC patients for the presence of EGFR mutations, ALK gene rearrangements, and ROS1, and more recently, for BRAF gene mutations. In the Czech Republic, reflex testing for EGFR mutations is done for all newly diagnosed patients with NSCLC with adenocarcinoma histology, unspecified NSCLC, and at the request of the clinician, also for NSCLC with squamous cell histology.

Improvement in the prognosis of patients with an activating mutation in the EGFR gene was brought about by targeted EGFR TKIs (1st generation: gefitinib and erlotinib; 2nd generation: afatinib). However, resistance develops during treatment with 1st and 2nd generation EGFR TKIs. 60% of these resistances arise due to the T790M mutation in exon 20 of the EGFR gene. The third-generation EGFR tyrosine kinase inhibitor osimertinib is currently the only EGFR TKI approved in the Czech Republic not only for the 1st line treatment of patients with an activating EGFR mutation but also for the treatment of patients with the T790M mutation, which causes resistance to 1st and 2nd generation EGFR inhibitors.

Case Description

A 67-year-old man was diagnosed with bronchogenic carcinoma of the right middle lung lobe in June 2015. Based on cytological examination from pleural effusion aspiration, the tumor was classified as T1bN0M1a, stage IV. Genetic analysis demonstrated an activating EGFR mutation, deletion in exon 19, and treatment with afatinib was initiated in June 2015.

Partial regression was achieved with this treatment, which persisted until November 2017, when PET/CT examination revealed glucose hypermetabolism foci suggestive of a tumor process in the skeleton. Due to the small extent of progression, palliative radiotherapy targeting the lesion in the left femur and the left branch of the pubic bone was chosen. Radiotherapy was completed in February 2018, but already in March 2018, another PET/CT examination showed generalization of the tumor process (lesion in the liver, increasing original lesion in the right lung, lesion in the right pleural cavity).

Afatinib therapy was terminated in March 2018 due to disease progression. A repeated liquid biopsy confirmed the original activating EGFR mutation and a new secondary EGFR T790M mutation, which causes resistance to afatinib. Treatment with osimertinib was initiated in April 2018. Subsequent PET/CT in October 2018 did not demonstrate generalization of the tumor process.

Conclusion

Osimertinib is currently the only available targeted treatment for patients with locally advanced or metastatic NSCLC with an activating EGFR mutation, who have developed the T790M mutation that causes resistance to 1st and 2nd generation EGFR tyrosine kinase inhibitors. Osimertinib treatment is covered for patients with locally advanced or metastatic NSCLC with the presence of the EGFR T790M mutation after prior EGFR TKI therapy with a performance status (PS) of 0–1, and continues until disease progression due to the accumulation of additional mutations causing resistance to osimertinib.

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Source: Koubková L. Case studies of patients treated with osimertinib. Case Studies in Allergology, Pneumology and ENT 2019; 16 (1): 18–21.