A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer

J.S. Lind, A.M. Dingemans, H.J. Groen, F.B. Thunnissen, O. Bekers, D.A. Heideman, R. J. Honeywell, E. Giovannetti, G.J. Peters, P.E. Postmus, R.J. van Suylen, E.F. Smit

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Abstract

PURPOSE: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Chemotherapy-naive patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. RESULTS: Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. CONCLUSION: Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted.
Original languageEnglish
Pages (from-to)3078-3087
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number11
DOIs
Publication statusPublished - 1 Jun 2010

Keywords

  • GROWTH-FACTOR RECEPTOR
  • TYROSINE KINASE INHIBITOR
  • REFRACTORY SOLID TUMORS
  • FOOT SKIN REACTION
  • COMBINATION
  • EGFR
  • BAY-43-9006
  • RECURRENT
  • TOXICITY
  • MUTATION

Cite this

Lind, J.S. ; Dingemans, A.M. ; Groen, H.J. ; Thunnissen, F.B. ; Bekers, O. ; Heideman, D.A. ; Honeywell, R. J. ; Giovannetti, E. ; Peters, G.J. ; Postmus, P.E. ; van Suylen, R.J. ; Smit, E.F. / A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 11. pp. 3078-3087.
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title = "A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer",
abstract = "PURPOSE: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Chemotherapy-naive patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. RESULTS: Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74{\%}: 12 (24{\%}) partial response and 25 (50{\%}) stable disease. Ultimately, the ORR was 28{\%}. Median time to progression was 5.0 months [95{\%} confidence interval (95{\%} CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95{\%} CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16{\%}), hand-foot skin reaction (16{\%}), rash (16{\%}), diarrhea (14{\%}), and hypophosphatemia (42{\%}). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19{\%}) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. CONCLUSION: Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted.",
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author = "J.S. Lind and A.M. Dingemans and H.J. Groen and F.B. Thunnissen and O. Bekers and D.A. Heideman and Honeywell, {R. J.} and E. Giovannetti and G.J. Peters and P.E. Postmus and {van Suylen}, R.J. and E.F. Smit",
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Lind, JS, Dingemans, AM, Groen, HJ, Thunnissen, FB, Bekers, O, Heideman, DA, Honeywell, RJ, Giovannetti, E, Peters, GJ, Postmus, PE, van Suylen, RJ & Smit, EF 2010, 'A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer', Clinical Cancer Research, vol. 16, no. 11, pp. 3078-3087. https://doi.org/10.1158/1078-0432.CCR-09-3033

A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer. / Lind, J.S.; Dingemans, A.M.; Groen, H.J.; Thunnissen, F.B.; Bekers, O.; Heideman, D.A.; Honeywell, R. J.; Giovannetti, E.; Peters, G.J.; Postmus, P.E.; van Suylen, R.J.; Smit, E.F.

In: Clinical Cancer Research, Vol. 16, No. 11, 01.06.2010, p. 3078-3087.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer

AU - Lind, J.S.

AU - Dingemans, A.M.

AU - Groen, H.J.

AU - Thunnissen, F.B.

AU - Bekers, O.

AU - Heideman, D.A.

AU - Honeywell, R. J.

AU - Giovannetti, E.

AU - Peters, G.J.

AU - Postmus, P.E.

AU - van Suylen, R.J.

AU - Smit, E.F.

PY - 2010/6/1

Y1 - 2010/6/1

N2 - PURPOSE: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Chemotherapy-naive patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. RESULTS: Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. CONCLUSION: Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted.

AB - PURPOSE: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Chemotherapy-naive patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. RESULTS: Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. CONCLUSION: Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted.

KW - GROWTH-FACTOR RECEPTOR

KW - TYROSINE KINASE INHIBITOR

KW - REFRACTORY SOLID TUMORS

KW - FOOT SKIN REACTION

KW - COMBINATION

KW - EGFR

KW - BAY-43-9006

KW - RECURRENT

KW - TOXICITY

KW - MUTATION

U2 - 10.1158/1078-0432.CCR-09-3033

DO - 10.1158/1078-0432.CCR-09-3033

M3 - Article

VL - 16

SP - 3078

EP - 3087

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 11

ER -