• 11/9/2006
  • Prague, Czech Republic
  • Chris Berrie
  • Doctor’s Guide (www.docguide.com)

The broad-spectrum antitumour agent sorafenib has modest efficacy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or nasopharyngeal carcinoma (NPC), according to a single-arm, phase 2 trial.

However, the drug is well tolerated and easy to deliver, and provides an attractive option for combination treatment in these patients, the researcher said in a presentation here on November 8th at the 18th European Organisation for Research and Treatment of Cancer – National Cancer Institute – American Association for Cancer Research (AACR-NCI-EORTC) 18th Symposium on Molecular Targets and Cancer Therapeutics.

“For patients with squamous cell carcinoma of the head and neck and NPC there is no very effective first-line therapy, and although there can be some response for nasopharyngeal cancer, survival is still around a year, and for both of these diseases there is no standard second-line therapy,” said investigator Christine Elser, MD, clinical fellow, medical oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.

Sorafenib has previously demonstrated broad-spectrum, antitumour activity through its actions as a multikinase inhibitor that targets the pathways for epidermal growth factor (EGF) receptor-Ras-Raf-MEK-ERK and vascular endothelial growth factor (VEGF) receptor signalling.

Dr. Elser and colleagues therefore conducted their study to determine the efficacy of sorafenib as a single agent in patients with recurrent or metastatic SCCHN or NPC. The study’s secondary objectives were to assess the rate of stable disease, time to disease progression, median survival duration, safety and adverse events.

Patient were eligible if they had measurable, histologically confirmed, recurrent and/or metastatic SCCHN or NPC, with no more than 1 prior systemic therapy for recurrent and/or metastatic disease, as well as Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and adequate organ function.

The study excluded patients who were previously treated with farnesyl-transferase or Raf-kinase inhibitors, those who underwent significant surgery, and those who received myelosuppressive radiotherapy or agents targeting VEGF within 4 weeks prior to study entry.

The 27 patients enrolled had a mean age of 53 years (male, 63%) and received sorafenib 400 mg BID on a continuous basis for 28-day cycles. Baseline ECOG performance status was 0 in 30%, 1 in 59%, and 2 in 11%. Seventy-four percent had SCCHN. Local recurrence and metastasis were seen in 41% and 19%, respectively, with the remaining 41% had both. Prior patient treatments included: surgery, 67%; radiation, 96%; systemic therapy, 70%; chemoradiation only, 22%.

Patient were assessments for tumour measurements every 2 cycles using the Response Evaluation Criteria in Solid Tumours (RECIST) criteria, with toxicities assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The following biomarkers were also assessed in a subgroup of 5 patients as paired biopsies from 7 days prior treatment to 4 weeks sorafenib by immunohistochemistry: signal transduction (pERK), cell proliferation (Ki67), angiogenesis (CD31 and alpha-SMA) and cell apoptosis (MCL-1).

Following administration of 72 cycles (median, 2 cycles/patient; range, 1-7), one patient (3.7%) with SCCHN had a confirmed partial response, 10 (37.0%) had stable disease (from 2-6 cycles), and 15 (55.6%) had progressive disease. One patient was not evaluable.

Median time to progression was 1.8 months (95% confidence interval [CI], 1.6-3.4 months), and median overall survival was 4.2 months (95% CI, 3.6-8.7 months). The 6-month and 1-year overall survivals were 34.7% and 11.6%, respectively.

Of the range of any-grade adverse events that were potentially related to sorafenib treatment, those of grade 3 were: lymphopenia, 17% of cycles; fatigue, 7%; hyponatraemia, 3%; leukopenia, 3%; lipase, 3%; hand-foot reaction, 1%; and rash/ desquamation, 1%.

“Although [sorafenib] doesn’t have a lot of activity as a single agent in these patients, there was some hint of activity that was accompanied by suppression of pERK in all of the paired tumour biopsies,” Dr. Elser indicated. Similarly, this sorafenib treatment inhibited both cell proliferation (Ki67) and the proapoptotic protein MCL-1 in 4 of the 5 biopsies, with some changes seen for angiogenesis.

Although no definitive correlation between paired biopsies and clinical outcome can be made based on these findings, the modest efficacy of sorafenib in these patients now points to its potential in combination therapies. “There is a study planned [for sorafenib] in combination with radiation [therapy] in head and neck cancer,” Dr Elser added.

The study was sponsored by Bayer Pharmaceuticals, Inc.

Presentation title: Phase 2 Trial of Sorafenib in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) or Nasopharyngeal Carcinoma (NPC): Final Results. Abstract 47