title: Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non-small cell lung cancer patients with KRAS-activated tumors.
abstract: BACKGROUND
  The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents.
  
  
  METHODS
  This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)-mutated/amplified non-small cell lung cancer.
  
  
  RESULTS
  Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m(2) for paclitaxel on day 1, and 3 × 10(10) 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m(2) for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months.
  
  
  CONCLUSIONS
  Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Elaine
authors.initials: E
authors.lastname: Lam
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
authors.affiliation: Department of Pathology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Timmons
authors.affiliation: Lombardi Cancer Center, Georgetown University, Washington, DC.
authors.forename: Deepa
authors.initials: D
authors.lastname: Subramaniam
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Erinn M
authors.initials: EM
authors.lastname: Hade
authors.affiliation: Oncolytics Biotech, Incorporated, Calgary, Canada.
authors.forename: George M
authors.initials: GM
authors.lastname: Gill
authors.affiliation: Oncolytics Biotech, Incorporated, Calgary, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Coffey
authors.affiliation: Oncolytics Biotech, Incorporated, Calgary, Canada.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Selvaggi
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Erin
authors.initials: E
authors.lastname: Bertino
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Bo
authors.initials: B
authors.lastname: Chao
authors.affiliation: Department of Radiology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Knopp
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D012089:Mammalian orthoreovirus 3; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D050130:Oncolytic Virotherapy / Q000379:methods; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; KRAS; epidermal growth factor receptor (EGFR); lung cancer; oncolytic virus