Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2006

Presenter: U. Gatzemeier
Presenter's Affiliation: Hospital Grosshansdorf, Grosshansdorf/Hamburg, Germany
Type of Session: Scientific


  • The Raf/MEK/ERK pathway is an attractive target in NSCLC
    • 20% Ras mutations which are upstream of Raf
    • EGFR is upstream of Raf, and inhibitors have shown activity in NSCLC
  • Angiogenesis is an attractive target in NSCLC
    • Bevacisumab has efficacy in NSCLC
  • Sorafenib is a multikinase inhibitor that inhibits Raf kinase and several receptor tyrosine kinases involved with angiogenesis
  • This is a Phase II trial of single agent sorafenib in relapsed/refractory NSCLC to evaluated efficacy and safety

Materials and Methods

  • Phase II: Uncontrolled, study of 52 patients:
  • Sorafenib (400 mg po twice daily, continuous). 1 cycle = 28 days
  • Primary endpoint: Responses by RECIST criteria (every 8 wks)
  • Biomarker study: Plasma for proteomic analysis (ELISA [n=44]; mass-spectrometry [n=43]) at screening, Day 21 of Cycle 1, and Day 1 of Cycle 3.
    • Circulating VEGF and soluble VEGFR-2
  • Patients:
    • 1 patient was Stage IIIB, rest were Stage IV. Brain mets were allowed.
    • Median age = 62 yr
    • Performance status: 94% ECOG 0/1, 6% ECOG 2
    • Histology: 54% adenocarcinoma, 31% squamous cell
    • Prior treatment: 2/3 had 1 prior regimen, rest had more
      • Prior gefitinib was allowed


  • Response Rate:
    • Stable disease: 30/51 (59%), Progressive disease: 35%, rest were unevaluable
    • Some near partial responses:
  • Tumor shrinkage was observed in 15 (29%) patients
  • 4 had >30% shrinkage
  • Several cases of minimal shrinkage by RECIST, but profound tumor cavitation
  • Median progression-free survival (PFS):
    • Patients with SD = 23.7 weeks
    • All evaluable patients = 11.9 weeks
    • Two patients continue on the drug for over 2 yrs
    • Median overall survival of all patients was 29.3 weeks
  • Adverse Events:
    •  Any Grade: diarrhea 40%, hand-foot skin reaction 37%, fatigue 27%, nausea 25%
    • Grade 3: hand-foot skin reaction 10%, hypertension 4%, diarrhea 2%
    • Three patients discontinued due to adverse events
    • 9 deaths within 30 days of discontinuation of sorafenib (n=5 progressive disease; n=2 cardiopulmonary arrest; n=1 hemoptysis; and n=1 unknown cause)
    • 3 patients had epistaxis
    • Quality of Life: FACT-L scores unchanged from cycle 2 to 4
  • Biomarker study:
    • Patients with high baseline serum VEGF levels had shorter survival
    • Patients whose VEGF levels decreased substantially (>78 pg/mL) had shorter survival
    • There was no significant correlation with sVEGFR-2 levels with any endpoint

Author's Conclusions

  • Sorafenib 400 mg bid is generally well tolerated and shows promising efficacy in patients with advanced, progressive NSCLC, with approximately 60% of pts achieving disease stabilization
  • Response rate with sorafenib was as least as good as gefitinib and erlotinib

Clinical/Scientific Implications

  • Sorafenib has comparable activity as a single-agent as other anti-angiogenic therapies and single-agent chemotherapy in NSCLC with similar progression-free survivals:
    • Sorafenib, 11.9 wks
    • ZD6474, 11 wks (ASCO 2006)
    • Sunitinib, 11.3 wks (ASCO 2006)
    • Docetaxel or Pemetrexate, 12.6 wks
  • A strength of this study was the incorporation of serum biomarkers to correlate with efficacy
  • Combination therapies with anti-angiogenic agents with chemotherapies are being explored
    • A Phase III trial with ~900 patients is being planned in metastatic NSCLC that randomizes patients to either A) carboplatin/taxol x 6 cycles followed by placebo maintenance, or B) carboplatin/taxol x 6 cycles + sorafenib followed by sorafenib maintenance