Renal Cell Carcinoma (Hypernephroma): Drug Therapy

Therapeutic target

Prolonging survival in metastatic renal cell carcinoma (RCC).

Therapy recommendations

• Therapy procedure of first choice is surgery.
• In metastatic clear cell renal cell carcinoma (approximately 75-80% of cases):
  • first-line therapy for metastatic renal cell carcinoma (mNCC) should be risk-adapted [S3 guideline]Criteria for this are: 6 International Metastatic RCC Database Consortium (IMDC) criteria: Anemia (anemia), neutrophilia (increase in the number of neutrophil granulocytes in the blood), thrombocytosis (increased number of platelets (thrombocytes) in the blood), hypercalcemia (calcium excess), Karnofsky index 80%, time to relapse after initial diagnosis (12 months).
    • Median overall survival:
      • Without risk factors: 43 months
      • Intermediate risk profile (one or 2 risk factors): 22, 5 months.
      • > 2 risk factors: 7, 8 months
  • cytokine therapy based on subcutaneous IL-2 and/or IFN alone should not be performed [recommendation grade A]The standard is always a combination therapy of two immunotherapeutics or of one immunotherapeutic and a tyrosine kinase inhibitor (TKI).
    • Low- or intermediate-risk patients should use sunitinib, pazopanib, or bevacizumab + INF in first-line therapy
      • Second-line therapy is TKI-based therapy.
      • Only after failure of at least one VEGF inhibitor should everolimus be used.
• If multiple metastases (daughter tumors) occur metachronously (“occurring at different times”) in only one organ system, local (topical) treatment should be considered.
• See also under “Further therapy”.

Further notes on clear cell renal cell carcinoma.

• Stratification into patients with favorable prognosis on one side and intermediate or unfavorable prognosis on the other side is performed to plan the first line of therapy.
  • Patients with favorable prognosis:
    • First-line therapy: bevacizumab/IFN; pazonib, sunitinib, tivozanib.
    • Second-line therapy: VEGFR failure: cabozantinib, nivolumab, lenvatinib/everolib.
    • Third-line therapy: see below.
  • Patients with intermediate prognosis:
    • First-line therapy: nivolumab + ipilimumab, carbozantinib.
    • Second-line therapy: CPI failure: no standard, cabozantinib, lenvatinib/everolism, other TKIs.
    • Third-line therapy: see below.
  • Patients with unfavorable prognosis:
    • First-line therapy: nivolumab + ipilimumab, cabozantinib, temsirolism.
    • Second-line therapy: mTor.failure: no standard, cabozantinib, nivolumab, lenvatinib/everolism, other TKIs.
    • Third-line therapy: see below.
  • Third-line therapy:
    • After TKI + TKI: cabozantinib, nivolumab, everolism.
    • After TKI + mTort: no standard, cabozantinib, nivolumab.
    • After TKI + CPI: no standard, cabozantinib, lenvatinib/everolumab.
    • After CPI + TKI: no standard, other TKI, everolism, lenvatinib/everolism.

Legend: IFNI: Interferon, TKI: tyrosine kinase inhibitor, CPI: checkpoint inhibition, VEGFR: vascular endothelial growth factor receptor, mTOR: mechanistic target of rapamycin.

Additional notes

• In a study of high-risk hypernephroma patients, patients treated with sunitinib relapsed in 6.8 years. In the placebo group, relapse occurred after 5.4 years.
• Second-line therapy with the PD-1 inhibitor (checkpoint inhibitor) nivolumab as another pillar of immunotherapeutic treatment: this blocks the receptor PD-1 on activated T lymphocytes and thus prevents the interaction with the ligand PD-L1 on other immune and tumor cells. This leads to the originally inhibited T cells being able to attack the tumor again. In a study, a significantly prolonged overall survival was shown compared to therapy with everolimus.
• The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive marketing authorization recommendation for avelumab in combination with axitinib for the first-line treatment of adult patients with advanced renal cell carcinoma (based on positive results from the phase III JAVELIN Renal 101 study: significant prolongation of median
• A combination therapy of VEGF and checkpoint inhibitors as first-line therapy for advanced renal cell carcinoma:
  • Avelumab/auxitinib prolonged progression free survival (PFS).
  • Pembrolizumab/auxitinib prolonged overall survival (OS).

  Both combinations have the potential to become new standards of first-line therapy.

• Bisphosphonates should be used for bone metastases; in addition to local radiatio (radiotherapy).

Agents (main indication)