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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
Ultima Vez Modificado: 6 de junio del 2006

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

Background

• 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

Results

• 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