What is the best evidence-based systemic therapy and role of adjuvant radiotherapy for a 67-year-old male with newly diagnosed metastatic renal cell carcinoma (RCC), International Metastatic Renal Cell Carcinoma Database (IMDC) poor risk presentation, right humerus fracture post-operative plating, and lung metastases shown on Computed Tomography (CT) scan?

Systemic Therapy for IMDC Poor-Risk Metastatic RCC with Bone Metastasis

For this 67-year-old gentleman with IMDC poor-risk metastatic clear cell RCC and bone metastasis, initiate cabozantinib-nivolumab combination therapy immediately, as this regimen demonstrates superior outcomes specifically in poor-risk patients with bone metastases. 1

First-Line Systemic Therapy Selection

Cabozantinib-nivolumab is the preferred regimen for IMDC poor-risk disease with bone involvement, showing improved PFS (HR 0.34; 95% CI 0.22-0.55) and OS (HR 0.54; 95% CI 0.32-0.92) compared to sunitinib in the bone metastases subgroup 1. This combination addresses both the poor-risk status and the bone-specific disease burden 1.

Alternative First-Line Options (if cabozantinib-nivolumab unavailable):

• Lenvatinib-pembrolizumab: Demonstrated significant OS advantage (HR 0.66,95% CI 0.49-0.88, P=0.005) with median OS not reached versus sunitinib 2, 3. This combination showed 71% ORR versus 36% for sunitinib, with median PFS of 23.9 months 2, 3.

• Ipilimumab-nivolumab: Specifically recommended for IMDC intermediate- and poor-risk disease 2. This dual checkpoint inhibitor approach is appropriate for poor-risk patients 2.

• Axitinib-pembrolizumab: Demonstrated efficacy in the ITT population with PFS HR 0.69 (95% CI 0.56,0.84) 4, though less bone-specific data than cabozantinib combinations.

Single-agent TKI monotherapy (sunitinib, pazopanib) should NOT be used in this poor-risk patient, as combination immunotherapy-based regimens have superseded these options 2.

Bone-Directed Therapy

Immediate Bone-Modifying Agents:

Initiate either zoledronic acid or denosumab immediately alongside systemic therapy to prevent skeletal-related events (SREs), as these agents delay time to first SRE and reduce annual incidence of SREs in metastatic RCC patients with bone involvement 1, 2.

Adjuvant Radiotherapy Post-Plating:

Yes, adjuvant radiotherapy to the plated humerus is recommended. 1, 2

• Bone-directed radiation therapy should be administered for symptomatic bone metastases 2, 5, which this patient has given the pathological fracture requiring surgical fixation.

• Stereotactic body radiotherapy (SBRT) is the preferred modality when feasible, showing 1-year local control of 90% with only 1% significant toxicity in RCC oligometastases 2, 1.

• Timing: SBRT can be delivered either concurrently with systemic therapy initiation or after establishing disease control 1. Given the post-operative setting, radiation should begin once surgical healing permits (typically 2-4 weeks post-plating).

• Rationale: The combination of surgery and radiotherapy improves survival and maintenance of function compared with irradiation alone in bone metastases 2.

Critical Management Considerations

Cytoreductive Nephrectomy:

Do NOT perform immediate cytoreductive nephrectomy in this IMDC poor-risk patient 2, 5, 6. The CARMENA trial demonstrated that sunitinib alone had longer median OS (18.4 vs 13.9 months) compared to immediate cytoreductive nephrectomy followed by sunitinib in intermediate- and poor-risk patients 2, 1.

• Deferred cytoreductive nephrectomy can only be considered after achieving durable response to systemic therapy 1, 6.

Performance Status and Treatment Initiation:

• Ensure adequate performance status before initiating combination therapy 2.
• The patient's post-operative status from humerus plating should be optimized before starting systemic therapy 1.
• Systemic therapy should ideally start within 12 weeks of definitive local therapy when applicable 2.

Treatment Monitoring and Duration

• Continue systemic therapy until disease progression or unacceptable toxicity 3, 4.
• For pembrolizumab-based regimens, checkpoint inhibitor therapy continues for maximum 24 months, though TKI component may continue beyond 3.
• Treatment beyond progression may be permitted if the patient is clinically stable and deriving clinical benefit, with consideration of local therapy (radiation, ablation) for limited progression sites 2, 5.

Common Pitfalls to Avoid

• Avoid single-agent TKI therapy in poor-risk disease when combination immunotherapy is available 2.
• Do not delay bone-modifying agents—these should start immediately with systemic therapy 1, 2.
• Do not pursue immediate cytoreductive nephrectomy in poor-risk patients requiring systemic therapy 2, 1.
• Do not omit adjuvant radiation to the surgical site in the setting of bone metastasis, as this improves local control and function 2, 1.