Understanding tumor biology has been the key to advancing treatment in metastatic RCC (mRCC). In 2003, a randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks.1 The time to progression of disease and the response rate was primary endpoints. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose bevacizumab, and 39 to high-dose bevacizumab), there was a significant prolongation of the time to progression of disease in the high-dose bevacizumab group as compared with the placebo group (HR 2.55, p<0.001). Additionally, the probability of being progression-free for patients given high-dose bevacizumab, low-dose bevacizumab, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months.
Since the publication of this seminal trial, the development of VEGF-directed therapies has been rapid. As follows is a table summarizing the published VEGF-directed tyrosine kinase inhibitor (TKI) trials:
Additionally, approval for VEGF and mammalian target of rapamycin (mTOR) inhibitors has been dramatic over the last 15 years:
Dr. Escudier notes that the combination of VEGF TKIs and/or mTOR inhibitors has mostly been a failure (ie. temsirolimus plus bevacizumab, everolimus plus bevacizumab, and sunitinib plus bevacizumab). These combinations have failed to improve progression-free survival, response, or overall survival while proving to be more toxic than compared to single-agent therapy. One combination that does appear efficacious and feasible is lenvatinib plus everolimus.2 Among patients with mRCC, the combination of lenvatinib plus everolimus significantly improved progression-free survival, with a median 14.6 months (95% CI 5.9-20.1) for combination therapy and a median 5.5 months (95% CI 3.5-7.1) for everolimus alone (HR 0.40, 95%CI 0.24-0.68).
Unfortunately, a survival plateau was reached with VEGF/TKIs and mTOR inhibitors: ~30 months in the first-line setting and ~18 months in the second-line setting. Thus, additional approaches were necessary, ushering in the immunotherapy era for the treatment of mRCC. In 2015, the publication of the CheckMate-025 study showed that nivolumab was more effective than everolimus after TKI therapy, improving OS and response rate, as well as inducing dramatic responses in a subset of patients.3
Dr. Escudier concluded that the immunotherapy era once again relied on understanding tumor biology, which has led to the recent wave of combination trials featuring immune checkpoint inhibitors plus TKIs (ie. JAVELIN Renal 101, KEYNOTE-426).
Presented by: Bernard Escudier, MD; Chair of the Renal Cancer Unit, Institut Gustave Roussy, Villejuif, France
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, USA, Twitter: @zklaassen_md at the ASCO20 Virtual Education Program, #ASCO20, August 8-10, 2020
References:
1. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003 Jul 31;349(5):427-434.
2. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomized, phase 2, open-label, multi-centre trial. Lancet Oncol 2015;16(15):1473-1482.
3. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1803-1813.