Researchers have found that patients with an advanced form of kidney cancer, for which there is no standard treatment and a very poor prognosis, respond well to a combination of two existing anticancer drugs. The combination of bevacizumab (Avastin) and erlotinib (Tarceva) produced excellent response rates with tolerable side effects in patients with advanced papillary renal cell carcinoma and in those with hereditary leiomyomatosis and renal cell cancer, a highly aggressive form of the disease. The findings were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona.1
“The genetic and biochemical events that lead to papillary renal cell carcinoma are different to those that lead to the more common form of kidney cancer, clear cell renal carcinoma,” said Ramaprasad Srinivasan, MD, PhD, Head of the Molecular Cancer Therapeutics Section, Urologic Oncology Branch, of the National Cancer Institute in Bethesda, Maryland.
“Treatments that are effective in clear cell renal cell carcinoma are not particularly effective in papillary renal cell carcinoma. Some forms of papillary renal cell carcinoma, particularly those associated with hereditary leiomyomatosis and renal cell cancer, are characterized by altered cellular metabolism; the tumor cells obtain energy from a process called aerobic glycolysis, and they require high levels of glucose to survive. We believe the combination of erlotinib and bevacizumab may target this particular weakness, at least partly, by impairing glucose delivery to the tumor cells,” Dr. Srinivasan said.
Study Details
This phase II clinical trial included 41 patients with advanced papillary renal cell carcinoma (20 with advanced hereditary leiomyomatosis and renal cell cancer and 21 with advanced sporadic papillary renal cell carcinoma). Nineteen of the patients had received at least one previous systemic therapy, such as sunitinib (Sutent), that had not been successful in preventing their disease progressing. Patients received bevacizumab 10 mg/kg given intravenously once every 2 weeks, combined with erlotinib 150 mg taken orally every day. Treatment was continued until disease progression or unacceptable toxic side effects.
“Almost all the patients with hereditary leiomyomatosis and renal cell cancer responded with their tumours either shrinking or remaining stable and not progressin,” Dr. Srinivasan said. The overall response rate was 65%, with 13 patients showing tumor shrinkage of more than 30% and 7 patients with stable disease. “Many of the responses were long-lasting; some of patients have remained on the study for 3 years or more, which is a significant since metastatic hereditary leiomyomatosis and renal cell cancer is uniformly fatal and patients usually die within a year or so,” he added.
Among the patients with sporadic papillary renal cell carcinoma, approximately one-third demonstrated very good, often durable, partial responses. The overall response rate as 29%, 6 patients showed tumor shrinkage, and 12 patients had stable disease.
The median progression-free survival in the hereditary leiomyomatosis and renal cell cancer cohort was 24.2 months, while for sporadic papillary renal cell carcinoma cohort it was 7.4 months. This compares well with existing survival times for patients on other treatments. “The median progression-free survival for metastatic papillary renal cell carcinoma appears to be less than 6 months with most regimens commonly used today,” Dr. Srinivasan said. “This is also true for patients with metastatic hereditary leiomyomatosis and renal cell cancer, who generally demonstrate rapidly progressive fatal disease.
Manageable Side Effects
Treatment was well tolerated, and most patients reported a good quality of life. Side effects were mostly mild or moderate and included high blood pressure, acne, proteinuria, and fatigue, which could be managed effectively with drugs or other supportive measures. One patient died from a gastrointestinal hemorrhage, which may have been related to the bevacizumab.
“The combination of erlotinib and bevacizumab for treating patients with advanced papillary renal cell carcinoma shows excellent response rates with tolerable side effects. This is particularly true of patients with hereditary leiomyomatosis and renal cell cancer,” Dr. Srinivasan concluded. “The current data are sufficiently encouraging for this combination to be explored further in larger trials as a possible standard-of-care treatment for papillary renal cell carcinoma patients. We are in the process of designing these studies. It is also important to try and identify specific subgroups of patients most likely to benefit from this regimen and our group is working on this issue.” ■
Disclosure: The study authors reported no potential conflicts of interest.
Reference
1. Srinivasan R, et al: Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Abstract 5. Presented November 19, 2014.
