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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Clear cell renal cell carcinoma

Managing Metastatic and Advanced ccRCC

At a Glance

Metastatic clear cell renal cell carcinoma (ccRCC) is primarily treated with systemic drug combinations, such as dual immunotherapies (IO/IO) or immunotherapy plus targeted pills (IO/TKI). Doctors use your IMDC risk score to determine the most effective first-line therapy for your specific case.

When clear cell renal cell carcinoma (ccRCC) has spread beyond the kidney (metastatic or advanced disease), the focus of treatment shifts to systemic therapies that work throughout the entire body. Today, these treatments are more effective and personalized than ever before, using your specific “risk profile” to guide the choice of medication [1][2].

The IMDC Risk Score: Mapping Your Treatment

To choose the right first-line treatment, doctors use a system called the IMDC (International Metastatic RCC Database Consortium) criteria [3]. This tool looks at six clinical factors to predict how the cancer will behave and how well you might respond to certain drugs [4][5]:

  1. Time from diagnosis to treatment less than one year [3].
  2. Performance Status: A measure of your ability to perform daily activities [3].
  3. Hemoglobin: Low red blood cell count (anemia) [3].
  4. Calcium: High levels of calcium in the blood [3].
  5. Neutrophils: High levels of a specific type of white blood cell [3].
  6. Platelets: High levels of blood-clotting cells [3].
Risk Category Number of Factors Typical Treatment Strategy
Favorable 0 Factors Often IO/TKI or TKI alone [2][6]
Intermediate 1–2 Factors IO/IO or IO/TKI combinations [7][8]
Poor 3–6 Factors IO/IO or IO/TKI combinations [7][8]

First-Line Treatment Options

The current standard of care involves using two different types of drugs together to attack the cancer from multiple angles [1].

  • IO/IO (Immuno-Oncology Combination): This uses two immunotherapy drugs (like ipilimumab plus nivolumab) to supercharge your immune system [7]. This combination is known for providing very durable, long-term responses, especially in patients in the Intermediate and Poor risk groups [9].
  • IO/TKI (Immunotherapy + Targeted Therapy): This pairs an immunotherapy drug (like pembrolizumab or nivolumab) with a Tyrosine Kinase Inhibitor (TKI) pill (like axitinib, cabozantinib, or lenvatinib) [2][8]. TKIs are the specific drugs designed to block the new blood vessel growth driven by the broken VHL/HIF pathway we discussed earlier [10].

While highly effective, TKIs have distinct side effects, including chronic diarrhea, high blood pressure, fatigue, and “hand-foot syndrome” (redness and pain in the palms and soles). Being aware of these is essential for managing your daily quality of life.

The Role of Belzutifan

Belzutifan is a newer type of drug called a HIF-2α inhibitor. It works by “turning off” the signal that tells the tumor to grow blood vessels [11][12]. Currently, it is used for patients with VHL disease and for those with advanced ccRCC whose cancer has progressed after they have already tried immunotherapy and other targeted treatments [13][14].

Surgery in Advanced Disease

In the past, most patients with metastatic kidney cancer had their primary kidney tumor removed (cytoreductive nephrectomy). However, modern research has shown that for many patients in the Intermediate and Poor risk groups, starting with systemic drug therapy is often better than having immediate surgery [15][16]. Surgery is now often “deferred” (delayed) and only considered if the drugs are working well or if the kidney tumor is causing significant pain or bleeding [17][18].

Common questions in this guide

What is an IMDC risk score for kidney cancer?
The IMDC criteria is a tool doctors use to predict how your clear cell renal cell carcinoma will behave and respond to treatments. It uses six clinical factors from your bloodwork and daily functioning to place you in a favorable, intermediate, or poor risk category.
What is the first-line treatment for metastatic ccRCC?
The current standard of care uses a combination of two systemic drugs to attack the cancer from different angles. This usually involves either two immunotherapy drugs working together, or one immunotherapy drug paired with a targeted therapy pill.
Will I need surgery to remove my kidney if the cancer has already spread?
While removing the primary kidney tumor used to be standard practice, modern treatment often starts with systemic drug therapy instead. Surgery is now frequently delayed or avoided entirely unless the kidney tumor is causing severe symptoms like bleeding or pain.
What is belzutifan and when is it used for ccRCC?
Belzutifan is a targeted medication that turns off the signal telling the tumor to grow new blood vessels. It is typically used for patients whose advanced kidney cancer has continued to grow after trying immunotherapy and other targeted therapies.
What are the common side effects of TKI targeted therapies?
Tyrosine kinase inhibitors (TKIs) can cause unique daily side effects like chronic diarrhea, high blood pressure, and fatigue. They can also cause hand-foot syndrome, which involves painful redness in the palms of your hands and soles of your feet.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What is my IMDC risk category (Favorable, Intermediate, or Poor), and how does that influence the choice between IO/IO and IO/TKI therapy?
  2. 2.Given my risk category, what are the pros and cons of an IO/IO combination versus an IO/TKI combination for me?
  3. 3.What is the goal of our first-line treatment—durable long-term response, immediate tumor shrinkage, or symptom control?
  4. 4.Should we consider a cytoreductive nephrectomy (removing the kidney) now, or should we start with systemic drug treatment first?
  5. 5.If my first treatment stops working, would I be a candidate for belzutifan or other newer targeted therapies?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (18)
  1. 1

    Approaches to First-Line Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

    Chen YW, Rini BI

    Current oncology reports 2022; (24(6)):695-702 doi:10.1007/s11912-022-01196-1.

    PMID: 35247142
  2. 2

    Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

    Choueiri TK, Powles T, Burotto M, et al.

    The New England journal of medicine 2021; (384(9)):829-841 doi:10.1056/NEJMoa2026982.

    PMID: 33657295
  3. 3

    Serum Lactate Dehydrogenase Before Nivolumab Treatment Could Be a Therapeutic Prognostic Biomarker for Patients With Metastatic Clear Cell Renal Cell Carcinoma.

    Shirotake S, Takamatsu K, Mizuno R, et al.

    Anticancer research 2019; (39(8)):4371-4377 doi:10.21873/anticanres.13606.

    PMID: 31366532
  4. 4

    Contemporary Treatment of Metastatic Renal Cell Carcinoma.

    Stukalin I, Alimohamed N, Heng DY

    Oncology reviews 2016; (10(1)):295 doi:10.4081/oncol.2016.295.

    PMID: 27471582
  5. 5

    Addition of Primary Metastatic Site on Bone, Brain, and Liver to IMDC Criteria in Patients With Metastatic Renal Cell Carcinoma: A Validation Study.

    Massari F, Di Nunno V, Guida A, et al.

    Clinical genitourinary cancer 2021; (19(1)):32-40 doi:10.1016/j.clgc.2020.06.003.

    PMID: 32694008
  6. 6

    Risk Stratification and Treatment Algorithm of Metastatic Renal Cell Carcinoma.

    Grimm MO, Leucht K, Foller S

    Journal of clinical medicine 2021; (10(22)) doi:10.3390/jcm10225339.

    PMID: 34830621
  7. 7

    New First Line Treatment Options of Clear Cell Renal Cell Cancer Patients with PD-1 or PD-L1 Immune-Checkpoint Inhibitor-Based Combination Therapies.

    Grimm MO, Leucht K, Grünwald V, Foller S

    Journal of clinical medicine 2020; (9(2)) doi:10.3390/jcm9020565.

    PMID: 32092974
  8. 8

    Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

    Motzer R, Alekseev B, Rha SY, et al.

    The New England journal of medicine 2021; (384(14)):1289-1300 doi:10.1056/NEJMoa2035716.

    PMID: 33616314
  9. 9

    Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.

    Motzer RJ, Tannir NM, McDermott DF, et al.

    The New England journal of medicine 2018; (378(14)):1277-1290 doi:10.1056/NEJMoa1712126.

    PMID: 29562145
  10. 10

    Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

    Rathmell WK, Rumble RB, Van Veldhuizen PJ, et al.

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2022; (40(25)):2957-2995 doi:10.1200/JCO.22.00868.

    PMID: 35728020
  11. 11

    Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan.

    Ren X, Diao X, Zhuang J, Wu D

    Molecular pharmacology 2022; (102(6)) doi:10.1124/molpharm.122.000525.

    PMID: 36167425
  12. 12

    Targeting HIF-2α and anemia: A therapeutic breakthrough for clear-cell renal cell carcinoma.

    Rioja P, Rey-Cardenas M, De Velasco G

    Cancer treatment reviews 2024; (129()):102801 doi:10.1016/j.ctrv.2024.102801.

    PMID: 39032449
  13. 13

    Belzutifan: a novel therapy for von Hippel-Lindau disease.

    Zhou J, Gong K

    Nature reviews. Nephrology 2022; (18(4)):205-206 doi:10.1038/s41581-022-00544-5.

    PMID: 35132216
  14. 14

    Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma.

    Choueiri TK, Powles T, Peltola K, et al.

    The New England journal of medicine 2024; (391(8)):710-721 doi:10.1056/NEJMoa2313906.

    PMID: 39167807
  15. 15

    Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma.

    Bex A, Albiges L, Ljungberg B, et al.

    European urology 2018; (74(6)):805-809 doi:10.1016/j.eururo.2018.08.008.

    PMID: 30177291
  16. 16

    Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.

    Méjean A, Ravaud A, Thezenas S, et al.

    The New England journal of medicine 2018; (379(5)):417-427 doi:10.1056/NEJMoa1803675.

    PMID: 29860937
  17. 17

    Deferred cytoreductive nephrectomy in the management of metastatic renal cell carcinoma: A systematic review and meta-analysis.

    Britton CJ, Andrews JR, Wallis CJD, et al.

    Urologic oncology 2023; (41(3)):125-136 doi:10.1016/j.urolonc.2022.09.021.

    PMID: 38832909
  18. 18

    Predictors of survival after cytoreductive nephrectomy in metastatic renal cell carcinoma: A Real-world perspective.

    Menon AR, Pooleri GK, Sukumaran SV, et al.

    Indian journal of urology : IJU : journal of the Urological Society of India 2025; (41(4)):277-286 doi:10.4103/iju.iju_179_25.

    PMID: 41112722

This page provides educational information about metastatic ccRCC treatments and IMDC risk scores. It does not replace professional medical advice or treatment recommendations from your oncology team.

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