Targeted Therapy and Immunotherapy Lead to Rapid Regression of Advanced Non–Small Cell Lung Cancer with Multiple Driver Mutations
Authors: Chung-Kuan Wu, Shang-Jyh Kao, Hung-Chih Lai
Journal: Journal of Thoracic Oncology (2018)

Lung cancer is the leading cause of cancer deaths worldwide and is usually diagnosed at an advanced stage. In advanced NSCLC, platinum-based chemotherapy has shifted to targeted therapy of driver mutations because of breakthroughs related to the molecular pathophysiological mechanism.1Chan B.A. Hughes B.G. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future.Transl Lung Cancer Res. 2015; 4: 36-54Google Scholar Furthermore, immunotherapy has demonstrated effective responses in advanced NSCLC, especially in tumors with high programmed death ligand 1 expression.2Carbone D.P. Reck M. Paz-Ares L. et al.First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.N Engl J Med. 2017; 376: 2415-2426Google Scholar However, patients with advanced NSCLC with coexisting driver mutations still have limited options and poor prognosis.3Martin Martorell P. Huerta M. Compan Quilis A. et al.Coexistence of EGFR, KRAS, BRAF, and PIK3CA mutations and ALK rearrangement in a comprehensive cohort of 326 consecutive Spanish nonsquamous NSCLC patients.Clin Lung Cancer. 2017; 18: e395-e402Google Scholar We report a patient with advanced NSCLC showing multiple driver mutations who had a good clinical response after combination therapy with targeted anti–vascular endothelial growth factor receptor, EGFR tyrosine kinase inhibitor (TKI), and anti–programmed cell death 1 (PD-1) immunotherapy. A 56-year-old man with chronic hepatitis B, hypertension, and gastric ulcer presented with abdominal pain and anorexia in September 2016. He had lost more than 10 kg in a half year. Positron emission tomography–computed tomography (PET/CT) in October 2016 revealed intense uptake in the left upper lung tumor. with mediastinal invasion; bilateral pulmonary nodules; regional and distant lymphadenopathy; and uptake foci in the brain, both adrenal glands, and bones (Fig. 1A). Histopathological examination of the tumor revealed adenocarcinoma with positive staining for thyroid transcription factor-1 and cytokeratin 7. A high serum carcinoembryonic antigen (CEA) level of 477.7 ng/mL was detected. Mutation analysis revealed simultaneous mutation of EGFR and its downstream factor KRAS (Fig. 1B). The diagnosis was T4N3M1b, stage IV lung adenocarcinoma. The patient started treatment with the EGFR TKI gefitinib, 250 mg daily, and subcutaneous injection of denosumab, 120 mg every 4 weeks. However, his serum CEA level went up to 800.3 ng/mL after 3 weeks of therapy. Thus, gefitinib was replaced with a combination therapy with triweekly intravenous administration of an anti–PD-1 monoclonal antibody (nivolumab, 2 mg/kg) and anti–vascular endothelial growth factor therapy (bevacizumab, 4 mg/kg)) and the oral EGFR TKI erlotinib, 150 mg daily, on October 31, 2016. Thereafter, the patient's serum CEA level showed a significant decrease (Fig. 1C). PET/CT in January 2017 demonstrated a remarkable response, with tumor shrinkage after four cycles of therapy (see Fig. 1A); a sustained good response was confirmed by PET/CT in April 2017. Regarding adverse events, he displayed eczema on his back, chest wall, and limbs that resolved completely with desoximetasone and fusidic acid onitment. EGFR TKI is an effective first-line therapy for patients with stage IV NSCLC displaying a tumor with an EFGR-sensitizing mutation and a performance status of 0 to 2. However, the outcomes of patients with multiple drive mutations are rarely reported, and the response to targeted treatment remains uncertain. The combination of erlotinib plus bevacizumab has demonstrated good median progression-free survival for Asian patients with advanced NSCLC harboring EGFR mutations.4Yoshida K. Yamada Y. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harboring EGFR mutations (JO25567): an open-label, randomized, multicenter, phase II study.Transl Lung Cancer Res. 2015; 4: 217-219Google Scholar Although the results of the correlation between PD-1/programmed death ligand 1 expression and EGFR expression are controversial,5Ji M. Liu Y. Li Q. et al.PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation.J Transl Med. 2015; 13: 5Google Scholar the anti–PD-1 antibody nivolumab has been approved for advanced NSCLC and has demonstrated a significant survival advantage over docetaxel.2Carbone D.P. Reck M. Paz-Ares L. et al.First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.N Engl J Med. 2017; 376: 2415-2426Google Scholar In our patient, combined erlotinib, bevacizumab, and nivolumab yielded a remarkable response in advanced NSCLC with coexisting EGFR and its downstream mutations. Thus, this combination may be considered as a potential therapeutic option for advanced NSCLC with multiple driver mutations. Future studies are warranted to assess the efficacy and safety of these combinations.