by Dr. C.H. Weaver M.D. updated 8/2019
It is estimated there will be 73,820 individuals diagnosed with kidney cancer this year and 14,770 will succumb to their disease. (1) Metastatic renal cell cancer (RCC) currently has a 5-year survival rate of ~ 12% but several recently approved medications are improving the outcomes for individuals with advanced renal cell cancer.
Tyrosine Kinase - Checkpoint Inhibitor Immunotherapy Combinations Improve Survival in Advanced Kidney Cancer
Checkpoint inhibitors are novel precision cancer immunotherapy drugs that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are the proteins that inhibit this immune response, allowing cancer cells to evade an attack by the body’s immune cells. Checkpoint inhibitor drugs block the PD-1 pathway and enhance the ability of the immune system to fight the cancer.
Results from clinical trials evaluating the checkpoint inhibitor drugs Keytruda® (pembrolizumab) and Bavencio® (avelumab) combined with the tyrosine kinase inhibitor Inlyta® (axitinib) were approved in 2019 and became the new standard of care for advanced RCC because these combinations delay cancer recurrence and prolong survival.
The US Food and Drug Administration (FDA) has also approved the checkpoint inhibitor Opdivo (nivolumab) combined with Yervoy as first-line, treatment for patients with advanced kidney cancer.
Other Medications Approved for the Treatment of Kidney Cancer
For individuals with advanced RCC unable to benefit from treatment with checkpoint inhibitor immunotherapy several other medications are available that include various chemotherapy drugs, immunotherapy and precision cancer medicines.
Genomic-biomarker testing can be performed on the cancer or in blood and is used to identify the genomic alterations in a cancers DNA that is driving the growth of a specific cancer. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision medicines have been developed for the treatment of RCC with identifiable cancer driving mutations and patients should discuss the role of genomic biomarker testing with their treating physician.
Sutent (sunitinib) is an oral multi-targeted tyrosine kinase inhibitor that targets proteins responsible for stimulating cancer cell growth. TwopPhase II clinical trials have shown that approximately 40% of patients with recurrent renal cell cancer respond to treatment with Sutent, and approximately one-quarter of patients experienced stable disease for three months after treatment. (6) Additionally, a phase III trial has demonstrated that Sutent is superior to interferon-alfa. (7) The FDA approved Sutent in 2006 and in 2017 for use as adjuvant therapy.
Inlyta® (axitinib) is an oral targeted drug known as a small-molecule tyrosine kinase inhibitor. It works by blocking certain proteins that play a role in cancer growth. In the US, Inlyta is approved for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. FDA approved in 2012.
Afinitor (everolimus) is an oral targeted therapy that works by inhibiting a protein known as the mammalian target of rapamycin (mTOR). The mTOR protein plays an important role in the growth, division, and metabolism of cancer cells. In a Phase II clinical trial, roughly 70% of patients with metastatic renal cell cancer experienced either a reduction in detectable cancer or stable disease following treatment with Afinitor® leading to FDA approval in 2007. (8)
Opdivo (nivolumab) is a precision cancer immunotherapy that belongs to a class of medicines called PD-1 checkpoint inhibitors which help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Opdivo works by blocking PD-1, allowing the immune system to work more effectively. FDA approved 2015.
Cabometyx (cabozantinib) is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as other biologic pathways involved in the spread of kidney cancer. Cabometyx is thought to inhibit the action of the receptor tyrosine kinases including MET, VEGFR-1, -2, and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. FDA approved in 2016.
Nexavar (sorafenib) is and oral targeted therapy that inhibits several tyrosine kinases, including VEGF (vascular endothelial growth factor) receptors. A phase III clinical trial compared Nexavar to placebo in more than 900 patients with previously treated, advanced renal cell cancer. Treatment with Nexavar significantly improved progression-free survival (survival without a worsening of the cancer).8 A later analysis of these data also suggested that Nexavar significantly improved overall survival.(9) Based on the results of this study, Nexavar was FDA-approved for use in renal cell cancer in 2005.
Votrient® (pazopanib) is an oral targeted agent that work by inhibiting multiple biologic pathways involved in cancer growth and spread and inhibits angiogenesis which may help slow or prevent the growth of new blood vessels, which deprives the cancer of the oxygen and nutrients it needs to grow. The approval of Votrient for advanced kidney carcinoma was prompted in part by a phase III clinical trial showed that the drug delayed cancer progression. (13)
Torisel (Temsirolimus) targets mTOR (mammalian target of rapamycin kinase), which regulates cell growth and proliferation. The clinical trial that prompted FDA approval of Torisel included 626 patients with metastatic renal cell cancer who had a poor prognosis and had not received prior therapy. (11) Patients were treated with either Torisel, interferon alfa, or a combination of Torisel plus interferon alfa (combination group).
- Patients treated with Torisel had longer survival by nearly 3.6 months and significantly longer progression-free survival than patients treated with interferon alone.
- Patients in the combination group did not experience a significant improvement in survival compared with patients treated with interferon alone.
Avastin (bevacizumab) is a monoclonal antibody, or protein made in the laboratory, that selectively binds to VEGF. VEGF plays a key role in the development of new blood vessels. By blocking VEGF, Avastin deprives the cancer of nutrients and oxygen and inhibits its growth. This renders VEGF unable to bind to its receptor on existing vessels and thus halts angiogenesis mediated through this mechanism. Many cancer cells have high levels of VEGF and are thought to produce an overabundance of the proteins. FDA approved in 2009. For patients with metastatic kidney cancer, treatment with a combination of Avastin and interferon alfa results in a longer time to cancer progression than treatment with interferon alpha alone. (12)
Lenvima (lenvatinib) is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1-3. Lenvima™ also inhibits other RTKs that have been implicated in cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFR?), KIT, and RET. FDA approval in 2016.
Immunotherapy works by stimulating the immune system to fight the cancer. Checkpoint inhibitors are a relatively precise immunotherapy. Proleukin® (interleukin-2) and alfa interferon work in a more general manner to stimulate the immune system.
Proleukine (Interleukine-12) is an immunotherapy that can be given in high doses as an inpatient or lower doses SQ. FDA approved in1992. Prior to the FDA-approval of newer precision cancer medicines, Proleukin was the standard of care for patients with advanced renal cell cancer. It is typically administered in high doses as an inpatient treatment and has historically been associated with severe side effects. The safety of high-dose Proleukin has significantly improved over the past decade.
Unfortunately, long-term results of clinical trials indicate that only approximately 15% of patients with advanced renal cell carcinoma have an anticancer response when treated with high-dose Proleukin. (14)
Interferon: Interferon is naturally produced in the body and stimulates the immune system. Interferon alfa is a compound produced in a laboratory that mimics the action of natural interferon and has been shown to stimulate the immune system to recognize and destroy some types of cancer cells.
Treatment of renal cell carcinoma with interferon appears to produce anticancer responses in less than 15% of patients with advanced renal cell cancer. Because side effects can be severe and it has not been shown to improve survival, the use of interferon alone in the treatment of renal cell carcinoma remains controversial.
- George D, Motzer R, Rini B, et al. Sunitinib malate (SU11248) shows antitumor activity in patients with metastatic renal cell carcinoma: updated results from Phase II trials. Proceedings from the 2005 annual Chemotherapy Foundation Symposium. New York, NY. Abstract #18.
- Amato RJ, Jac J, Giessinger S et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer [early online publication]. March 20, 2009.
- Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal cell cancer. New EnglandJournal of Medicine. 2007; 356:125-34.
- Bukowski RM, Eisen T, Szczylik C et al. Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis. Presented at the 2007 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. Abstract 5023.
- Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. New England Journal of Medicine. 2007; 356:2271-2281.
- Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-11.
- Sternberg CN, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. Journal of Clinical Oncology. 2010;28:1061-1068.
- Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of Clinical Oncology. 1995;13(3):688-696.
- Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomized controlled trial. The Lancet. 2004; 363:594-599.