Bob T Li1, Tristan A Barnes2, David L Chan3, Jarushka Naidoo4, Adrian Lee3, Mustafa Khasraw3, Gavin M Marx5, Mark G Kris6, Stephen J Clarke3, Alexander Drilon6, Charles M Rudin6, Nick Pavlakis7. 1. Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. 2. Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. 3. Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. 4. Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 301 Building Suite 4500, Baltimore, MD 21224, USA. 5. Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; SAN Integrated Cancer Centre, Sydney Adventist Hospital, 185 Fox Valley Rd, Wahroonga, NSW 2076, Australia. 6. Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA. 7. Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Electronic address: nick.pavlakis@sydney.edu.au.
Abstract
OBJECTIVES: The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy. MATERIALS AND METHODS: We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology. RESULTS: The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI. CONCLUSION: The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.
OBJECTIVES: The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy. MATERIALS AND METHODS: We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology. RESULTS: The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI. CONCLUSION: The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.
Authors: Edward B Garon; Tudor-Eliade Ciuleanu; Oscar Arrieta; Kumar Prabhash; Konstantinos N Syrigos; Tuncay Goksel; Keunchil Park; Vera Gorbunova; Ruben Dario Kowalyszyn; Joanna Pikiel; Grzegorz Czyzewicz; Sergey V Orlov; Conrad R Lewanski; Michael Thomas; Paolo Bidoli; Shaker Dakhil; Steven Gans; Joo-Hang Kim; Alexandru Grigorescu; Nina Karaseva; Martin Reck; Federico Cappuzzo; Ekaterine Alexandris; Andreas Sashegyi; Sergey Yurasov; Maurice Pérol Journal: Lancet Date: 2014-06-02 Impact factor: 79.321
Authors: Hossein Borghaei; Luis Paz-Ares; Leora Horn; David R Spigel; Martin Steins; Neal E Ready; Laura Q Chow; Everett E Vokes; Enriqueta Felip; Esther Holgado; Fabrice Barlesi; Martin Kohlhäufl; Oscar Arrieta; Marco Angelo Burgio; Jérôme Fayette; Hervé Lena; Elena Poddubskaya; David E Gerber; Scott N Gettinger; Charles M Rudin; Naiyer Rizvi; Lucio Crinò; George R Blumenschein; Scott J Antonia; Cécile Dorange; Christopher T Harbison; Friedrich Graf Finckenstein; Julie R Brahmer Journal: N Engl J Med Date: 2015-09-27 Impact factor: 91.245
Authors: Luis G Paz-Ares; Bonne Biesma; David Heigener; Joachim von Pawel; Timothy Eisen; Jaafar Bennouna; Li Zhang; Meilin Liao; Yan Sun; Steven Gans; Kostas Syrigos; Etienne Le Marie; Maya Gottfried; Johan Vansteenkiste; Vincente Alberola; Uwe Phillip Strauss; Elaine Montegriffo; Teng Jin Ong; Armando Santoro Journal: J Clin Oncol Date: 2012-07-30 Impact factor: 44.544
Authors: John V Heymach; Luis Paz-Ares; Filippo De Braud; Martin Sebastian; David J Stewart; Wilfried E E Eberhardt; Anantbhushan A Ranade; Graham Cohen; Jose Manuel Trigo; Alan B Sandler; Philip D Bonomi; Roy S Herbst; Annetta D Krebs; James Vasselli; Bruce E Johnson Journal: J Clin Oncol Date: 2008-10-20 Impact factor: 44.544
Authors: Ibrahim A Darwish; Nasr Y Khalil; Nawaf A Alsaif; Rashed N Herqash; Ahmed Y A Sayed; Hamdy M Abdel-Rahman Journal: Drug Des Devel Ther Date: 2021-03-12 Impact factor: 4.162