(UPDATE) Cabozantinib in Renal Cell Carcinoma
Updated: Tuesday, August 20, 2019
Original Spotlight posted June 22, 2017.
The incidence of renal cell carcinoma, a once-obscure cancer, continues to rise, but new biologic hypotheses and therapeutic approaches hold promise. Approximately 73,820 new cases of renal cell carcinoma were diagnosed in the United States in 2019, with 30% to 35% initially presenting with either regional or distant disease.1
The biology of renal cell carcinoma relevant to clear cell histology disease still hinges on VHL mutation as an important initiating event in most tumors. The challenge for clinicians is the lack of effective diagnostics in the early stages of the disease and increased resistance to therapies.2
Expanding Indications for Cabozantinib
Since the initial Spotlight in 2017, the indications for cabozantinib (Cabometyx) have been expanded to include the treatment of patients with advanced renal cell carcinoma, regardless of previous therapies.3 Moreover, a newly launched trial will explore the combination of cabozantinib with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313 trial).4 This is a multicenter, randomized, double-blinded, controlled phase III trial of cabozantinib in combination with nivolumab and ipilimumab versus nivolumab and ipilimumab in combination with a matched placebo. Approximately 676 eligible subjects with intermediate- or poor-risk advanced or metastatic renal cell carcinoma will be randomly assigned to treatment in a 1:1 ratio.
The treatment landscape for advanced renal cell carcinoma has evolved with the introduction of new systemic therapies, such as immunotherapies and combination immunotherapies. The role of immunotherapy and combination immunotherapy is an active area of research, and some combination therapies are already FDA approved and included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer.5 Cabozantinib is still a preferred option for patients with poor or intermediate risk in first line and in the second line for all patients with clear cell renal cell carcinoma.
Adverse Effects Akin to Those of Other Tyrosine Kinase Inhibitors
In addition to its anti-VEGF (vascular endothelial growth factor) activity, cabozantinib is also thought to target MET and AXL—both believed to be involved in resistance to anti-VEGF drugs.6,7 However, cabozantinib is essentially a tyrosine kinase inhibitor (TKI) with a safety profile similar to other drugs in its class. The side effect profile of cabozantinib makes it a preferred option in certain patients who cannot tolerate immunotherapy-related toxicities.
“Over the past 10 to 15 years, we have had experience with anti-VEGF TKIs and targeted agents in general—sunitinib, sorafenib, axitinib, pazopanib—so the adverse effects associated with cabozantinib do not come as a surprise,” explained Toni K. Choueiri, MD, the Jerome and Nancy Kohlberg Chair at Harvard Medical School. “They are generally anticipated as class effects associated with this category of medications.”
Dr. Choueiri, who is also Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, pointed out that “in the large trial of cabozantinib compared with everolimus as second-line treatment for patients with advanced kidney cancer that had progressed on VEGFR-targeted therapy, the adverse effects of each drug were as expected.8 And, in a smaller, ongoing front-line trial of sunitinib versus cabozantinib,9 adverse effects are roughly similar for the two groups.”
Update on Recent Trials in Metastatic Renal Cell Carcinoma
According to the results of a study published in March 2019, a combination of two drugs—one an immunotherapy agent—could become a new standard, first-line treatment for patients with metastatic renal cell carcinoma, noted Dr. Choueiri, senior author of the JAVELIN Renal 101 trial in The New England Journal of Medicine.10 The study reported results from a phase III clinical trial. Patients who received the immunotherapy avelumab plus the targeted agent axitinib had a significant advantage in progression-free survival compared with those who received sunitinib. “Patients receiving the drug combination also had a higher response rate than the sunitinib-only group,” commented Dr. Choueiri. This is a preferred option in the NCCN Guidelines.5
In recent years, guidelines on renal cell carcinoma have been updated and published to incorporate newer data, namely from the CARMENA and SURTIME trials.11 These trials supported earlier use of systemic therapy. The KEYNOTE 046 trial supported pembrolizumab plus axitinib as a new standard of care for patients diagnosed with renal cell carcinoma that has metastasized and who did not receive any prior treatment.12 This recommendation applies to all risk groups, as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria. Additionally, results of a phase III trial supported ipilimumab and nivolumab in advanced renal cell carcinoma.13
Focus on Treatment of Elderly Patients
Many elderly patients with metastatic renal cell carcinoma—who are often underrepresented in clinical trials of treatments in kidney cancer—are seeing overall survival benefits from treatment with targeted therapies, according to a recent study from Penn Medicine researchers published in JAMA Network Open.14 Analyzing 13 years of data on Medicare patients, the study investigators found that those who received targeted therapies were more medically complex than those who received the older, more toxic treatments that were available earlier in the study period.
According to a quote in Penn Medicine News by senior researcher Jalpa A. Doshi, PhD, Professor of Medicine in the Perelman School of Medicine at the University of Pennsylvania, “Renal cell carcinoma is a cancer where people can often try other treatment options if the first one isn’t effective, so even small gains may mean that a person might live long enough to try the next innovation. What’s more, studies are showing that current treatments, including immunotherapies, are leading to even better outcomes than those that were observed during our study time frame.”14
[Editor’s Note: At the end of this update, see a Commentary by Robert J. Motzer, MD, JNCCN 360 Site Editor, about the use of cabozantinib in the treatment of renal cell carcinoma in 2019.]
1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: kidney and renal pelvis cancer. Available at https://seer.cancer.gov/statfacts/html/kidrp.html. Accessed July 24, 2019.
2. Braga EA, Fridman MV, Loginov VI, et al. Molecular mechanisms in clear cell renal cell carcinoma: role of miRNAs and hypermethylated miRNA genes in crucial oncogenic pathways and processes. Front Genet 2019;10:320.
3. Cabozantinib (Cabometyx). U.S. Department of Health and Human Services. U.S. Food & Drug Administration. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208692. Accessed July 1, 2019.
4. Phase III Trial Launches to Investigate Cabozantinib Plus Nivolumab/Ipilimumab in Frontline RCC. Targeted Oncology. Available at https://www.targetedonc.com/news/phase-iii-trial-launches-to-investigate-cabozantinib-plus-nivolumabipilimumab-in-frontline-rcc. Accessed July 1, 2019.
5. Motzer RJ, Jonasch E, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 2.2020. To view the most recent version of these guidelines, visit NCCN.org. Accessed August 5, 2019.
6. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2015;35:2687–2697.
7. Choueiri TK, Pal SK, McDermott DF, et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014;25:1603–1608.
8. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814–1823.
9. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35:591–597.
10. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–1115.
11. Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines for cytoreductive nephrectomy in patients with synchronous metastatic clear-cell renal cell carcinoma. Eur Urol 2018;74:805–809.
12. Rini BO, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal call carcinoma. N Engl J Med 2019;380:1116–1127.
13. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–1290.
14. Li P, Jahnke J, Pettit AR, et al. Comparative survival associated with use of targeted vs nontargeted therapy in medicare patients with metastatic renal cell carcinoma. JAMA Netw Open. 2019;2:e195806.
Commentary by Kidney Cancer Site Editor for JNCCN 360, Robert J. Motzer, MD
Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center, New York
We continue to make progress in therapeutics for advanced kidney cancer. Cabozantinib and other tyrosine kinase inhibitors (TKIs) as monotherapy served as the mainstay of treatment for nearly 15 years. Recently, investigators have focused on combining TKIs with checkpoint inhibitors. The success of this approach has been demonstrated by the recent regulatory approval of two combination regimens: axitinib plus pembrolizumab1 and axitinib plus avelumab.2 Moreover, the combination of cabozantinib plus nivolumab is being compared with sunitinib in a large phase III trial, CheckMate 9ER, which completed accrual and awaits analysis (ClinicalTrials.gov identifier NCT03141177). Additionally, the study cited in this update, the COSMIC-313 trial,3 will compare the efficacy and safety of cabozantinib in combination with ipilimumab and nivolumab versus the checkpoint inhibitor combination plus placebo.
- U.S. Food & Drug Administration. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma. Accessed July 24, 2019.
- U.S. Food & Drug Administration. FDA approves avelumab plus axitinib for renal cell carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avelumab-plus-axitinib-renal-cell-carcinoma. Accessed July 24,2019.
- Phase III Trial Launches to Investigate Cabozantinib Plus Nivolumab/Ipilimumab in Frontline RCC. Targeted Oncology. Available at https://www.targetedonc.com/news/phase-iii-trial-launches-to-investigate-cabozantinib-plus-nivolumabipilimumab-in-frontline-rcc. Accessed August 18, 2019.
Dr. Motzer has served as a consultant for Exelixis, Eisai, Genentech, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Incyte, Lilly Oncology, and Pfizer Inc.