title: First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer.
abstract: OBJECTIVE
  To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer.
  
  
  METHODS
  We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m(2), infused at 10 mg/m(2) per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out.
  
  
  RESULTS
  From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS).
  
  
  CONCLUSIONS
  Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation.
authors.affiliation: Department of Medical Oncology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Vanja
authors.initials: V
authors.lastname: Vaccaro
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Alain
authors.initials: A
authors.lastname: Gelibter
authors.forename: Luca
authors.initials: L
authors.lastname: Moscetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mansueto
authors.forename: Enzo Maria
authors.initials: EM
authors.lastname: Ruggeri
authors.forename: Teresa
authors.initials: T
authors.lastname: Gamucci
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018395:CA-19-9 Antigen / Q000097:blood; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018579:Patient Selection; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D018395:CA-19-9 Antigen; D011799:Quinazolines; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine
keywords: Cutaneous rash; Erlotinib; Fixed dose-rate; Gemcitabine; Pancreatic cancer; Phase II trial; Prognostic factors
references.citation: N Engl J Med. 2005 Jul 14;353(2):123-32
references.pmid: 16014882
references.citation: J Clin Oncol. 2003 Sep 15;21(18):3402-8
references.pmid: 12885837
references.citation: Stat Med. 2001 Mar 30;20(6):859-66
references.pmid: 11252008
references.citation: J Clin Oncol. 2007 May 20;25(15):1960-6
references.pmid: 17452677
references.citation: J Clin Oncol. 2010 Dec 20;28(36):5327-47
references.pmid: 21060039
references.citation: Cancer. 2005 Sep 15;104(6):1237-45
references.pmid: 16078261
references.citation: J Clin Oncol. 1997 Jun;15(6):2403-13
references.pmid: 9196156
references.citation: N Engl J Med. 2004 Jul 22;351(4):337-45
references.pmid: 15269313
references.citation: Anticancer Res. 1999 Jul-Aug;19(4A):2433-5
references.pmid: 10470171
references.citation: N Engl J Med. 2011 May 12;364(19):1817-25
references.pmid: 21561347
references.citation: Br J Cancer. 2003 Oct 20;89(8):1413-7
references.pmid: 14562009
references.citation: Ann Oncol. 2012 Jul;23(7):1919-25
references.pmid: 22156621
references.citation: Br J Cancer. 2005 Jul 25;93(2):195-9
references.pmid: 15999098
references.citation: Anticancer Res. 2012 May;32(5):2191-7
references.pmid: 22593509
references.citation: Cancer. 2007 Aug 1;110(3):525-33
references.pmid: 17577216
references.citation: Cancer Invest. 2007 Aug;25(5):366-71
references.pmid: 17661212
references.citation: BMC Cancer. 2008 Mar 28;8:82
references.pmid: 18373843
references.citation: Gut. 2013 May;62(5):751-9
references.pmid: 22773551
references.citation: Clin Cancer Res. 2007 Jul 1;13(13):3913-21
references.pmid: 17606725
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Br J Cancer. 2000 Mar;82(5):1013-6
references.pmid: 10737382
references.citation: Oncologist. 2010;15(2):e1-4
references.pmid: 20189980
references.citation: Oncologist. 2007 May;12(5):610-21
references.pmid: 17522250
references.citation: Curr Drug Targets. 2012 Jun;13(6):731-43
references.pmid: 22458519
references.citation: J Clin Oncol. 2009 Aug 10;27(23):3778-85
references.pmid: 19581537
references.citation: Lancet. 2009 May 2;373(9674):1525-31
references.pmid: 19410716
references.citation: J Clin Oncol. 2009 May 1;27(13):2231-7
references.pmid: 19307500