Updates in the First-Line Treatment of Advanced Renal Cell Carcinoma

Pharmacy Times Oncology Edition, August 2021, Volume 3, Issue 4

Current guideline recommendations include various combinations of targeted therapy with immunotherapy.

The treatment of advanced renal cell carcinoma (aRCC) has drastically changed over the past 30 years.1 In 1992, the FDA approved the first immunotherapy in aRCC, interleukin 2.2 More than a decade later, the FDA approved the first targeted agent, sorafenib (Nexavar; Bayer).3 Since the mid-2000s, the treatment armamentarium for aRCC has expanded with approvals of additional immuno- and targeted therapies.1

Current guideline recommendations include various combinations of targeted therapy with immunotherapy.4 So far in 2021, results from a pair of phase 3 trials—CLEAR (NCT02811861) and CheckMate 9ER (NCT03141177)—were published; the trials evaluated the combination of 2 different tyrosine kinase inhibitors (TKIs) with immunotherapy.5,6 To better understand how these 2 trials impact clinical decision-making for first-line treatment of patients with aRCC, these trials were evaluated in the context of other guideline-recommended treatments. These investigational combination immuno- and targeted therapies appear poised to contribute to the evolving treatment landscape of aRCC.


The theory behind the combination stems in part from a main proangiogenic factor, VEGF, which is associated with renal cell carcinoma tumor growth and immunosuppression.7 VEGF stimulates the growth of blood vessels, leading to tumor angiogenesis, and causes immunosuppression through the promotion of regulatory T cells and inhibition of effector T cells. VEGF-targeted TKIs can control vasculature growth and normalize immune function, leading to better immune cell penetration of tumors especially in the presence of immunotherapy. Because of this control, the combination of a TKI and immunotherapy can have a synergistic antitumor effect.7


The phase 3 CLEAR trial randomized patients to receive either lenvatinib (Lenvima; Eisai Co, Ltd) 20 mg daily plus pembrolizumab (Keytruda; Merck) 200 mg every 21 days (n = 355) or sunitinib (Sutent; Pfizer Inc) 50 mg daily (4 weeks on with 2 weeks off per cycle) (n = 357).6

The study showed improved progression free survival (PFS), overall survival (OS), and objective response rate (ORR) with lenvatinib plus pembrolizumab versus sunitinib. The median PFS was longer with lenvatinib plus pembrolizumab than sunitinib (23.9 months vs 9.2 months; P < .001).6 Median OS was not reached in either arm but favored lenvatinib plus pembrolizumab (P = .005). The ORR was also significantly higher in the lenvatinib plus pembrolizumab group compared with the sunitinib group (71% vs 36.1%; HR, 1.97; 95% CI; 1.69-2.29).6 The subgroup analysis for PFS and OS trended better for lenvatinib plus pembrolizumab in all subgroups except for the favorable risk subgroup.

The CLEAR trial also evaluated lenvatinib plus everolimus (Afinitor; Novartis) in a third arm compared with sunitinib. Lenvatinib plus everolimus statistically outperformed sunitinib in PFS and ORR but showed no difference in OS.6 Efficacy results were numerically lower in all categories with lenvatinib plus everolimus compared with lenvatinib plus pembrolizumab. Although caution should be used comparing results between different studies, the PFS, ORR, and complete response were the highest recorded in the lenvatinib plus pembrolizumab group compared with any other trial (see Table6-11).

Any adverse event grade 3 or higher occurred more often with lenvatinib plus pembrolizumab than with sunitinib (82.4% vs 71.8%, respectively). Two of the most common grade 3 or higher adverse events in both arms included diarrhea and hypertension. Discontinuation of at least 1 of the study drugs was seen in 37.2% of the lenvatinib-pembrolizumab arm compared with 14.4% of the sunitinib arm. Dose reductions occurred more frequently with lenvatinib than with sunitinib (68.8% vs 50.3%).6

The combination of lenvatinib and pembrolizumab was recently added to the National Comprehensive Cancer Network guidelines as a preferred category 1 recommendation regardless of risk categorization.5


The FDA approved nivolumab (Opdivo; Bristol Myers Squibb) plus cabozantinib (Cabometyx; Exelixis, Inc) in January for first-line treatment of aRCC based on results from the CheckMate 9ER study.12

CheckMate 9ER randomized 651 patients to receive cabozantinib 40 mg daily with nivolumab 240 mg every 14 days (n = 323) or sunitinib 50 mg daily (4 weeks on with 2 weeks off per cycle) (n = 328).7

The trial demonstrated a benefit in PFS, OS, and ORR with cabozantinib plus nivolumab compared with sunitinib. The median PFS was twice as long with cabozantinib plus nivolumab (16.6 months vs 8.3 months; HR 0.51; 95% CI: 0.41-0.64; P < .001), and the median OS was not reached but favored the cabozantinib-plus-nivolumab group (HR 0.60; 95% CI: 0.40-0.89; P = .001).7 The confirmed ORR favored cabozantinib plus nivolumab vs sunitinib (55.7% vs. 27.1%; P < .001). In the subgroup analysis, all subgroups trended better with cabozantinib plus nivolumab.7

Adverse events grade 3 or higher were similar across both treatment arms, with 75.3% seen in the cabozantinib-nivolumab arm and 70.6% reported in the sunitinib arm. The more common grade 3 adverse events across groups included diarrhea, palmar-plantar erythrodysesthesia, and hypertension. Treatment discontinuation of at least 1 drug was more common in the cabozantinib plus nivolumab group compared with the sunitinib group (19.7% vs 5.6%, respectively). Dose reductions occurred more frequently with cabozantinib than with sunitinib (56.3% vs 51.6%, respectively).7

The NCCN guidelines have been updated to include cabozantinib plus nivolumab as a preferred first-line option in all risk categories with a category 1 recommendation in intermediate- or poor-risk patients.5


In the first-line treatment setting of aRCC, various therapies have shown improved efficacy compared with sunitinib. However, data comparing these therapies with each other are lacking.6-11 Without direct comparative data, therapy decisions are frequently driven by patient-specific factors or provider preference.

Notably, first-line treatment selection may also affect treatment decisions in the subsequent-line setting. Significant overlap exists between the TKIs used in the first-line setting (combined with immunotherapy) and the TKIs in subsequent lines.5 For example, lenvatinib plus everolimus is a therapy option in the subsequent-line setting. If a patient receives pembrolizumab plus lenvatinib in the firstline setting, the combination of lenvatinib plus everolimus may not be appropriate because TKI resistance may develop following disease progression.13

With the many therapy options available, trials evaluating sequencing therapy would benefit clinical practice. New trials are needed to guide practitioners on which first-line therapy options are preferred from direct comparator studies. End points such as PFS2 (time from randomization to second disease progression) could help determine the best sequence of subsequent lines of therapy. Furthermore, the use of sunitinib as a comparator in the first-line setting should= be discouraged in new trials of previously untreated RCC, as this is no longer the standard of care.

Several ongoing trials could change therapy protocols. The COSMIC-313 trial (NCT03937219) and the PDIGREE trial (NCT03793166) are evaluating different combinations of ipilimumab (Yervoy; Bristol Myers Squibb), nivolumab, and cabozantinib.14,15 Results of both trials are pending. A novel HIF2A inhibitor, MK-6482 (Belzutifan; Merck), received a priority review from the FDA based on a phase 2 trial of patients with Von Hippel—Lindau disease—associated renal cell carcinoma.16 A phase 3 trial (NCT04195750) is currently underway to compare MK-6482 vs everolimus in patients with aRCC following progression on immunotherapy and a TKI.17


For patients with aRCC, combination therapy with an immune checkpoint inhibitor and a TKI is often the preferred first-line treatment modality. The CLEAR and CheckMate 9ER trials showed promising results, supporting the use of lenvatinib plus pembrolizumab and nivolumab plus cabozantinib, respectively. Among the first-line treatment options, lenvatinib plus pembrolizumab demonstrated the highest ORR and PFS; however, caution should be used when comparing results between trials.6-11 New trials with end points that span multiple lines of therapy are needed to help sequence the therapy of patients with aRCC.


Kelly M. Brunk, PharmD, BCOP, is a clinical oncology pharmacist at The University of Kansas Health System in Kansas City.

TJ Schieber, MBA, is a 2021 PharmD candidate at the University of Missouri-Kansas City School of Pharmacy.


1. Cancer progress timeline: kidney cancer. American Society of Clinical Oncology. Accessed March 13, 2021. https://www.asco.org/research-guidelines/cancer-progress-timeline/kidney-cancer

2. Rosenberg SA. Interleukin 2 for patients with renal cancer. Nat Clin Pract Oncol. 2007;4(9):497. doi:10.1038/ncponc0926

3. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-134. doi:10.1056/NEJMoa060655

4. National Comprehensive Cancer Network. Kidney cancer, version 3.2021. Accessed March 23, 2021. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

5. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14)1289-1300. doi:10.1056/NEJMoa2035716

6. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib vs sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

7. Rassy E, Flippot R, and Albiges L. Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. [published online ahead of print] Ther Adv Med Oncol. 2020; 12:1758835920907504. doi:10.1177/1758835920907504

8. 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(6):591-597. doi:10.1200/JCO.2016.70.7398

9. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

10. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

11. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi:10.1056/NEJMoa1816047

12. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. US Food & Drug Administration. January 22, 2021. Accessed March 13, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma

13. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35(21):2687-2697. doi:10.1038/onc.2015.343

14. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). ClinicalTrials.gov. Posted May 3, 2019. Accessed March 17, 2021.

15. Immunotherapy with nivolumab and ipilimumab followed by nivolumab or nivolumab with cabozantinib for patients with advanced kidney cancer, the PDIGREE Study. ClinicalTrials.gov. Posted January 4, 2019. Accessed March 17, 2021. https://clinicaltrials.gov/ct2/show/NCT03793166?term=NCT03793166&draw=2&rank=1

16. Merck receives priority review from FDA for new drug application for HIF-2a inhibitor belzutifan (MK-6482). News release. Merck. March 16, 2021. Accessed March 17, 2021. https://www.merck.com/news/merck-receives-priority-review-from-fda-for-new-drug-application-for-hif-2%CE%B1-inhibitor-belzutifan-mk-6482/

17. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Posted December 12, 2019. Accessed March 17, 2021. https://clinicaltrials.gov/ct2/show/NCT04195750?term=NCT04195750&draw=2&rank=1