Evolving Landscape of First-Line Therapy for Metastatic Renal Cell Carcinoma

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In the past 3 years, we have seen a dramatic shift in the treatment paradigm for first-line therapy for metastatic clear cell renal cell carcinoma. Multiple phase III clinical trials have demonstrated improved efficacy with combinations compared with sunitinib, leading to the regulatory approval of ipilimumab plus nivolumab,1 axitinib plus pembrolizumab,2 and axitinib plus avelumab.3 These studies have established PD-1/PD-L1 immune checkpoint inhibitor–containing combination therapies as the new standard of care for most patients with newly diagnosed metastatic renal cell carcinoma.

These regimens build upon a PD-1 inhibitor backbone combined with either a VEGF-targeted tyrosine kinase inhibitor or an anti–CTLA-4 agent. Both approaches (tyrosine kinase inhibitor/immune checkpoint inhibitor and dual immune checkpoint inhibition) have shown improved clinical outcomes vs a single-agent tyrosine kinase inhibitor (sunitinib). However, these two approaches have not been prospectively compared with each other in clinical trials, and there remains debate in the field regarding the optimal first-line therapy.

Key Results From KEYNOTE-426

KEYNOTE-426 is a randomized phase III clinical trial that compared the combination of axitinib/pembrolizumab to sunitinib. It demonstrated improved rates of objective response, progression-free survival, and overall survival at the first interim analysis, which was performed at 12.8 months of median follow-up.2 Recently published in The Lancet Oncology and reviewed in the December 10, 2020, issue of The ASCO Post were the results of extended follow-up (median 30.6 months).4

“There remains debate in the field regarding the optimal first-line therapy [for metastatic clear cell renal cell carcinoma].”
— Chung-Han Lee, MD, PhD

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With extended follow-up, the combination of axitinib/pembrolizumab continues to show an improved objective response rate (60% vs 40%), progression-free survival (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.6–0.84, P < .0001), and overall survival (HR = 0.68, 95% CI = 0.55–0.85, P = .0003) compared with sunitinib in the intent-to-treat population, which included all risk categories. At the 2-year landmark analysis, 37.6% of the patients treated with the axitinib/pembrolizumab combination remained progression free, and it remains to be seen whether these results will be durable with longer follow-up. In a subgroup analysis of patients with favorable-risk disease, differences in overall survival (HR = 1.06, 95% CI = 0.60–1.86, P = .58) and progression-free survival (HR = 0.79, 95% CI = 0.57–1.09, P = .078) were not yet seen.

Other Clinical Trial Updates

Other notable tyrosine kinase inhibitor/immune checkpoint inhibitor combinations include those evaluated in CheckMate 9ER ( identifier NCT03141177), which reported positive results with nivolumab plus cabozantinib vs sunitinib at the European Society for Medical Oncology (ESMO) Virtual Congress 2020,5 and KEYNOTE-581/CLEAR (Study 307; NCT02811861), for which only a press release is currently available.6

CheckMate 9ER is a randomized phase III trial of cabozantinib/nivolumab vs sunitinib. It demonstrated an improved objective response rate (55.7% vs 27.1%, P < .0001), progression-free survival (HR = 0.51, 95% CI = 0.41–0.64, P < .0001), and overall survival (HR = 0.60, 98.89% CI = 0.40–0.89, P = .0010), with a median follow-up of 18.1 months.5 For KEYNOTE-581/CLEAR, which is evaluating lenvatinib in combination with either everolimus or pembrolizumab vs sunitinib, data have yet to be presented; however, the study is reported to have met its primary endpoints.6 Together, tyrosine kinase inhibitor/immune checkpoint inhibitor combinations appear to be an important treatment option for patients with metastatic renal cell carcinoma.

Another PD-1 inhibitor–based approach includes dual immune checkpoint inhibition targeting PD-1 and CTLA-4. CheckMate 214 compared ipilimumab/nivolumab vs sunitinib.7 With a minimum follow-up of 42 months, in patients with intermediate- or poor-risk disease, ipilimumab/nivolumab was associated with an improved objective response rate (42% vs 26%, P < .001) and overall survival (HR = 0.66, 95% CI = 0.55–0.80, P < .0001).7

Clinical Decision-Making: Individualized Choice

Currently, the decision regarding an upfront dual immune checkpoint inhibitor vs tyrosine kinase inhibitor/immune checkpoint inhibitor approach remains a clinical decision in which outcomes must be individualized based on multiple factors, including the aggressiveness of the disease, patient performance status/medical comorbidities, availability of resources for toxicity management, subsequent-line therapy options, and patient preferences. Efforts for biomarker development to help stratify patients remain critical; however, to date, they have not yet been broadly applied in clinical practice.

“Tyrosine kinase inhibitor/immune checkpoint inhibitor combinations appear to be an important treatment option for patients with metastatic renal cell carcinoma.”
— Chung-Han Lee, MD, PhD

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Also of particular interest will be the development of triplet therapy with dual immune checkpoint inhibition with anti–CTLA-4/anti–PD-1 and a tyrosine kinase inhibitor, such as used in COSMIC-313 (NCT03937219). This trial is comparing ipilimumab/nivolumab/cabozantinib with ipilimumab/nivolumab/placebo.

More Information

For more on the KEYNOTE-426 trial of pembrolizumab plus axitinib vs sunitinib for renal cell carcinoma, see a joint interview with Neeraj Agarwal, MD, and Thomas Powles, MD, PhD, on The ASCO Post Newsreels at

The clinical development of agents in clear cell renal cell carcinoma has rapidly accelerated, with improved outcomes for our patients. Now, we have multiple phase III clinical trials that have shown objective response rates higher than 50%, and the discussion about efficacy now includes questions regarding durability and tolerability. This shift represents a very meaningful impact on the quantity and quality of life for patients with metastatic renal cell carcinoma. 

Publisher's Note: This article was originally published in the January 25, 2021 issue of The ASCO Post.

DISCLOSURE: Dr. Lee has served as a consultant or advisor to Amgen, Bristol Myers Squibb, Eisai, Pfizer/EMD Serono, Merck, and Exelixis; has received institutional research funding from Bristol Myers Squibb, Calithera Biosciences, Eisai, Eli Lilly, and Exelixis; has been reimbursed for travel, accommodations, or other expenses by Calithera Biosciences and Eisai; and has received honoraria from Intellisphere.


1. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.

2. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019.

3. Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103-1115, 2019.

4. Powles T, Plimack ER, Soulières D, et al: Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): Extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 21:1563-1573, 2020.

5. Choueiri TK, Powlest T, Burotto M, et al: Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. ESMO Virtual Congress 2020. Abstract 696O_PR. Presented September 19, 2020.

6. Eisai: Lenvima Plus Keytruda Demonstrated Statistically Significant Improvement in Progression-Free Survival, Overall Survival and Objective Response Rate Versus Sunitinib as First-Line Treatment for Patients With Advanced Renal Cell Carcinoma. Available at Accessed December 16, 2020.

7. Tannir NM, McDermott DF, Escudier B, et al: Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: First-line nivolumab + ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. 2020 Genitourinary Cancers Symposium. Abstract 609. Presented February 15, 2020.

Dr. Lee is a medical oncologist practicing at Memorial Sloan Kettering Cancer Center, New York.