J R Brahmer1, J W Lee2, A M Traynor3, M M Hidalgo4, J M Kolesar3, J M Siegfried5, P P Guaglianone6, J D Patel7, M D Keppen8, J H Schiller9. 1. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States. Electronic address: brahmju@jhmi.edu. 2. Dana-Farber Cancer Institute, Boston, MA, United States. 3. University of Wisconsin, Madison, WI, United States. 4. Hospital Madrid Sanchinarro, Madrid, Spain. 5. University of Pittsburgh, Pittsburgh, PA, United States. 6. Decatur Memorial Hospital, Decatur, IL, United States. 7. Northwestern University, Chicago, IL, United States. 8. Sanford Cancer Center, Sioux Falls, SD, United States. 9. University of Texas Southwestern Medical Center, Dallas, TX, United States.
Abstract
BACKGROUND: The development of a rash has been retrospectively associated with increased response and improved survival when treated with erlotinib at the standard dose of 150 mg per day. The objective of this trial was to evaluate the association of the activity of erlotinib in the first-line setting in patients with advanced non-small-cell lung cancer (NSCLC) with the development of a tolerable rash via dose escalation of erlotinib or tumour characteristics. METHODS: Patients, with advanced NSCLC without prior systemic therapy, were treated with erlotinib 150 mg orally per day. The dose was increased by 25mg every two weeks until the development of grade 2/tolerable rash or other dose limiting toxicity. Tumour biopsy specimens were required for inclusion. RESULTS: The study enrolled 137 patients, 135 were evaluable for safety and 124 were eligible and evaluable for response. Only 73 tumour samples were available for analysis. Erlotinib dose escalation occurred in 69/124 patients. Erlotinib was well tolerated with 70% of patients developing a grade 1/2 rash and 10% developing grade 3 rash. Response rate and disease control rate were 6.5% and 41.1% respectively. Median overall survival was 7.7 months. Toxicity and tumour markers were not associated with response. Grade 2 or greater skin rash and low phosphorylated mitogen-activated protein kinase (pMAPK) were associated with improved survival. CONCLUSIONS: Overall survival was similar in this trial compared to first-line chemotherapy in this unselected patient population. Dose escalation to the development of grade 2 skin rash was associated with improved survival in this patient population.
BACKGROUND: The development of a rash has been retrospectively associated with increased response and improved survival when treated with erlotinib at the standard dose of 150 mg per day. The objective of this trial was to evaluate the association of the activity of erlotinib in the first-line setting in patients with advanced non-small-cell lung cancer (NSCLC) with the development of a tolerable rash via dose escalation of erlotinib or tumour characteristics. METHODS: Patients, with advanced NSCLC without prior systemic therapy, were treated with erlotinib 150 mg orally per day. The dose was increased by 25mg every two weeks until the development of grade 2/tolerable rash or other dose limiting toxicity. Tumour biopsy specimens were required for inclusion. RESULTS: The study enrolled 137 patients, 135 were evaluable for safety and 124 were eligible and evaluable for response. Only 73 tumour samples were available for analysis. Erlotinib dose escalation occurred in 69/124 patients. Erlotinib was well tolerated with 70% of patients developing a grade 1/2 rash and 10% developing grade 3 rash. Response rate and disease control rate were 6.5% and 41.1% respectively. Median overall survival was 7.7 months. Toxicity and tumour markers were not associated with response. Grade 2 or greater skin rash and low phosphorylated mitogen-activated protein kinase (pMAPK) were associated with improved survival. CONCLUSIONS: Overall survival was similar in this trial compared to first-line chemotherapy in this unselected patient population. Dose escalation to the development of grade 2 skin rash was associated with improved survival in this patient population.
Authors: Rafael Rosell; Enric Carcereny; Radj Gervais; Alain Vergnenegre; Bartomeu Massuti; Enriqueta Felip; Ramon Palmero; Ramon Garcia-Gomez; Cinta Pallares; Jose Miguel Sanchez; Rut Porta; Manuel Cobo; Pilar Garrido; Flavia Longo; Teresa Moran; Amelia Insa; Filippo De Marinis; Romain Corre; Isabel Bover; Alfonso Illiano; Eric Dansin; Javier de Castro; Michele Milella; Noemi Reguart; Giuseppe Altavilla; Ulpiano Jimenez; Mariano Provencio; Miguel Angel Moreno; Josefa Terrasa; Jose Muñoz-Langa; Javier Valdivia; Dolores Isla; Manuel Domine; Olivier Molinier; Julien Mazieres; Nathalie Baize; Rosario Garcia-Campelo; Gilles Robinet; Delvys Rodriguez-Abreu; Guillermo Lopez-Vivanco; Vittorio Gebbia; Lioba Ferrera-Delgado; Pierre Bombaron; Reyes Bernabe; Alessandra Bearz; Angel Artal; Enrico Cortesi; Christian Rolfo; Maria Sanchez-Ronco; Ana Drozdowskyj; Cristina Queralt; Itziar de Aguirre; Jose Luis Ramirez; Jose Javier Sanchez; Miguel Angel Molina; Miquel Taron; Luis Paz-Ares Journal: Lancet Oncol Date: 2012-01-26 Impact factor: 41.316
Authors: Marta Hamilton; Julie L Wolf; Jason Rusk; Shannon E Beard; Gary M Clark; Karsten Witt; Pablo J Cagnoni Journal: Clin Cancer Res Date: 2006-04-01 Impact factor: 12.531
Authors: Frances A Shepherd; José Rodrigues Pereira; Tudor Ciuleanu; Eng Huat Tan; Vera Hirsh; Sumitra Thongprasert; Daniel Campos; Savitree Maoleekoonpiroj; Michael Smylie; Renato Martins; Maximiliano van Kooten; Mircea Dediu; Brian Findlay; Dongsheng Tu; Dianne Johnston; Andrea Bezjak; Gary Clark; Pedro Santabárbara; Lesley Seymour Journal: N Engl J Med Date: 2005-07-14 Impact factor: 91.245
Authors: Martin H Cohen; Grant A Williams; Rajeshwari Sridhara; Gang Chen; W David McGuinn; David Morse; Sophia Abraham; Atiqur Rahman; Chenyi Liang; Richard Lostritto; Amy Baird; Richard Pazdur Journal: Clin Cancer Res Date: 2004-02-15 Impact factor: 12.531
Authors: J Guillermo Paez; Pasi A Jänne; Jeffrey C Lee; Sean Tracy; Heidi Greulich; Stacey Gabriel; Paula Herman; Frederic J Kaye; Neal Lindeman; Titus J Boggon; Katsuhiko Naoki; Hidefumi Sasaki; Yoshitaka Fujii; Michael J Eck; William R Sellers; Bruce E Johnson; Matthew Meyerson Journal: Science Date: 2004-04-29 Impact factor: 47.728
Authors: Joseph M Amann; Ju-Whei Lee; Heinrich Roder; Julie Brahmer; Adriana Gonzalez; Joan H Schiller; David P Carbone Journal: J Thorac Oncol Date: 2010-02 Impact factor: 15.609
Authors: A C Mita; K Papadopoulos; M J A de Jonge; G Schwartz; J Verweij; M M Mita; A Ricart; Q S-C Chu; A W Tolcher; L Wood; S McCarthy; M Hamilton; K Iwata; B Wacker; K Witt; E K Rowinsky Journal: Br J Cancer Date: 2011-08-30 Impact factor: 7.640
Authors: Mariette Labots; Lisette M Schütte; Johannes C van der Mijn; Thang V Pham; Connie R Jiménez; Henk M W Verheul Journal: Oncologist Date: 2014-09-03
Authors: Lonneke Timmers; Christel C L M Boons; J Moes-Ten Hove; Egbert F Smit; Peter M van de Ven; Joachim G Aerts; Eleonora L Swart; Epie Boven; Jacqueline G Hugtenburg Journal: J Cancer Res Clin Oncol Date: 2015-03-06 Impact factor: 4.553
Authors: Amir Sonnenblick; Evandro de Azambuja; Dominique Agbor-Tarh; Ian Bradbury; Christine Campbell; Yingjie Huang; Amylou C Dueck; Kathleen I Pritchard; Antonio C Wolff; Christian Jackisch; Istvan Lang; Michael Untch; Ian Smith; Frances Boyle; Binghe Xu; Henry Gomez; Edith A Perez; Martine Piccart; Hatem A Azim Journal: J Natl Cancer Inst Date: 2016-04-20 Impact factor: 13.506
Authors: Jin S Im; Amanda C Herrmann; Chantale Bernatchez; Cara Haymaker; Jeffrey J Molldrem; Waun Ki Hong; Roman Perez-Soler Journal: PLoS One Date: 2016-07-28 Impact factor: 3.240