The third representative skin growth factor receptor (egfr) tyrosine kinase inhibitor (TKI) has achieved significant success in the treatment of patients with non-small cell lung cancer (NSCLC) with advanced EGFR mutation. However, one of the main limitations of targeted therapy is that the tumor response is not long-lasting, and patients inevitably develop resistance. Therefore, the exploration of the mechanism of drug resistance of osimertinib and subsequent treatment options is a hot topic of research in recent years.
After oscitinib resistance, the t790m/c797s mutation is the most common mutation. The analysis of resistance in the aura3 study on second-line treatment with osimertinib is as follows:
Acquired egfr mutations: 21%;
met amplification: 19%;
Cell cycle gene changes: 12%;
Her2 amplification: 5%;
PIK3CA amplification/mutation: 5%;
Oncogene fusion: 4%;
braf v600e: 3%。
T790m/c797s cis-mutation (cis-) means that two genes are on the same DNA strand, and t79om/c7975 trans-mutation (trans-) is that two genes are located on different DNA strands.
On 28 April 2021, the Europe PMC literature database reported a case of maintenance therapy benefiting from 2 courses of osimertinib plus anlotinib after the onset of t790m+c797s cis mutation and chemotherapy, with an overall survival of 39 months!
A 52-year-old female patient was admitted to the hospital in June 2017 for one month with sputum production and a PS score of 1. Computed tomography (ct) of the chest reveals consolidation of the lower right lung with right pleural effusion and miliary opacification of both lungs. The patient then underwent fibronchoscopy and was diagnosed as stage IV (ctxnxm1) and histopathology as adenocarcinoma.
Genetic testing revealed deletion of exon 19 of egfr (19del) in tissues. Subsequently, patients are given gefitinib as first-line therapy. In September 2017, imaging tests showed that the lesion had achieved partial remission (pr) and progression-free survival (pfs) of 7 months.
In January 2018, chest CT showed multiple nodules in the lower right lung, pleural effusion on the right side, and lung infection. The disease progresses.
Blood samples were tested in patients after disease progression and a common mutation of egfr 19 del (pe746_a750del, allele frequency (af): 0.07%) and t790 m (af: 0.16%) was found. The patient then switched to osimertinib in February of the same year and achieved partial remission with a progression-free survival of 10 months.
In December of the same year, the patient developed a progression of the disease, chest CT showed enlarged right lung lesions, increased pleural effusion, and right lung atelectasis.
The same NGS test was performed on plasma and pleural effusion samples, and both samples showed egfr 19del and t790m+c797s (trans mutations), of which egfr 19 del (af: 0.24%), t790m (af: 0.20%), c797s (af: 0.38%).
In January 2019, patients began receiving oscitinib (80 mg once daily) in combination with gefitinib (250 mg once daily) as a third-line treatment. After a month of re-examination, the lesions of the right lung narrowed, the pleural effusion decreased, and only few side effects such as paronychia and rash appeared. Overall efficacy was assessed as partial remission, with progression-free survival of 8 months.
In September 2019, the disease progressed, and imaging examination showed shortness of the right lower lobe bronchi, increased pleural effusion on the right side, multiple nodules in the right lung, and aggravated lung infection.
NGS testing again showed egfr 19del, t790m + c797s (cis mutation), of which egfr 19 del (af: 0.62%), t790m (af: 0.45%), c797s (af: 0.57%).
Patients are subsequently treated with osimertinib + anlotinib + pemetrexed + cisplatin. After a cycle of treatment, the lesions of the right lung shrink, the pleural effusion decreases, and the right lung infection is relieved. After two cycles of combination therapy, cisplatin was discontinued due to severe gastrointestinal side effects.
In December 2019, a review ct showed continued partial relief. This was followed by protractive therapy with osimertinib plus anlotinib until may 2020.
In June 2020, the patient underwent NGS testing again, and unexpectedly, egfr 19del, t790m+ c797s (cis + trans co-mutation), of which egfr 19 del (af: 0.68%), t790m (af: 0.49%), c797s cis (af: 0.24%) and c797s trans (af: 0.12%).
Therefore, the patient began to receive bevacizumab + albumin-binding paclitaxel therapy. After a period of treatment, the symptoms of chest tightness and shortness of breath are reduced, and the mental state and appetite are improved. But after two cycles, due to poor physical condition, the treatment was terminated. Unfortunately, the patient passed away in August 2020 with an overall survival (OS) of 39 months.
Figure note: Patient's treatment history and tumor lesion response timeline
Note: Allele background and frequency of egfr c797s and egfr t790m mutations during treatment
This case provides the first clinical evidence of the potential efficacy of oscitinib combined with anlotinib in the treatment of cis mutation c797s! Moreover, the importance of dynamic monitoring of the mutant state after osimtinib resistance is highlighted, which may provide patients with more opportunities for targeted therapy and improve survival time after the progression of osimtinib.
【Important Note】The article information of this public number [Family Says] is for reference only, and the specific treatment should follow the doctor's advice!