The Value of Early Depth of Response in Predicting Long-Term Outcome in EGFR-Mutant Lung Cancer

Chee Khoon Lee, Sally Lord, Ian Marschner, Yi Long Wu, Lecia Sequist, Rafael Rosell, Masahiro Fukuoka, Tetsuya Mitsudomi, Rebecca Asher, Lucy Davies, Val Gebski, Richard J. Gralla, Tony Mok, James Chih-Hsin Yang

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of Thoracic Oncology
DOIs
StateAccepted/In press - Jan 1 2018

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Disease-Free Survival
Lung Neoplasms
Drug Therapy
Neoplasms
Lung
Survival
Disease Progression
Therapeutics

Keywords

  • Chemotherapy
  • Depth of response
  • EGFR mutation
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Lee, C. K., Lord, S., Marschner, I., Wu, Y. L., Sequist, L., Rosell, R., ... Chih-Hsin Yang, J. (Accepted/In press). The Value of Early Depth of Response in Predicting Long-Term Outcome in EGFR-Mutant Lung Cancer. Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2018.03.010

The Value of Early Depth of Response in Predicting Long-Term Outcome in EGFR-Mutant Lung Cancer. / Lee, Chee Khoon; Lord, Sally; Marschner, Ian; Wu, Yi Long; Sequist, Lecia; Rosell, Rafael; Fukuoka, Masahiro; Mitsudomi, Tetsuya; Asher, Rebecca; Davies, Lucy; Gebski, Val; Gralla, Richard J.; Mok, Tony; Chih-Hsin Yang, James.

In: Journal of Thoracic Oncology, 01.01.2018.

Research output: Contribution to journalArticle

Lee, CK, Lord, S, Marschner, I, Wu, YL, Sequist, L, Rosell, R, Fukuoka, M, Mitsudomi, T, Asher, R, Davies, L, Gebski, V, Gralla, RJ, Mok, T & Chih-Hsin Yang, J 2018, 'The Value of Early Depth of Response in Predicting Long-Term Outcome in EGFR-Mutant Lung Cancer', Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2018.03.010
Lee, Chee Khoon ; Lord, Sally ; Marschner, Ian ; Wu, Yi Long ; Sequist, Lecia ; Rosell, Rafael ; Fukuoka, Masahiro ; Mitsudomi, Tetsuya ; Asher, Rebecca ; Davies, Lucy ; Gebski, Val ; Gralla, Richard J. ; Mok, Tony ; Chih-Hsin Yang, James. / The Value of Early Depth of Response in Predicting Long-Term Outcome in EGFR-Mutant Lung Cancer. In: Journal of Thoracic Oncology. 2018.
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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.",
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AU - Lee, Chee Khoon

AU - Lord, Sally

AU - Marschner, Ian

AU - Wu, Yi Long

AU - Sequist, Lecia

AU - Rosell, Rafael

AU - Fukuoka, Masahiro

AU - Mitsudomi, Tetsuya

AU - Asher, Rebecca

AU - Davies, Lucy

AU - Gebski, Val

AU - Gralla, Richard J.

AU - Mok, Tony

AU - Chih-Hsin Yang, James

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N2 - 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.

AB - 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.

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