title: Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancers.
abstract: Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity. In this phase I trial we evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Nine patients enrolled before premature termination of the study. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Regorafenib had acceptable tolerability and minor pharmacokinetic interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs.
  
  
  BACKGROUND
  The combination of bevacizumab, an antiangiogenesis agent, with cytotoxic chemotherapy improves survival in patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. In this phase I trial we evaluated the safety, pharmacokinetics (PK), and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs.
  
  
  METHODS
  Chemotherapy-naive patients with advanced nsNSCLCs were treated with regorafenib 60 mg/d continuously and cisplatin 75 mg/m(2) with pemetrexed 500 mg/m(2) once every 21 days for up to 6 cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance.
  
  
  RESULTS
  Nine patients enrolled before premature termination of the study because of slow recruitment and a change in the development strategy of regorafenib by the study sponsor. Five patients experienced at least 1 treatment-related Grade 3 adverse event. No Grade 4 or 5 toxicity occurred. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Minor PK interactions between regorafenib and chemotherapy were observed.
  
  
  CONCLUSIONS
  Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naive patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results.
authors.affiliation: Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY. Electronic address: hellmanm@mskcc.org.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hellmann
authors.affiliation: Department of Clinical Pharmacology Oncology, Bayer HealthCare, Berlin, Germany.
authors.forename: Isrid
authors.initials: I
authors.lastname: Sturm
authors.affiliation: Department of Clinical Pharmacology Oncology, Bayer HealthCare, Berlin, Germany.
authors.forename: Zuzana Jirakova
authors.initials: ZJ
authors.lastname: Trnkova
authors.affiliation: Department of Clinical Pharmacology Oncology, Bayer HealthCare, Whippany, NJ.
authors.forename: John
authors.initials: J
authors.lastname: Lettieri
authors.affiliation: Department of Clinical Pharmacology Oncology, Bayer HealthCare, Berlin, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Diefenbach
authors.affiliation: Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY.
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.affiliation: Department of Medicine, Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven, CT.
authors.forename: Scott N
authors.initials: SN
authors.lastname: Gettinger
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D000075202:Contraindications; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000191:economics*; D000068437:Pemetrexed / Q000008:administration & dosage / Q000009:adverse effects; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; D000068437:Pemetrexed; C559147:regorafenib; D000068258:Bevacizumab; D002945:Cisplatin
keywords: Angiogenesis; Chemotherapy; Clinical Trial; NSCLC; Regorafenib