Combination therapy of erlotinib/crizotinib in a lung adenocarcinoma patient with primaryEGFR mutation plus secondaryMET amplification and a novel acquired crizotinib-resistant mutationMET G1108C
Authors: Y.Q. Li, S.S. Song, S.H. Jiang, X.Y. Zhang
Journal: Annals of Oncology (2017)

A 36-year-old non-smoking Chinese woman was diagnosed as stage IV lung adenocarcinoma and pneumonia by chest computed tomography (CT) scan (Figure 1A) and biopsy in June 2016. CT scan and brain enhanced magnetic resonance imaging (MRI) showed left pleural effusion and multiple metastases in lymph nodes, liver and brain. The patient adopted chest drainage and was given pemetrexed and nedaplatin for treatment. However, the disease massively progressed after 2 weeks post-treatment (Figure 1A). An immediate peripheral ctDNA analysis was carried out based on next-generation sequencing. The results showed L858R mutation (allele frequency, AF, 58%) and copy number amplification (log ratio, LR, 1.32) of epidermal growth factor receptor (EGFR). Thus, the patient was switched to receive erlotinib 150 mg/day in July 2016. The patient demonstrated significantly decreased tumor biomarkers (Figure 1B) and improved clinical symptoms within 10 days post-erlotinib treatment. After 3 months, MRI detected complete responses of brain metastases, and CT detected partial responses of lung and liver lesions free of pleural effusion. The patient maintained stable disease for about 6 months. However, metastasis in right adrenal occurred in November 2016. Clinical symptoms and chest CT revealed disease progression a month later together with multiple bone metastases. Apart from the continually presentEGFR L858R mutation (AF 74.94%) and amplification (LR 2.68), the secondary ctDNA analysis revealed copy number amplification ofMET (LR 2.77), considered responsible for erlotinib resistance [1.Bean J. Brennan C. Shih J.-Y. et al.MET amplification occurs with or without T790Mmutations inEGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.Proc Natl Acad Sci USA. 2007; 104: 20932-20937Crossref PubMed Scopus (1462) Google Scholar]. Subsequently, the patient was treated with erlotinib (150 mg/day) and crizotinib (250 mg/day) in January 2017, based on the confirmed safe use by a phase I clinical trial [2.Ignatius Ou S.-H. Govindan R. Eaton K.D. et al.Brief report: phase I results from a study of crizotinib in combination with erlotinibin patients with advanced non-squamous non-small cell lung cancer.J Thorac Oncol. 2017; 12: 145-151Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. Four weeks after the combination therapy, cough was significantly relieved and a dramatic response was observed in lung (Figure 1A). Yet the combination therapy resulted in severe side-effects including vomiting and rash. Nine weeks post-combination therapy, nevertheless, the patient again showed progressed symptoms. The following ctDNA analysis demonstrated three novel mutations:NRAS Q61H (AF 4.06%),KRAS G12D (AF 0.64%) andMET G1108C (AF 7.84%), in addition toEGFR L858R mutation (AF 33.91%) and amplification (LR 1.68).NRAS Q61H andKRAS G12D are capable of conferring erlotinib-resistance [3.Pao W. Wang T.Y. Riely G.J. et al.KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.PLOS Med. 2005; 2: e17Crossref PubMed Scopus (1380) Google Scholar]. Interestingly, the novel acquiredMET G1108C mutation is located within the kinase domain next to the binding site of crizotinib. Steric stabilization and increased hydrophilic of cysteine residue may influence drug binding, resulting in crizotinib-resistance (Figure 1C). In April 2017, the patient suffered from severe pneumonia and infection and finally died. The patient has shown free brain lesions since October 2016, indicating a great benefit of erlotinib for brain metastases. However, high levels ofEGFR mutation and amplification were detected throughout the therapy, implying other TKIs could be considered for the continued treatment when patient's brain metastases disappeared. Upon detectingEGFR mutations with concurrentMET amplification, we observed dramatic response post to the combination therapy of erlotinib/crizotinib. Yet due to paucity of the drugs targeting the upcomingMET-resistant mutation andRAS mutations, we were unable to control the aggressive recurrence of this case. The development of new drugs for treating these mutations is required. Of note, disease monitoring via ctDNA sequencing is crucial for targeted therapy in lung adenocarcinoma. None declared.