Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial

George R. Blumenschein, Pierre Saintigny, Suyu Liu, Edward S. Kim, Anne S. Tsao, Roy S. Herbst, Christine Alden, J. Jack Lee, Ximing Tang, David J. Stewart, Merrill S. Kies, Frank V. Fossella, Hai T. Tran, L. Mao, Marshall E. Hicks, Jeremy Erasmus, Sanjay Gupta, Luc Girard, Michael Peyton, Lixia DiaoJing Wang, Suzanne E. Davis, John D. Minna, Ignacio Wistuba, Waun K. Hong, John V. Heymach, Scott M. Lippman

Research output: Contribution to journalArticle

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Abstract

Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program. Patients and Methods: Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progressionfree survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS). Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04-3.58] and 8.48 months (95% CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-kB, and hypoxia pathways were identified potential drivers of sorafenib resistance. Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials.

Original languageEnglish (US)
Pages (from-to)6967-6975
Number of pages9
JournalClinical Cancer Research
Volume19
Issue number24
DOIs
StatePublished - Dec 15 2013

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Lung Neoplasms
Biomarkers
Survival
Therapeutics
Non-Small Cell Lung Carcinoma
erbB-1 Genes
Gene Dosage
sorafenib
Confidence Intervals
Fibroblast Growth Factor 1
Mutation
NF-kappa B
Tumor Cell Line
Transcriptome
Survival Rate
Biopsy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Blumenschein, G. R., Saintigny, P., Liu, S., Kim, E. S., Tsao, A. S., Herbst, R. S., ... Lippman, S. M. (2013). Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. Clinical Cancer Research, 19(24), 6967-6975. https://doi.org/10.1158/1078-0432.CCR-12-1818

Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. / Blumenschein, George R.; Saintigny, Pierre; Liu, Suyu; Kim, Edward S.; Tsao, Anne S.; Herbst, Roy S.; Alden, Christine; Lee, J. Jack; Tang, Ximing; Stewart, David J.; Kies, Merrill S.; Fossella, Frank V.; Tran, Hai T.; Mao, L.; Hicks, Marshall E.; Erasmus, Jeremy; Gupta, Sanjay; Girard, Luc; Peyton, Michael; Diao, Lixia; Wang, Jing; Davis, Suzanne E.; Minna, John D.; Wistuba, Ignacio; Hong, Waun K.; Heymach, John V.; Lippman, Scott M.

In: Clinical Cancer Research, Vol. 19, No. 24, 15.12.2013, p. 6967-6975.

Research output: Contribution to journalArticle

Blumenschein, GR, Saintigny, P, Liu, S, Kim, ES, Tsao, AS, Herbst, RS, Alden, C, Lee, JJ, Tang, X, Stewart, DJ, Kies, MS, Fossella, FV, Tran, HT, Mao, L, Hicks, ME, Erasmus, J, Gupta, S, Girard, L, Peyton, M, Diao, L, Wang, J, Davis, SE, Minna, JD, Wistuba, I, Hong, WK, Heymach, JV & Lippman, SM 2013, 'Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial', Clinical Cancer Research, vol. 19, no. 24, pp. 6967-6975. https://doi.org/10.1158/1078-0432.CCR-12-1818
Blumenschein, George R. ; Saintigny, Pierre ; Liu, Suyu ; Kim, Edward S. ; Tsao, Anne S. ; Herbst, Roy S. ; Alden, Christine ; Lee, J. Jack ; Tang, Ximing ; Stewart, David J. ; Kies, Merrill S. ; Fossella, Frank V. ; Tran, Hai T. ; Mao, L. ; Hicks, Marshall E. ; Erasmus, Jeremy ; Gupta, Sanjay ; Girard, Luc ; Peyton, Michael ; Diao, Lixia ; Wang, Jing ; Davis, Suzanne E. ; Minna, John D. ; Wistuba, Ignacio ; Hong, Waun K. ; Heymach, John V. ; Lippman, Scott M. / Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 24. pp. 6967-6975.
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abstract = "Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program. Patients and Methods: Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progressionfree survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS). Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2{\%}. The median PFS and OS were 2.83 [95{\%} confidence interval (CI), 2.04-3.58] and 8.48 months (95{\%} CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-kB, and hypoxia pathways were identified potential drivers of sorafenib resistance. Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials.",
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AU - Blumenschein, George R.

AU - Saintigny, Pierre

AU - Liu, Suyu

AU - Kim, Edward S.

AU - Tsao, Anne S.

AU - Herbst, Roy S.

AU - Alden, Christine

AU - Lee, J. Jack

AU - Tang, Ximing

AU - Stewart, David J.

AU - Kies, Merrill S.

AU - Fossella, Frank V.

AU - Tran, Hai T.

AU - Mao, L.

AU - Hicks, Marshall E.

AU - Erasmus, Jeremy

AU - Gupta, Sanjay

AU - Girard, Luc

AU - Peyton, Michael

AU - Diao, Lixia

AU - Wang, Jing

AU - Davis, Suzanne E.

AU - Minna, John D.

AU - Wistuba, Ignacio

AU - Hong, Waun K.

AU - Heymach, John V.

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N2 - Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program. Patients and Methods: Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progressionfree survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS). Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04-3.58] and 8.48 months (95% CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-kB, and hypoxia pathways were identified potential drivers of sorafenib resistance. Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials.

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