Teaching pack: Renal cell carcinoma

Renal cell carcinoma is a cancer of the kidney's tubules, increasingly found by chance on scans done for other reasons. Three quarters are clear-cell tumours defined by loss of the VHL gene, which leaves the oxygen-sensing HIF-2α switch permanently on and makes the tumour intensely vascular and immune-infiltrated. That biology explains the whole modern treatment story: anti-VEGF pills (2005-2012), immunotherapy (2015 onward), their combination (2018 onward), and the first HIF-2α inhibitor, belzutifan (2021).

For metastatic disease, four immunotherapy-based first-line regimens have survival benefit: nivolumab-ipilimumab (CheckMate 214, durable remissions in a fifth of intermediate/poor-risk patients, still visible at eight years) and three IO-TKI doublets (pembrolizumab-axitinib, nivolumab-cabozantinib, lenvatinib-pembrolizumab). Attempts to do better in first line with triplets failed on survival (COSMIC-313) or fell short (LITESPARK-012), and two trials (CONTACT-03, TiNivo-2) showed that restarting immunotherapy after it fails does not help. After surgery, adjuvant pembrolizumab (KEYNOTE-564) was the first adjuvant immunotherapy in any solid tumour to improve overall survival, and in 2026 belzutifan plus pembrolizumab (LITESPARK-022) became the first adjuvant combination, though three other adjuvant immunotherapy trials were negative.

• Adjuvant immunotherapy with OS benefit.
• HIF-2α inhibition.
• Four immunotherapy-based first-line regimens with survival benefit; durable remissions off treatment in ~20% with nivolumab-ipilimumab at 8 years.
• Adjuvant pembrolizumab improves overall survival (KEYNOTE-564); pembrolizumab + belzutifan approved as adjuvant combination (2026).
• Belzutifan validates HIF-2α as a target in VHL disease and pretreated RCC.
• Two negative rechallenge trials (CONTACT-03, TiNivo-2) and two failed first-line intensification trials (COSMIC-313, LITESPARK-012) have sharpened the algorithm rather than widened it.

1. 1992High-dose IL-2 approved
2. 1992High-dose IL-2 approved: first immunotherapy for RCC, with rare cures
3. 1993VHL gene identified; the molecular basis of clear-cell RCC
4. 2001Cytoreductive nephrectomy improves survival with interferon (SWOG 8949)
5. 2005Sorafenib/sunitinib: VEGF era
6. 2005Sorafenib approved: first VEGF-pathway TKI in RCC
7. 2006Sunitinib approved; replaces interferon
8. 2009Everolimus approved second line (RECORD-1)
9. 2012Axitinib approved (AXIS)
10. 2015Nivolumab beats everolimus (CheckMate 025): immunotherapy returns to RCC

• Raludotatug deruxtecan (product)
• Intismeran autogene (product)
• LITESPARK-022 (trial)
• CAIX PET (89Zr-girentuximab) (technology)
• CAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy (idea)
• Biomarker-selected adjuvant therapy in RCC (ctDNA, CAIX PET, gene signatures) (idea)
• Belzutifan (product)
• IMDC risk → first-line regimen choice (RCC) (pairing)
• Caution: PD-1 rechallenge after progression on immunotherapy (RCC) (pairing)
• Allogeneic (off-the-shelf) cell therapy (technology)
• Partial nephrectomy, ablation & active surveillance of small renal masses (technology)
• Radio-antibody & radio-ADC (technology)

• CheckMate 214 (phase 3, n=1,096): Overall survival, intermediate/poor risk (8-year follow-up): pending
• KEYNOTE-426 (phase 3, n=861): Overall survival (final, 5-year): 47.2 months vs 40.8 months, HR 0.84
• CLEAR (KEYNOTE-581) (phase 3, n=1,069): Progression-free survival: 23.9 months vs 9.2 months, HR 0.39
• CheckMate 9ER (phase 3, n=651): Progression-free survival: 16.6 months vs 8.3 months, HR 0.51
• LITESPARK-005 (phase 3, n=746): Progression-free survival: pending
• COSMIC-313 (phase 3, n=855): Progression-free survival: pending

• Non-clear-cell histologies understudied.
• No validated predictive biomarker for IO.
• No predictive biomarker to choose between IO-IO and IO-TKI, or to identify the 20% who achieve durable remission.
• Adjuvant therapy treats many who would never relapse; ctDNA shedding is too low for standard MRD approaches.
• Favourable-risk disease has no proven OS benefit from any first-line combination.
• Non-clear-cell histologies lack dedicated phase 3 evidence.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
3. What was the first personalised cancer vaccine to win a phase 3 trial?
   Answer

   Intismeran autogene (V940/mRNA-4157, Moderna/Merck) with pembrolizumab in resected stage IIB-IV melanoma: INTerpath-001 met recurrence-free and distant-metastasis-free survival, announced 19 August 2026.
4. How is a personalised mRNA cancer vaccine made?
   Answer

   The tumour and normal DNA are sequenced, software predicts up to 34 neoantigens unique to the tumour, a patient-specific mRNA encoding them is manufactured in lipid nanoparticles over about six weeks, and it is given with a PD-1 blocker.
5. What were the first checkpoint inhibitor and the first ADC ever approved?
   Answer

   Ipilimumab (2011) was the first checkpoint inhibitor; gemtuzumab ozogamicin (Mylotarg, 2000) was the first ADC, withdrawn in 2010 and re-approved in 2017.
6. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.

• NCI PDQ: renal cell cancer treatment: https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq
• CheckMate 214 8-year follow-up: https://www.annalsofoncology.org/article/S0923-7534(24)01516-3/fulltext
• Wikipedia: https://en.wikipedia.org/wiki/Renal_cell_carcinoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440