Advances in kidney cancer

March marks Kidney Cancer Awareness Month. Renal cell carcinoma (RCC) ranks as the third most common urologic malignancy. In 2026, it’s estimated that there will be 80,450 new cases and 15160 deaths from RCC in the United States.¹

Only 9% of patients exhibit the classic triad of symptoms: hematuria, abdominal pain and a palpable mass. In recent years, there has been an increase in diagnoses of stage 1 RCC and a decrease in stage 4 disease, largely due to the frequent use of imaging studies, which have led to more incidental findings.

Early-stage RCC

For small renal tumors that can be removed, needle biopsies before surgery should be avoided. Kidney-sparing approaches like partial nephrectomy are preferred when possible. For tumors under 3 cm, less invasive techniques such as cryotherapy or radiofrequency ablation may be recommended. In elderly patients with other health issues, active surveillance is appropriate for small tumors. For complex tumors or those involving vascular structures, radical nephrectomy may be required.

The use of adjuvant (postoperative) therapy in renal cell carcinoma was debated for many years because earlier clinical trials using targeted therapies did not demonstrate clear benefits.

• One study called S-TRAC showed improved progression-free survival with sunitinib, a VEGF receptor tyrosine kinase inhibitor (TKI), administered for one year after nephrectomy. However, the study did not demonstrate an overall survival benefit.²
• In another trial, KEYNOTE-564, pembrolizumab was given for one year after surgery to patients with intermediate- to high-risk disease. These patients showed improved progression-free survival as well as overall survival.³ This updated trial data has established pembrolizumab as a standard of care for adjuvant therapy in patients with resected RCC.

Metastatic RCC

With modern drugs such as VEGF-TKIs and immune checkpoint inhibitors, cytoreductive nephrectomy is no longer appropriate for all patients with metastatic RCC.

A clinical trial called CARMENA showed that for patients with intermediate- to poor-risk disease, treatment with sunitinib alone produced overall survival outcomes that were not inferior to surgery followed by sunitinib.⁴ Surgery may still be appropriate for patients with low-risk, low-volume disease. In some cases, deferred surgery may be considered after initial systemic therapy if the patient has a strong response.

Many combination therapies are now approved for first-line treatment of metastatic RCC.

Nivolumab (a PD-1 inhibitor) combined with ipilimumab (a CTLA-4 inhibitor) demonstrated better overall survival than sunitinib in patients with intermediate- or poor-risk metastatic RCC. Updated data now show durable survival benefits extending to nine years.⁵

Since 2019, four combinations of VEGF TKIs and PD-1/PD-L1 inhibitors have been approved:

• Axitinib + pembrolizumab
• Axitinib + avelumab
• Cabozantinib + nivolumab
• Lenvatinib + pembrolizumab

These regimens have comparable overall survival and response rates. Common side effects include hypertension, diarrhea, fatigue and hypothyroidism.

Later-line treatment and emerging therapies

In the second- or third-line setting, several treatment options are available, including axitinib, cabozantinib, lenvatinib, sorafenib and tivozanib. Studies have shown that patients previously treated with one VEGF TKI may still experience a response to another VEGF-targeted therapy.

A recent clinical trial evaluated a novel HIF-2α inhibitor, belzutifan, in patients with metastatic RCC previously treated with VEGF-targeted therapy and immune checkpoint inhibitors. Compared with everolimus, belzutifan showed improved progression-free survival, higher response rates and a favorable toxicity profile, leading to its FDA approval.⁶

Researchers are also studying combinations of HIF-2α inhibitors such as belzutifan with immune checkpoint inhibitors or TKIs. Early-stage trials reported in 2025 have shown promising results.

For some patients with oligometastatic disease, metastasectomy or radiation therapy may also be considered as part of treatment.

Supportive treatments — including bone-targeting therapies, nutritional support and palliative care — can help improve patients’ quality of life during treatment.

Conclusion

The management of renal cell carcinoma continues to evolve as researchers deepen their understanding of tumor biology, discover new therapeutic agents and reassess traditional treatment strategies in the era of modern systemic therapies.

Participation in clinical trials remains essential for developing new treatments and improving outcomes for patients with kidney cancer.

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1. Siegel, Rebecca L., Tyler B. Kratzer, Nikita Sandeep Wagle, Hyuna Sung, and Ahmedin Jemal. “Cancer Statistics, 2026.” CA: A Cancer Journal for Clinicians (2026). https://doi.org/10.3322/caac.70043
2. Ravaud A, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med. 2016;375(23):2246-2254.
3. Choueiri TK, et al. Overall Survival Results from the Phase 3 KEYNOTE-564 Study of Adjuvant Pembrolizumab versus Placebo for Clear Cell RCC. J Clin Oncol. 2025;43:4514.
4. Méjean A, et al. Sunitinib Alone or After Nephrectomy in Metastatic Renal-Cell Carcinoma (CARMENA). N Engl J Med. 2018;379(5):417-427.
5. Motzer RJ, et al. Nivolumab Plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290. Updated long-term survival analysis published in Annals of Oncology.
6. Choueiri TK, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024;391(8):710-721.