Advances in Therapeutic Strategies for Advanced Renal Cell Carcinoma: A Comprehensive Review

Pedro Barata | February 21, 2024

Advanced renal cell carcinoma (RCC) accounts for about 2% of cancer deaths globally, and its incidence is increasing in the United States and worldwide.1 Clear cell RCC (ccRCC) comprises about 75% of RCCs and is the most aggressive subtype, although survival rates are substantially improving with the advent of targeted systemic therapies and immune checkpoint inhibitors. In this editorial, I update readers on current therapeutic approaches for patients with advanced RCC, including clear cell and other histotypes. I also review the role of (neo)adjuvant treatment and biomarkers in advanced RCC management.

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Pedro Barata, MD, MSc

Pedro Barata, MD, MSc, FACP is a board-certified, fellowship-trained medical oncologist at University Hospitals Seidman Cancer Center and an Associate Professor of Medicine at Case Western Reserve University. Dr Barata serves as the director of the clinical genitourinary medical oncology research program and the co-leader of the genitourinary disease team at Seidman Cancer Center. He is a clinical trialist and his research interests include cancer genomic profiling and novel therapeutics for genitourinary tumors.

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Written by Zachary Klaassen, MD, MSc
March 31, 2021
Cancers of the kidney and renal pelvis (when considered in aggregate despite different histology) represent the 6th most common newly diagnosed tumors in men and 8th most common in women in the United States in 20201, representing an estimated 73,750 new diagnoses and 14,830 deaths.
Written by Jason Zhu, MD
January 29, 2019
Kidney cancer represents 5% of all new cancer diagnoses in the United States, with approximately 64,000 new cases and 14,970 deaths in 2018.1,2 The most common type of kidney cancer is renal cell carcinoma (RCC) and the most common histologic subtype of RCC is clear cell RCC, accounting for over 80% of cases.3
January 21, 2019
As highlighted in prior articles on the Etiology and Epidemiology of Kidney Cancer, cancers of the kidney and renal pelvis comprise the 6th most common newly diagnosed tumors in men and 10th most common in women1 and account for an estimated 65,340 people new diagnoses and 14,970 cancer-related deaths in 2018 in the United States.
Written by Jason Zhu, MD
November 29, 2018
Kidney cancer is the 12th most common cancer in the world, with over 300,000 new cases annually, of which 65,340 new cases will be diagnosed in the United States in 2018.1 The incidence of renal cell carcinoma (RCC) varies substantially based on the country – rates of RCC are higher in Europe and North America and much lower in Asia and South America.2
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Peer-reviewed Abstract Supplemental Commentaries
Written by Matthew D. Tucker, MD
Immunotherapy-based combinations have had a dramatic improvement in outcomes for patients with metastatic renal cell carcinoma, with some patients having deep and durable responses. Developing biomarkers to predict which patients are most
Written by Zhamshid Okhunov, MD
Department of Urology, University of California, Irvine Urology
Though nephrectomy is the gold standard treatment for renal cell carcinoma, 20%-40% of patients have a recurrence and 20-30% of patients present with metastatic disease1.
Written by Zhamshid Okhunov, MD
Department of Urology, University of California, Irvine Urology
Partial nephrectomies are the standard of care with treatment of T1a or T1b tumors due to their better functional outcomes and decrease cardiovascular morbidity.
Written by Zhamshid Okhunov, MD
Department of Urology, University of California, Irvine Urology
Laparoscopic renal surgery (LRS) has long been recognized for its improvements over open renal surgery for patient quality of life.
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Conference Highlights Written by Physician-Scientist
Presented by Thomas Powles, MBBS, MRCP, MD
Thomas Powles presented the patient-reported outcomes from the phase 3 LITESPARK-005 study of belzutifan versus everolimus in patients with previously treated advanced renal cell carcinoma (RCC).
Presented by Ulka N. Vaishampayan, MBBS

Ulka Vaishampayan delivered the discussant for the preceding two presentations: Subcutaneous nivolumab (NIVO SC) versus intravenous nivolumab in patients with previously treated advanced or metastatic clear cell renal cell carcinoma: Pharmacokinetics, efficacy, and safety results from CheckMate 67T and Belzutifan versus everolimus in participants with previously treated advanced renal cell carcinoma: Patient-reported outcomes in the phase 3 LITESPARK-005 study.

Presented by Saby George, MD, FACP
Saby George presented the late-breaking pharmacokinetics, efficacy, and safety results from CheckMate 67T comparing subcutaneous and intravenous nivolumab in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (RCC).
Presented by Sophia C. Kamran, MD

Sophia Kamran discussed the role of radiation therapy for the management of RCC primary tumors and distant metastatic sites. Dr. Kamran noted that the ‘historical teaching’ is that radiation is not effective for RCC in either the primary or metastatic setting, with radiation primarily reserved for palliative purposes. But in contemporary practice, is RCC radioresistant?

Presented by Toni K. Choueiri, MD
The 2024 GU ASCO annual meeting featured an oral abstract renal cell carcinoma session and a presentation by Dr. Toni Choueiri discussing overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma.
Presented by Andrea B. Apolo, MD

Dr. Andrea Apolo delivered the discussant for the preceding two late-breaking oral abstract presentations: EV-302/KEYNOTE-A39: Open-Label, Randomized Phase 3 Study of Enfortumab Vedotin in Combination with Pembrolizumab (EV+P) Vs Chemotherapy (Chemo) in Previously Untreated Locally Advanced Metastatic Urothelial Carcinoma (la/mUC), Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: results from the phase 3 CheckMate 901 trial

 

Presented by Neeraj Agarwal, MD
During the 2023 ESMO annual congress, Dr. Neeraj Agarwal presented the results of the phase II LITESPARK-013 study that evaluated the safety and efficacy of two doses of belzutifan in patients with advanced renal cell carcinoma (RCC).
Presented by Brian Rini, MD, FASCO
Dr. Brian Rini kicked off the initial talk of the SUO session at the AUA 2023 Annual Meeting, focusing on the management of metastatic non-clear cell renal cell carcinoma (nccRCC). First, he focused on papillary renal cell carcinoma (RCC).
Presented by Toni K. Choueiri, MD
The Presidential Symposium III at the ESMO Annual Congress, Dr. Chouieri presented highly awaited results from the COSMIC-313 trial, examining the role of triplet therapy with cabozantinib, nivolumab and ipilimumab as first-line treatment in patients with advanced renal cell carcinoma (aRCC).
Presented by Kate Young, MD
Following presentations from Dr. Camillo Porta discussing updated results from the CLEAR trial on outcomes of the combination of Lenvatinib and pembrolizumab as first-line therapy in advanced renal cell carcinoma (RCC) and from Dr. Grimm discussing a tailored approach using nivolumab either as monotherapy or in combination with ipilimumab in metastatic RCC, Dr. Young provided an invited discussion to contextualize these results in the Mini Oral session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers.
Presented by Marc-Oliver Grimm, MD
At the ESMO Annual Congress focusing on non-prostate genitourinary cancers, Dr. Grimm presented the final results of the TITAN-RCC trial, assessing a tailored approach to systemic therapy in patients with metastatic renal cell carcinoma (mRCC).
Presented by Camillo G. Porta, MD, Professor, Bari, Italy
In the Mini Oral session of the ESMO Annual Congress focusing on non-prostate genitourinary cancers, Dr. Porta provided an updated analysis of the CLEAR trial examining the role of the combination of lenvatinib and pembrolizumab, as compared to sunitinib, as first-line therapy in advanced renal cell carcinoma (aRCC).
Presented by Thomas Powles, MD
The 2022 ASCO annual meeting featured a poster discussion session on kidney and bladder cancer, including a presentation by Dr. Tom Powles discussing an analysis of progression after first subsequent therapy in KEYNOTE-426, which tested pembrolizumab + axitinib versus sunitinib as first-line therapy for advanced clear cell RCC.
Presented by Eric Jonasch, MD,
The 2022 ASCO annual meeting featured a session on kidney and bladder cancer, including a presentation by Dr. Eric Jonasch discussing updated results of the LITESPARK-004 phase 2 study of belzutifan, an oral hypoxia-inducible factor 2α inhibitor (HIF-2α), for von Hippel-Lindau (VHL) disease.
Presented by Daniel Shapiro, MD
The 2022 American Urological Association (AUA) Annual Meeting included the Society of Urologic Oncology (SUO) session and a presentation by Dr. Daniel Shapiro discussing the role of cytoreductive nephrectomy in 2022.
Presented by Will Ince, FRCR, MRCP, MRCGP, MB BS
The 2022 International Kidney Cancer Symposium (IKCS) European Annual meeting included an oral abstract session and presentation by Dr. Will Ince discussing the real world impact of immune checkpoint inhibitors on survival in metastatic RCC.
Presented by Laurence Albiges, MD, PhD,
In the sixth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on later-lines of systemic therapy in advanced kidney cancer, Drs. Camillo Porta and Laurence Albiges debated the approach to second-line therapy in metastatic renal cell carcinoma (mRCC).
Presented by Camillo Porta, MD
In the sixth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on later lines of systemic therapy in advanced kidney cancer, Drs. Camillo Porta and Laurence Albiges debated the approach to second-line therapy in metastatic renal cell carcinoma (mRCC). Dr. Porta presented first, emphasizing evidence-based second line treatment approaches.
Presented by Lisa Pickering, MD, PhD
In the fifth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on first-line systemic therapy in advanced kidney cancer (metastatic renal cell carcinoma, mRCC), Dr. Pickering presented the first side of a debate regarding treatment selection, defending the approach of immune checkpoint inhibition combined with tyrosine kinase inhibitor (IO/TKI).
Presented by Aristotelis Bamias, MD, PhD
In the fifth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on first-line systemic therapy in advanced kidney cancer, Dr. Aristotelis Bamias presented the second side of the debate regarding treatment selection, defending the approach of dual immune checkpoint inhibition with nivolumab and ipilimumab.
Presented by Bernard Escudier, MD,
The 2022 International Kidney Cancer Symposium (IKCS) European Annual meeting included an oral abstract session and presentation by Dr. Bernard Escudier discussing nivolumab + ipilimumab + cabozantinib for previously untreated advanced renal cell carcinoma (RCC), which was a discontinued study arm in the phase 3 CheckMate 9ER trial.
Presented by Sun Young Rha MD, PhD
In Poster Session C on the third day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 focused on Renal Cell Cancer; Adrenal, Penile, Urethral, and Testicular Cancers. In this session, Dr. Rha presented subgroup analyses of efficacy and safety from the CLEAR trial of Lenvatinib and pembrolizumab among East Asian patients with advanced renal cell carcinoma (aRCC).
Presented by David Cella, PhD
The 2022 GU ASCO Annual meeting included a renal cell carcinoma (RCC) session highlighting work from Dr. David Cella and investigators presenting results assessing HRQoL in previously untreated patients with advanced renal cell carcinoma in the CheckMate 9ER trial. 
Presented by Axel Bex, MD, PhD
In an oral abstract Dr. Axel Bex presented results of the NeoAvAx study examining neoadjuvant avelumab and axitinib following nephrectomy for patients who are at high risk for recurrence.
Presented by Toni K. Choueiri, MD
In an oral abstract Dr. Toni Choueiri presented 30-month follow-up from the KEYNOTE-564 trial of post-nephrectomy adjuvant pembrolizumab in patients with renal cell carcinoma (RCC).
Presented by Martin H Voss, MD
Dr. Martin Voss presented the PIVOT IO 011 study, a phase 1/2 study evaluating of bempegaldesleukin plus nivolumab and TKI versus nivolumab and TKI alone in patients with previously untreated advanced or metastatic RCC.
Presented by Toni K. Choueiri MD
Dr. Toni Choueiri presented the rationale and design of the TiNivo-2 trial, examining tivozanib with or without nivolumab in patients with renal cell carcinoma (RCC) who have progressed following one or two lines of therapy, one of which was an immune checkpoint inhibitor.
Presented by Neil Shah, MBBS
Dr. Neil Shah and colleagues presented results of a real-world assessment of changing treatment patterns and sequence for patients with metastatic renal cell carcinoma in the first-line setting. 
Presented by Robert Dreicer, MD, MS, MACP, FASCO
The SUO 2021 annual meeting in Orlando, FL hosted a second State of the Art Lecture by Dr. Robert Dreicer, MD, MS, MACP, FASCO discussing adjuvant therapy for kidney cancer.
Presented by Kevin Lu, MD
The SIU 2021 annual meeting included a master class on advanced kidney cancer with a presentation by Dr. Kevin Lu discussing nephrectomy as part of the sequencing options in metastatic renal cell carcinoma (RCC) with the primary in place.
Presented by Pedro C. Barata, MD, MSc

At the 2021 International Kidney Cancer Symposium (IKCS): North America meeting, Dr. Barata presented their work examining gene expression profiling (GEP) in non-clear cell renal cell carcinoma. They employed DNA/RNA next-generation sequencing of tumor samples from the Caris Life Sciences lab. They defined molecular subgroups according to the criteria set out by Motzer et al. and examined 7 clusters.

Presented by Bradley McGregor, MD
The International Kidney Cancer Symposium 2021 annual hybrid meeting included a non-clear cell renal cell carcinoma (RCC) session and a presentation by Dr. Bradley McGregor discussing recent and future studies of systemic therapy for non-clear cell RCC.
Presented by Toni K. Choueiri, MD
In a session of the 2021 International Kidney Cancer Symposium (IKCS): North America meeting focused on the role and effects of adjuvant immunotherapy in renal cell carcinoma (RCC) on subsequent first-line therapy, Dr. Choueiri provided an overview of his perspective of the future of adjuvant therapy in this disease space.
Presented by Toni K. Choueiri, MD
In this presentation, Dr. Toni Choueiri discussed patient-reported outcomes (PROs) from KEYNOTE-564, a randomized phase 3 study of adjuvant Pembrolizumab versus placebo in patients with renal cell carcinoma (RCC).
Presented by Naveen S. Vasudev, PhD, MRCP, MBChB, BMSc (Hons)
The ESMO 2021 annual meeting’s non-prostate cancer proffered paper session included a presentation by Dr. Naveen Vasudev discussing results of the phase II PRISM trial assessing nivolumab combination with alternatively scheduled ipilimumab in first-line treatment of advanced renal cell carcinoma (RCC).
Presented by Yann Vano, MD
The ESMO 2021 virtual annual meeting’s non-prostate cancer session included a presentation by Dr. Yann Vano discussing the CABIR study of patients receiving cabozantinib-nivolumab versus nivolumab-cabozantinib after receiving a prior VEGFR TKI for metastatic clear cell RCC. Nivolumab and cabozantinib are two approved agents after a prior TKI in metastatic RCC patients.
Presented by Brina Rini, MD
The ESMO 2021 annual meeting’s non-prostate cancer session included a presentation by Dr. Brian Rini discussing a new 3-arm phase 3 trial concept and design, which will randomize patients with advanced clear cell RCC in the first-line setting to either pembrolizumab + belzutifan + lenvatinib versus MK-1308A + lenvatinib versus pembrolizumab + lenvatinib.
Presented by Robert J. Motzer, MD
The ESMO 2021 virtual annual meeting’s non-prostate cancer session included a presentation by Dr. Robert Motzer discussing updated data from the CheckMate 214 trial with 5-years of follow-up.
Presented by Toni K. Choueiri, MD
The ESMO 2021 annual meeting’s non-prostate cancer session included a presentation by Dr. Toni Choueiri discussing outcomes of subgroup analyses and a toxicity update among patients in the phase 3 CLEAR trial for advanced renal cell carcinoma (RCC).
Presented by Toni K. Choueiri. MD
In this presentation, Dr. Toni Choueiri presented results from KEYNOTE-564, a study of adjuvant pembrolizumab administered for one year after complete surgical resection of clear cell RCC. The eligibility and study design are shown below. The primary endpoint was disease-free survival by investigator assessment. 
Presented by Rana R. McKay, MD
The much anticipated ASCO 2021 annual program plenary session included a discussant presentation by Dr. Rana McKay providing her expertise on the recently presented KEYNOTE 564 phase 3 trial with her talk entitled “A Quantum Leap in Cancer Adjuvant Immunotherapy”.
Presented by Ramaprasad Srinivasan, M.D., Ph.D

Building on the presentations from Dr. Linehan regarding the genetic causes of renal cell carcinoma (RCC) and from Dr. McDermott regarding current and future direction for immunotherapy in RCC, Dr. Srinivasan presented on challenges and emerging strategies for systemic therapy in kidney cancer.

Presented by David F. McDermott, MD
The European International Kidney Cancer Symposium 2021 virtual meeting’s keynote lecture was provided by Dr. David McDermott discussing kidney cancer as a model for a curable neoplasm. 
Presented by Yann-Alexandre Vano, MD
Dr. Vano discussed biomarker-driven trials. He first argued for the rationale of biomarker-driven trials based on the rationale that metastatic kidney cancer represents an incurable disease and current therapies have significant toxicity. He further emphasized that, based on drug development over the past two decades, there are many treatment options in mRCC that improve survival.
Presented by Thomas Powles, MBBS, MRCP, MD
The European International Kidney Cancer Symposium 2021 Virtual Meeting included a systemic therapy session and a presentation by Dr. Thomas Powles discussing tissue-based biomarkers for potential clinical adoption in renal cancer.
Presented by Camillo Porta, MD
To help guide treatment choices for those who progress on first-line therapy, Dr. Camillo Porta discussed modern therapeutic approaches in second-line and later therapies in a presentation at the European International Kidney Cancer 2021 Virtual Annual Meeting.
Presented by Stephanie A. Berg, DO
Following presentations by Dr. Robert Motzer discussing results of the CLEAR study of lenvatinib plus pembrolizumab or everolimus versus sunitinib in first-line treatment of advanced renal cell carcinoma and by Dr. Sumanta Pal looking at the SWOG 1500 trial of sunitinib, cabozantinib, crizotinib, and savolitinib in patients with metastatic papillary renal cell carcinoma.
Presented by Brian I. Rini, MD
The activity of tivozanib after axitinib has not been previously defined, and as such the activity of tivozanib after prior therapy types including axitinib is of clinical relevance. At the 2021 ASCO GU, Dr. Brian Rini and colleagues presented results of the TIVO-3 trial testing tivozanib in patients with advanced RCC who had progressed after prior axitinib treatment.
Presented by David Cella, PhD
The treatment landscape for first-line therapy among patients with metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 2 years. In 2018, publication of the CheckMate214 data demonstrated a survival benefit for patients treated with nivolumab and ipilimumab compared with sunitinib in intermediate and poor-risk mRCC, ushering in the immunotherapy era for mRCC.
Presented by Andrea B. Apolo, MD
Cabozantinib, nivolumab, and ipilimumab have been increasingly utilized for a number of genitourinary malignancies, most prominently in renal cell carcinoma. In a dose-escalation study, combinations of cabozantinib and nivolumab (CaboNivo) and cabozantinib, nivolumab, and ipilimumab (CaboNivoIpi) demonstrated promising efficacy and safety in a dose-escalation phase I study.
Presented by Toni Choueiri, MD, MS
In this state-of-the-art presentation, Dr. Toni Choueiri gave an overview of the management of advanced kidney cancer. Several years ago, before the era of immunotherapy, when vascular endothelial growth factor (VEGF) receptor inhibitors were compared and used to treated advanced kidney cancer patients, the median overall survival was only 13 months.
Presented by Yann-Alexandre Vano, MD, PhD
Sunitinib was standard first line treatment for metastatic clear cell renal cell carcinoma (mccRCC) for many years until multiple clinical trials showed superior efficacy of various treatment combinations including nivolumab and ipilimumab in International Metastatic RCC Database Consortium (IMDC) intermediate or poor-risk disease.
Presented by Tim Q. Eisen, PhD, MB, BChir
Barcelona, Spain (UroToday.com) Four large, randomized Phase 3 clinical trials (S-TRAC, ASSURE, PROTECT, and ATLAS) evaluated adjuvant VEGF tyrosine kinase inhibitors in patients with resected renal cell carcinoma (RCC).
Presented by Axel Bex, MD, PhD
Barcelona, Spain (UroToday.com) The current standard for advanced localized renal cell carcinoma (RCC) is nephrectomy. Unfortunately, for better or worse, the series of adjuvant therapy
Presented by Marc-Oliver Grimm
Barcelona, Spain (UroToday.com) Dr. Marc-Oliver Grimm provided an overview of the many changes in the landscape for advanced renal cell carcinoma at the urogenital cancer treatment at a glance session. He started by highlight that the guidelines for advanced kidney cancer have been revamped recently
Presented by Cristina Suarez, MD
Munich, Germany (UroToday.com) IMmotion 150 (Phase II) compared the efficacy of atezolizumab (atezo) plus bevacizumab (bev) with atezolizumab alone and sunitinib alone