Chee Khoon Lee1, Sally Lord2, Ian Marschner3, Yi Long Wu4, Lecia Sequist5, Rafael Rosell6, Masahiro Fukuoka7, Tetsuya Mitsudomi8, Rebecca Asher9, Lucy Davies9, Val Gebski9, Richard Gralla10, Tony Mok11, James Chih-Hsin Yang12. 1. NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia; Clinical Research Unit, St. George Hospital, Sydney, Australia. 2. NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia; School of Medicine, The University of Norte Dame, Sydney, Australia. 3. NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia; Department of Statistics, Macquarie University, Sydney, Australia. 4. Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong, China. 5. Massachusetts General Hospital and Harvard Medical School, Boston, United States. 6. Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain. 7. Department of Medical Oncology, Izumi Municipal Hospital, Osaka, Japan. 8. Department of Surgery, Division of Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. 9. NHMRC Clinical Trials Centre, The University of Sydney, Sydney, Australia. 10. Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, New York. 11. Hong Kong Cancer Institute, Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, China. 12. Graduate Institute of Oncology, National Taiwan University and Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: chihyang@ntu.edu.tw.
Abstract
INTRODUCTION: Traditionally, marked tumor shrinkage has been assumed to portend better outcome. We investigated whether depth of tumor response was associated with improved survival outcomes in advanced EGFR-mutant NCLC. METHODS: Individual patient data from randomized trials (EURTAC, IPASS, ENSURE, LUX-Lung 3, and LUX-Lung 6) were used. The association of depth of response with progression-free survival (PFS) and overall survival was examined using landmark analyses. Depth of response based on radiologic assessments at 6 weeks and 12 weeks was calculated as the relative changes in the sum of the longest diameters of the target lesions from baseline. RESULTS: Of 1081 evaluable patients at 6 weeks with no disease progression, 71.2% achieved Response Evaluation Criteria in Solid Tumors response. Using a landmark analysis, EGFR-TKI was more effective than chemotherapy (PFS hazard ratio = 0.36, p < .0001); and was associated with greater mean tumor shrinkage than chemotherapy (35.1% versus 18.5%, p < .0001). However, there was no significant difference in the relative PFS benefit between treatment groups across the entire spectrum of tumor shrinkage (p = .18 for test of interaction between treatment and continuously measured depth of response). Depth of response at 6 weeks was not associated with PFS when adjusted for treatment effect (hazard ratio = 0.96, p = .78). Similar results were obtained for 12-week landmark analysis and for OS outcome. CONCLUSIONS: The PFS advantage of EGFR-TKI over chemotherapy in advanced EGFR mutant NCLC is not explained by depth of response at 6 or 12 weeks. It should not be used as a surrogate of benefit in future trials or routine clinical decision making.
INTRODUCTION: Traditionally, marked tumor shrinkage has been assumed to portend better outcome. We investigated whether depth of tumor response was associated with improved survival outcomes in advanced EGFR-mutant NCLC. METHODS: Individual patient data from randomized trials (EURTAC, IPASS, ENSURE, LUX-Lung 3, and LUX-Lung 6) were used. The association of depth of response with progression-free survival (PFS) and overall survival was examined using landmark analyses. Depth of response based on radiologic assessments at 6 weeks and 12 weeks was calculated as the relative changes in the sum of the longest diameters of the target lesions from baseline. RESULTS: Of 1081 evaluable patients at 6 weeks with no disease progression, 71.2% achieved Response Evaluation Criteria in Solid Tumors response. Using a landmark analysis, EGFR-TKI was more effective than chemotherapy (PFS hazard ratio = 0.36, p < .0001); and was associated with greater mean tumor shrinkage than chemotherapy (35.1% versus 18.5%, p < .0001). However, there was no significant difference in the relative PFS benefit between treatment groups across the entire spectrum of tumor shrinkage (p = .18 for test of interaction between treatment and continuously measured depth of response). Depth of response at 6 weeks was not associated with PFS when adjusted for treatment effect (hazard ratio = 0.96, p = .78). Similar results were obtained for 12-week landmark analysis and for OS outcome. CONCLUSIONS: The PFS advantage of EGFR-TKI over chemotherapy in advanced EGFR mutant NCLC is not explained by depth of response at 6 or 12 weeks. It should not be used as a surrogate of benefit in future trials or routine clinical decision making.
Authors: James J Choi; Robert J Allen; Manjit S Bains; Marc A Cohen; Yao Yu; Nassrene Elmadhun; David R Jones; Gaetano Rocco Journal: JTCVS Tech Date: 2020-08-15