title: A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non-Small-Cell Lung Cancer.
abstract: Second-line therapy options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n [ 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy.
  
  
  BACKGROUND
  Volasertib is a potent, selective, cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In this study we compared volasertib, volasertib with pemetrexed, and pemetrexed alone in patients with advanced non-small-cell lung cancer (NSCLC) whose disease progressed after first-line platinum-based chemotherapy.
  
  
  METHODS
  A run-in phase (n = 12) was used to determine whether volasertib could be combined in full dose with pemetrexed 500 mg/m(2). Subsequent patients were randomized to volasertib (n = 37), volasertib with pemetrexed (n = 47), or pemetrexed (n = 47) administered on day 1 every 21 days. The primary end point was progression-free survival (PFS); secondary end points included objective response rate and pharmacokinetics.
  
  
  RESULTS
  Volasertib 300 mg was chosen for the randomized phase. Recruitment to single-agent volasertib was stopped early because of lack of efficacy. Median PFS was 5.3 months with pemetrexed compared with 3.3 months with volasertib with pemetrexed (hazard ratio [HR], 1.141; 95% confidence interval [CI], 0.73-1.771) and 1.4 months with volasertib (HR, 2.045; 95% CI, 1.27-3.292). ORRs were 10.6% with pemetrexed, 21.3% for volasertib with pemetrexed, and 8.1% with volasertib. The most common all-grade related adverse events (pemetrexed/volasertib with pemetrexed/volasertib) were: fatigue (28 [61%]/27 [59%]/11 [31%]), nausea (21 [46%]/19 [41%]/0 [0%]), decreased apetite (14 [31%]/13 [28%]/2 [6%]), neutropenia (4 [9%]/8 [17%]/9 [25%]), rash (9 [20%]/8 [17%]/2 [6%]), vomiting (6 [13%]/13 [28%]/0 [0%]), and diarrhea (8 [17%]/11 [24%]/0 [0%]). Pharmacokinetics analyses showed no drug-drug interactions between volasertib and pemetrexed.
  
  
  CONCLUSIONS
  For treatment in the second-line for advanced or metastatic NSCLC, the combination of volasertib with standard pemetrexed did not increase toxicity significantly but also did not improve efficacy compared with single-agent pemetrexed.
authors.affiliation: Juravinski Cancer Centre, Hamilton, Ontario, Canada. Electronic address: ellisp@hhsc.ca.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Ellis
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
authors.affiliation: McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.affiliation: The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.
authors.forename: M Neil
authors.initials: MN
authors.lastname: Reaume
authors.affiliation: Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada.
authors.forename: Normand
authors.initials: N
authors.lastname: Blais
authors.affiliation: RSM Durham Regional Cancer Centre, Oshawa, Ontario, Canada.
authors.forename: Rafal
authors.initials: R
authors.lastname: Wierzbicki
authors.affiliation: Boehringer Ingelheim Canada Ltd, Burlington, Ontario, Canada.
authors.forename: Behbood
authors.initials: B
authors.lastname: Sadrolhefazi
authors.affiliation: Boehringer Ingelheim Corporation, Ridgefield, CT.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
authors.forename: Korinna
authors.initials: K
authors.lastname: Pilz
authors.affiliation: Cross Cancer Centre, Edmonton, Alberta, Canada.
authors.forename: Quincy
authors.initials: Q
authors.lastname: Chu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000209:etiology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D000068437:Pemetrexed / Q000008:administration & dosage* / Q000009:adverse effects; D017671:Platinum Compounds / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D011621:Pteridines / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D000068437:Pemetrexed; D017671:Platinum Compounds; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C541363:BI 6727
keywords: Chemotherapy; Clinical trial; Pharmacokinetics; Polo-like kinase inhibition; Survival