Treating metastatic renal cell carcinoma (RCC) prior to surgery with Avastin (bevacizumab) and Tarceva (erlotinib) appears safe, effective, and may prolong patient survival, researchers reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (abstract 250). Although the two agents have been tested previously as postoperative treatment for the disease, the new data provide the first evidence that presurgical treatment with the drugs may improve patient outcomes.
PRAGUE, Czech RepublicTreating metastatic renal cell carcinoma (RCC) prior to surgery with Avastin (bevacizumab) and Tarceva (erlotinib) appears safe, effective, and may prolong patient survival, researchers reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (abstract 250). Although the two agents have been tested previously as postoperative treatment for the disease, the new data provide the first evidence that presurgical treatment with the drugs may improve patient outcomes.
Preliminary results covering 20 of the patients enrolled in a phase II study at M.D. Anderson Cancer Center showed that 1 patient experienced a complete remission in the primary tumor and stable disease in bone metastases, 3 patients had a partial remission, and 13 patients showed stable disease. All of the patients were still alive at the time of the presentation.
"These early data suggest presurgical treatment with bevacizumab and erlotinib is safe and efficacious in patients with previously unresected, untreated metastatic RCC, with shrinkage of both the metastatic disease and primary tumors," said Eric Jonasch, MD, assistant professor of genitourinary medical oncology. "Our findings indicate that this treatment approach might be applicable to a wide range of patients with renal cell carcinoma, and that we might be able to use systemic treatment before surgery to treat many more people with metastatic disease successfully."
Only three patients had progressive disease at the time of the presentation. "Without this treatment," Dr. Jonasch said, "I would have expected most of our patients to have progressive disease by now. The average time to progressive disease is usually about 12 weeks, and I would argue that our patients have more aggressive disease, as they have not had the benefit of previous treatment."
At the time of his presentation, the investigators had accrued 32 of the 50 patients they anticipate enrolling in the study, which began in March 2005, and had evaluated tissue from 20. Patients were treated with bevacizumab 10 mg/kg intravenously every 2 weeks for four doses and with erlotinib 150 mg orally each day for 8 weeks. Two weeks after receiving the last dose of erlotinib and 4 weeks after the last dose of bevacizumab, surgeons removed the patients' kidney tumors. Those patients who had stable disease or a response 1 month after surgery were restarted on the drug treatment and continued until disease progression.
The researchers examined the protein expression of key signaling molecules involved in controlling cell proliferation, survival, and migrationphospho and total EGFR, AKT, S6, FAK, and ERK. They found no difference between the tissues of their treated patients and the tissues of untreated patients housed in the cancer center's tissue bank, with one exception. The treated group of cancer patients had a slight increase in the expression of AKT, which meant that blocking the VEGF signaling pathway with bevacizumab might have resulted in a feedback to the AKT pathway, which is known to be involved in cell signaling.
"At the moment, we don't understand what mechanisms are operating to bring about the responses we have observed in patients," Dr. Jonasch said. "We are examining a number of other biomarkers to look for a 'signal' that can be associated with the response."
The goals, he said, "are to discover how these targeted therapies produce a response in renal cell carcinoma, what molecules and genes are controlling disease resistance and response, and, specifically, what role is played by the protein VHL, which is frequently mutated in patients with kidney cancer, and which is known to be an important driver of angiogenesis."ONI