A multicenter phase II study of sorafenib monotherapy in clinically selected patients with advanced lung adenocarcinoma after failure of EGFR-TKI therapy (Chinese Thoracic Oncology Group, CTONG 0805).
OBJECTIVE
Aim of the study was to investigate efficacy and safety of sorafenib in patients with advanced lung adenocarcinoma after failure of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy.


METHODS
Patients who were diagnosed with stage IIIB or stage IV lung adenocarcinoma, and benefited from one prior EGFR-TKI therapy and then failed, were eligible. No more than one previous chemotherapy regimen was permitted. Patients received oral sorafenib 400mg twice daily continuously until disease progression or intolerable toxicity. Primary endpoint was disease control rate (DCR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). For patients who agreed to provide peripheral blood or tumor tissue, we analyzed the genotype of Bcl-2-interacting mediator of cell death (BIM) deletion polymorphism and EGFR mutation status.


RESULTS
Of 65 enrolled patients, 64 were evaluable. The DCR was 32.8%, which did not meet the predefined statistical hypothesis of 38.4%. The median PFS and OS were 3.7 months [95% (confidence interval), 3.5-3.9 months] and 7.4 months (95% CI, 5.7-9.2 months), respectively. Logistic regression analysis showed no correlation between DCR and age, gender, smoking status and performance status. Hand-foot syndrome (HFS) was the predominant toxicity occurring in 71.9% of patients. Fourteen patients (21.9%) had ≥ grade 2 dermatologic reactions that resulted sorafenib dose reduction in three patients (4.7%). Of 36 patients, the BIM deletion polymorphism was found in 3, and no response to sorafenib was observed. In 30 tumor tissues, 22 EGFR active mutations were found. The DCR had no significant difference between mutation-positive and wild-type patients (31.8% vs. 42.9%, respectively; HR, 0.622; p=0.665).


CONCLUSIONS
Sorafenib monotherapy did not achieve positive result in patients defined in our trial and we need better biomarker to determine the population who can benefit from sorafenib treatment (ClinicalTrials.gov number: NCT00922584).
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Qing
Q
Zhou
Shanghai Pulmonary Hospital, Shanghai, China.
Cai-cun
CC
Zhou
Haerbin Medical University Affiliated Tumor Hospital, Haerbin, China.
Gong-yan
GY
Chen
Jilin Province Tumor Hospital, Jiling, China.
Ying
Y
Cheng
Fujian Province Tumor Hospital, Fuzhou, China.
Cheng
C
Huang
Sun Yat-Sen University Cancer Center, Guangzhou, China.
Li
L
Zhang
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Chong-rui
CR
Xu
Shanghai Pulmonary Hospital, Shanghai, China.
Ai-wu
AW
Li
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Hong-hong
HH
Yan
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Jian
J
Su
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Xu-chao
XC
Zhang
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Jin-ji
JJ
Yang
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China. Electronic address: syylwu@live.cn.
Yi-long
YL
Wu
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D063646:Carcinogenesis; D002681:China; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D005838:Genotype; D060831:Hand-Foot Syndrome / Q000209:etiology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D000077157:Sorafenib; D016019:Survival Analysis; D017211:Treatment Failure
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D009536:Niacinamide; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors
Carcinoma; EGFR-TKI; Non-small cell lung cancer; Phase II clinical trial; Resistance; Sorafenib