Pasi A Jänne1, Sai-Hong I Ou2, Dong-Wan Kim3, Geoffrey R Oxnard4, Renato Martins5, Mark G Kris6, Frank Dunphy7, Makoto Nishio8, Joseph O'Connell9, Cloud Paweletz10, Ian Taylor11, Hui Zhang12, Zelanna Goldberg13, Tony Mok14. 1. Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA. Electronic address: pasi_janne@dfci.harvard.edu. 2. Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA. 3. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. 4. Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA. 5. Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA. 6. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. Duke University Medical Center, Durham, NC, USA. 8. Department of Thoracic Medical Oncology, Cancer Institute Hospital of JFCR, Tokyo, Japan. 9. Pfizer Oncology, New York, NY, USA. 10. Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA. 11. Pfizer Oncology, Point Road, Groton, CT, USA. 12. Pfizer (China) Research & Development Co Ltd, Shanghai, China. 13. Pfizer Oncology, San Diego, CA, USA. 14. State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR, China.
Abstract
BACKGROUND: Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer. METHODS: In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [<100 cigarettes per lifetime] or former light smokers [<10 pack-years per lifetime] and ≥15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients. FINDINGS: Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4-84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2-98·9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded. INTERPRETATION: Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer. FUNDING: Pfizer.
BACKGROUND:Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinibas initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer. METHODS: In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [<100 cigarettes per lifetime] or former light smokers [<10 pack-years per lifetime] and ≥15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients. FINDINGS: Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4-84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2-98·9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded. INTERPRETATION:Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer. FUNDING: Pfizer.
Authors: Geoffrey R Oxnard; Katharine H Wilcox; Mithat Gonen; Mikhael Polotsky; Bradford R Hirsch; Lawrence H Schwartz Journal: JAMA Oncol Date: 2016-06-01 Impact factor: 31.777
Authors: Tejas Patil; Rao Mushtaq; Sydney Marsh; Christine Azelby; Miheer Pujara; Kurtis D Davies; Dara L Aisner; William T Purcell; Erin L Schenk; Jose M Pacheco; Paul A Bunn; D Ross Camidge; Robert C Doebele Journal: Clin Lung Cancer Date: 2019-11-21 Impact factor: 4.785
Authors: Dong-Wan Kim; Edward B Garon; Aminah Jatoi; Dorothy M Keefe; Mario E Lacouture; Stephen Sonis; Diana Gernhardt; Tao Wang; Nagdeep Giri; Jim P Doherty; Sashi Nadanaciva; Joseph O'Connell; Eric Sbar; Byoung Chul Cho Journal: Lung Cancer Date: 2017-02-01 Impact factor: 5.705
Authors: Takayuki Kosaka; Junko Tanizaki; Raymond M Paranal; Hideki Endoh; Christine Lydon; Marzia Capelletti; Claire E Repellin; Jihyun Choi; Atsuko Ogino; Antonio Calles; Dalia Ercan; Amanda J Redig; Magda Bahcall; Geoffrey R Oxnard; Michael J Eck; Pasi A Jänne Journal: Cancer Res Date: 2017-03-31 Impact factor: 12.701
Authors: Michael V Ortiz; Rachel Kobos; Michael Walsh; Emily K Slotkin; Stephen Roberts; Michael F Berger; Meera Hameed; David Solit; Marc Ladanyi; Neerav Shukla; Alex Kentsis Journal: Pediatr Blood Cancer Date: 2016-04-15 Impact factor: 3.167