Updates in Advanced Kidney Cancer, A Welcome Letter from the Editor

Welcome to UroToday’s new Advanced Kidney Cancer Center of Excellence. It is my great honor and pleasure to serve as its editor. Therapies for advanced kidney cancer are rapidly evolving, which can make it challenging to stay current with new developments. This website curates clinically relevant content in a variety of formats, including peer-to-peer video conversations between experts, articles and commentaries by physician-scientists, in-depth conference coverage, and newly released abstracts.

We aim to foster a deeper understanding of current standards of care, points of transition and possible controversy, and future treatment directions in advanced kidney cancer. Your engagement and feedback through this website, its associated newsletters, and social media are welcome and encouraged. In this first letter, I highlight some of the most important recent developments in kidney cancer and note some key study results to watch for. I will first discuss clear-cell renal cell carcinoma (ccRCC), as this is the predominant histology we see in our patients. I will then cover non-clear cell RCC, touch on molecular research, and leave you with a few key takeaways.

First-line treatment of advanced ccRCC: Over the past four years, the standard of care for the upfront treatment of advanced ccRCC has evolved from monotherapy with sunitinib, a multi-target tyrosine kinase inhibitor (TKI), to combination regimens that include one or more immune-oncologic (IO) checkpoint inhibitors.1 Currently recommended combinations—all of which have significantly outperformed sunitinib with respect to key clinical endpoints in large registrational phase 3 trials—include the PD-1 checkpoint inhibitor pembrolizumab plus the TKI axitinib (KEYNOTE-4262), pembrolizumab plus the TKI lenvatinib (CLEAR3), the PD-1 inhibitor nivolumab plus the TKI cabozantinib (CheckMate 9ER4), and dual-IO therapy with the CTLA-4 inhibitor ipilimumab plus nivolumab (CheckMate 2145). All these combinations have confirmed efficacy signals. Of note, ipilimumab/nivolumab is specifically approved for treating poor/intermediate-risk RCC, has the longest follow-up period to date (more than 5 years in Checkmate 214)6, and was the first to receive FDA approval, in 2018.

Risk stratification in ccRCC is important for treatment selection and is based on factors such as time since diagnosis, performance status, and the results of standard blood assays.1 Here are a few additional key updates reported this year from these trials: In KEYNOTE-426, pembrolizumab/axitinib significantly improved time to progression after first subsequent treatment (PFS2) across risk-stratified subgroups when compared with sunitinib.7 In CheckMate 9ER, after extended (median 32.9 months’) follow-up, nivolumab/cabozantinib continued to outperform sunitinib with respect to OS, PFS, and health-related quality of life (HRQoL).8,9 In the CLEAR trial, lenvatinib/pembrolizumab produced significant improvements in both PFS2 and HRQoL when compared with sunitinib.10 Note that with all IO-based regimens, patients should be educated about and monitored for immune-related adverse events, and clinicians should lean toward early treatment interruption and referral for specialized care if an event exceeds grade 1 to 2 in severity or is worsening.

We combine oncolytics with distinct mechanisms of action with the hopes of improving the probability of response and its speed, depth, and duration. However, combining drugs can increase the incidence and severity of toxicities and does not always achieve the synergy we hope to see. The phase 3 PIVOT-09 study terminated earlier this year after combined treatment with nivolumab plus bempegaldesleukin (NKTR-214), an engineered interleukin-2 pathway agonist, unexpectedly failed to improve the likelihood of response or OS when compared with control TKI therapy in patients with untreated RCC.11 This is important to note because this trial was widely expected to be positive based on prior phase 1/2 results. A separate study of the combination failed to show a benefit in urothelial carcinoma, and clinical development of bempegaldesleukin/nivolumab has ended.

Second and later-line systemic therapy for advanced ccRCC is with TKIs, IOs, or IO-TKI combinations. Studies of single-agent TKIs administered after IOs have shown that TKIs have activity in the treatment-refractory space.12,13 In a head-to-head trial (the randomized, controlled, phase 3 TIVO-3 study), third or later-line monotherapy with the TKI tivozanib significantly improved PFS at initial and subsequent (3 and 4-year) follow-up and was better tolerated than monotherapy with the TKI sorafenib.14,15 These findings led to the FDA approval of tivozanib in 2021 for treating advanced RCC in patients who have already received at least two lines of therapy.

While TKIs given as monotherapy are active, provocative data from a phase 2 study reported ORRs above 50% with IO-based combination for patients who progressed on prior IO therapy.16 Currently, the randomized, controlled phase 3 TiNivo-2 study is evaluating whether adding nivolumab to tivozanib further improves PFS in patients with pre-treated RCC; this study is currently enrolling, and primary PFS results are expected in 2024.17 Also, in the phase 3 CONTACT-03 study, patients whose RCC has progressed on a first or second-line IO have been randomized to receive either cabozantinib/atezolizumab or cabozantinib alone.18 Both clear and non-clear cell RCC subtypes are included in this study, for which initial PFS results are expected later this year.

Adjuvant Therapies for ccRCC are another notable area of progress. In general, we are seeing the start of a shift toward the adjuvant use of systemic treatments with novel mechanisms of action that were previously used only in advanced RCC. The first class of drugs to be evaluated in the adjuvant RCC setting were the TKI agents, including sunitinib, sorafenib, and axitinib. Thus far, only sunitinib has received an FDA approval in this space. The November 2017 approval was based on the results of the phase 3, placebo-controlled S-TRAC study, in which disease-free survival (DFS) was significantly greater with sunitinib versus placebo administered after nephrectomy in patients with locoregional ccRCC at high risk for recurrence.19 Unfortunately, toxicities, including grade 3 and 4 events, were approximately three times more frequent in the sunitinib arm compared with the placebo arm and frequently led to dose reductions and/or dose interruptions. Also, an updated analysis of the S-TRAC trial, median OS was not reached in either arm after more than 6.5 years’ median follow-up time.20 In addition, negative results and treatment-related deaths were observed in the large phase 3 randomized placebo-controlled ASSURE trial of adjuvant sunitinib.21 Meta-analyses of clinical trial data also have failed to show a significant OS benefit from TKI monotherapy in the adjuvant RCC setting.22,23 Currently, sunitinib, despite its FDA approval, is not widely used as adjuvant RCC therapy in practice.

With respect to the IO therapies, pembrolizumab is currently the only drug to be FDA-approved for adjuvant use in RCC. The November 2021 approval was based on data from the phase 3 randomized KEYNOTE study, in which adjuvant pembrolizumab therapy, compared with placebo, significantly improved DFS among patients with RCC at intermediate-high or high risk of recurrence after nephrectomy.24 The DFS benefit continued to be seen after longer (30 months of) follow-up, although the improvement in OS did not meet the pre-specified statistical boundary for significance.25

Unfortunately, the randomized phase 3 PROSPER RCC trial recently was stopped for futility; this study compared perioperative (neoadjuvant and adjuvant) nivolumab versus active monitoring alone in patients undergoing nephrectomy for RCC.26 We now await results from other randomized phase 3 adjuvant studies in this disease setting. IMMmotion010 compares atezolizumab with placebo; primary results are expected this year. CheckMate 914 compares adjuvant nivolumab, nivolumab plus ipilimumab, and placebo; results are expected in 2024.27 RAMPART compares adjuvant durvalumab, adjuvant durvalumab/tremelimumab, and active monitoring in patients with several RCC histotypes; results are expected in 2024. Finally, LITESPARK-022 (MK-6482-022) compares pembrolizumab plus belzutifan, which targets HIF-2α, with pembrolizumab alone; results are expected in 2027.28 Belzutifan was recently approved by the FDA for patients with RCC associated with a germline mutation in VHL; the approval was based on the findings of a phase 2 study in which single-agent belzutifan therapy produced a striking ORR of 49%.29

In addition to IOs, other novel therapies are being investigated in the adjuvant space, most notably everolimus, an mTOR inhibitor that is FDA-approved for treating advanced RCC after failure of sunitinib or sorafenib. Recently, in the phase 3, randomized, placebo-controlled EVEREST trial, everolimus missed its statistical cutoff for improving relapse-free survival (RFS) in patients with intermediate-risk or high-risk RCC.30 However, a subgroup analysis of very high-risk patients revealed a statistically significant 21% improvement in RFS. Treatment discontinuation was a factor in this trial—adverse events included oral mucositis, which can be particularly hard for some patients to tolerate. The benefit seen in the high-risk population might justify further investigation of everolimus in the adjuvant setting; biomarker analysis will be very important to guide decisions about the use of this therapy.

Neoadjuvant therapy (giving a therapeutic agent before primary treatment) currently is not a standard of care in RCC, but it is an active area of study. The most notable recent news comes from the single-arm phase 2 NeoAvAx trial, the first neoadjuvant study to combine an IO (avelumab) with a TKI (axitinib). At ASCO GU 2022, study investigators reported a 30% rate of partial response, there were 12 responders among 40 patients with locally advanced high-risk ccRCC.31 Median primary tumor downsizing was 20%, and 10 of the 12 responders remained disease-free after a median follow-up time of 23.5 months. These are not practice-changing results, but they do suggest that neoadjuvant avelumab/axitinib exhibits some antitumor activity in RCC. More studies of IO checkpoint therapies in the neoadjuvant setting are recruiting or are planned.

Non-clear cell RCC (nccRCC) comprises about 20%-25% of RCC cases. Histologic subtypes include papillary RCC (types 1 and 2), TFE3-translocation RCC, fumarate hydratase and succinate dehydrogenase-deficient RCC, chromophobe RCC, collecting duct RCC, and medullary RCC. Among these, the papillary histotype is most common. Importantly, postsurgical prognosis in localized nccRCC varies by histology. In a recent large observational study, 5-year OS among patients with sarcomatoid or collecting duct RCC was less than 45%, far lower than in the papillary and chromophobe subtypes.32

Non-clear cell RCC conventionally has been treated with the same therapies as those used in ccRCC, but rates of response are often lower, and patients with advanced nccRCC often have a poor prognosis, making clinical trial enrollment a high priority for these patients. Completed phase 2 studies of advanced nccRCC, such as ESPN,33 ASPEN,34 and RECORD-3,35 supported the upfront use of sunitinib over everolimus. More recently, however, in the randomized, open-label, phase 2 SWOG 1500 study of patients with untreated or previously treated advanced papillary RCC, cabozantinib demonstrated superior PFS when compared with sunitinib; in this study, no benefits were seen with the TKI crizotinib or the MET inhibitor savolitinib.36

In nccRCC, as in ccRCC, we are starting to see a shift toward the use of combination regimens to treat advanced disease. In a recent phase 2 study, combined cabozantinib/nivolumab therapy demonstrated promising responses in papillary RCC but limited or absent responses in chromophobe RCC, even though this latter cohort was quite small (7 patients) and had a relatively low number of progressors.37 These findings, which were reported at ASCO 2022, underscore the expanding role and importance of histology and molecular and genetic characterization in prognostication and treatment selection. Later this year, we expect to see primary survival results from the phase 3 CONTACT-03 study, in which patients with RCC of various histologies are receiving atezolizumab/cabozantinib or cabozantinib alone.38 The investigators plan to include biomarker assays in this study.

Finally, I would like to briefly touch on the use of gene expression signatures as a tool for prognostication and treatment selection. Although this is an early area of research, studies are linking tumor gene expression with tumor aggressiveness and response to both immune checkpoint inhibition and angiogenesis blockade.37,39-41 In the phase 2 BIONIKK study, which is the first prospective, biomarker-driven randomized trial in advanced ccRCC, a 35-gene expression signature assay is used to molecularly select patients for treatment with either sunitinib, nivolumab, or nivolumab plus ipilimumab.41 Data on ORRs were reported this year and supported the feasibility of this approach, although sample sizes were small. Also, the planned phase 2 OPTIC RCC study will use genetic testing of tumor tissue to prospectively select upfront advanced RCC therapy with ipilimumab/nivolumab or nivolumab/cabozantinib.42 Results for the primary endpoint of ORR are expected in 2025.

In summary, combination regimens are clearly superior to monotherapy when treating advanced ccRCC and have become the standard of care. We are seeing a transition toward the use of immune checkpoint inhibitors earlier in the disease course, which creates an opportunity to improve patient outcomes and potentially prevent some patients from developing metastatic disease. This shift also will have implications for treatment sequencing and thus will affect therapeutic decisions in the recurrent RCC setting. Non-clear cell histologies remain understudied, but we are seeing an increase in clinical research in this orphan disease state. More work on biomarkers is needed to improve the selection of patients for active surveillance and treatment and to help patients and clinicians transition toward individualized versus empirical therapy. This will be crucial as options for doublet and triplet therapy expand in the near future.

Written by: Pedro C. Barata, MD, MSc, Associate Professor of Medicine at Case Western University and the Director of Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland, Ohio. 


1. National Comprehensive Cancer Center. NCCN Clinical Practice Guidelines in Oncology (NCCN Guideilnes). Version 4.2022 - December 21, 2021. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed June 13, 2022.
2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med. 2019;380(12):1116-1127.
3. Motzer R, Alekseev B, Rha S-Y, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. New Engl J Med. 2021;384(14):1289-1300.
4. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. New Engl J Med. 2021;384(9):829-841.
5. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma. New Engl J Med. 2018;378(14):1277-1290.
6. Motzer RJ, Tannir NM, McDermott DF, et al. 661P Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol. 2021;32:S685-S687.
7. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Analysis of progression after first subsequent therapy in KEYNOTE-426. J Clin Oncol. 2022;40(16_suppl):4513-4513.
8. Cella D, Motzer RJ, Blum SI, et al. Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC): CheckMate 9ER updated results. J Clin Oncol. 2022;40(6_suppl):323-323.
9. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jun 7;S1470-2045(22)00290-X.
10. Motzer R, Porta C, Alekseev B, et al. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022;23(6):768-780.
11. Bristol Myers Squibb. Nektar and Bristol Myers Squibb Announce Update on Clinical Development Program for Bempegaldesleukin (BEMPEG) in Combination with Opdivo (nivolumab). https://news.bms.com/news/details/2022/Nektar-and-Bristol-Myers-Squibb-Announce-Update-on-Clinical-Development-Program-for-Bempegaldesleukin-BEMPEG-in-Combination-with-Opdivo-nivolumab/default.aspx. Published April 14, 2022. Accessed June 13, 2022.
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13. Procopio G, Pircher C, Claps M, et al. A phase II open-label study of cabozantinib after first-line treatment including an immune-checkpoint combination in patients with advanced or unresectable renal cell carcinoma: The BREAKPOINT trial (MeetUro trial 03 - EudraCT number 2018-000582-36). J Clin Oncol. 2021;39(6_suppl):326-326.
14. Atkins MB, Verzoni E, Escudier B, et al. Long-term PFS from TIVO-3: Tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC. J Clin Oncol. 2022;40(6_suppl):362-362.
15. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104.
16. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958.
17. Choueiri TK, Albiges L, Hammers HJ, et al. TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor. J Clin Oncol. 2022;40(6_suppl):TPS405-TPS405.
18. Pal SK, McGregor B, Suárez C, et al. Cabozantinib in combination with atezolizumab for advanced renal cell carcinoma: results from the COSMIC-021 study. J Clin Oncol. 2021;39(33):3725-3736.
19. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. New Engl J Med. 2016;375(23):2246-2254.
20. Motzer RJ, Ravaud A, Patard J-J, et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018;73(1):62-68.
21. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008-2016.
22. Riaz IB, Siddiqi R, Islam M, et al. Adjuvant tyrosine kinase inhibitors in renal cell carcinoma: a concluded living systematic review and meta-analysis. JCO Clin Cancer Inform. 2021(5):588-599.
23. Laukhtina E, Quhal F, Mori K, et al. Adjuvant therapy with tyrosine kinase inhibitors for localized and locally advanced renal cell carcinoma: an updated systematic review and meta-analysis. Urol Oncol. 2021;39(11):764-773.
24. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. New Engl J Med. 2021;385(8):683-694.
25. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: Results from 30-month follow-up of KEYNOTE-564. J Clin Oncol. 2022;40(6_suppl):290-290.
26. Harshman LC, Puligandla M, Haas NB, et al. PROSPER: A phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN 8143). J Clin Oncol. 2019;37(15_suppl):TPS4597-TPS4597.
27. Bex A, Russo P, Tomita Y, et al. A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914). J Clin Oncol. 2020;38(15_suppl):TPS5099-TPS5099.
28. Choueiri TK, Bedke J, Karam JA, et al. LITESPARK-022: A phase 3 study of pembrolizumab + belzutifan as adjuvant treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2022;40(16_suppl):TPS4602-TPS4602.
29. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau Disease. New Engl J Med. 2021;385(22):2036-2046.
30. Ryan CW, Tangen C, Heath EI, et al. EVEREST: Everolimus for renal cancer ensuing surgical therapy—A phase III study (SWOG S0931, NCT01120249). J Clin Oncol. 2022;40(17_suppl):LBA4500-LBA4500.
31. Bex A, Abu-Ghanem Y, Thienen JVV, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J Clin Oncol. 2022;40(6_suppl):289-289.
32. An J, Packiam VT, Chennamadhavuni A, et al. Patient characteristics and survival outcomes of non-metastatic, non-clear cell renal cell carcinoma. Front Oncol. 2021;11:786307.
33. Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): A randomized multicenter phase 2 trial. Eur Urol. 2016;69(5):866-874.
34. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016;17(3):378-388.
35. Knox JJ, Barrios CH, Kim TM, et al. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol. 2017;28(6):1339-1345.
36. Pal SK, Tangen C, Thompson IM, Jr., et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703.
37. Lee C-H, Voss MH, Carlo MI, et al. Phase II Trial of cabozantinib plus nivolumab in patients with non–clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol. 2022 Mar 17;JCO2101944.
38. Pal SK, Albiges L, Suarez Rodriguez C, et al. CONTACT-03: Randomized, open-label phase III study of atezolizumab plus cabozantinib versus cabozantinib monotherapy following progression on/after immune checkpoint inhibitor (ICI) treatment in patients with advanced/metastatic renal cell carcinoma. J Clin Oncol. 2021;39(6_suppl):TPS370-TPS370.
39. Motzer RJ, Banchereau R, Hamidi H, et al. Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell. 2020;38(6):803-817.e804.
40. Reig Torras O, Mishra A, Christie A, et al. Molecular genetic determinants of shorter time on active surveillance in a prospective phase 2 clinical trial in metastatic renal cell carcinoma. Eur Urol. 2022;81(6):555-558.
41. Vano Y-A, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumab+ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncol. 2022;23(5):612-624.
42. Clinicaltrials.gov. Genetic testing to select therapy for the treatment of advanced or metastatic kidney cancer, OPTIC RCC Study. https://clinicaltrials.gov/ct2/show/NCT05361720. Accessed June 16, 2022.