What is the role of immunotherapy, including checkpoint inhibitors like nivolumab (Opdivo) or pembrolizumab (Keytruda), in the treatment of a patient with advanced or metastatic renal cell carcinoma (RCC)?

Immunotherapy in Advanced/Metastatic Renal Cell Carcinoma

Immunotherapy-based combinations have become the standard first-line treatment for advanced/metastatic RCC, with PD-1 checkpoint inhibitors (nivolumab, pembrolizumab) combined with either CTLA-4 inhibition or VEGFR-TKIs demonstrating superior survival outcomes compared to historical TKI monotherapy. 1

First-Line Treatment Strategies

For Intermediate/Poor-Risk Clear Cell RCC

The following regimens are FDA-approved and guideline-recommended as first-line options: 1

• Nivolumab + ipilimumab (dual checkpoint inhibition) is approved specifically for intermediate- and poor-risk patients, demonstrating superior overall survival compared to sunitinib 1, 2

• Pembrolizumab + axitinib received FDA approval in April 2019 for first-line treatment across all IMDC risk groups 1

• Pembrolizumab + lenvatinib showed the strongest survival benefit with HR 0.66 for OS (95% CI 0.49-0.88, P=0.005) and median PFS of 23.9 months versus 9.2 months with sunitinib 1, 3

• Avelumab + axitinib was FDA-approved in May 2019 for first-line treatment 1

• Nivolumab + cabozantinib is also approved for first-line advanced RCC 2

There is no preferred VEGFR-TKI/PD-1 combination, and indirect cross-trial comparisons should not be made. 1, 3

For Favorable-Risk Clear Cell RCC

The OS signals in favorable-risk patients treated with VEGFR-PD-1 combinations remain immature and not yet superior to sunitinib, though better response rates and PFS data support combination use in this subset 1. VEGFR-TKI/PD-1 combinations are recommended across all IMDC risk groups, including favorable risk. 1, 3

For Sarcomatoid Histology

Nivolumab + ipilimumab is the strongly preferred regimen for sarcomatoid RCC regardless of IMDC risk factors (83% consensus recommendation). 1 This combination achieved:

• ORR of 56.7% versus 19.2% with sunitinib (P<0.0001) 1
• Complete response rate of 18.3% versus 0% with sunitinib 1
• PD-L1 expression ≥1% was observed in 50% of sarcomatoid tumors versus 27.5% of non-sarcomatoid tumors 1

Second-Line Treatment After Prior Anti-Angiogenic Therapy

Nivolumab monotherapy is FDA-approved for patients with advanced RCC who have received prior anti-angiogenic therapy. 1, 2 This was the first checkpoint inhibitor approved for RCC in November 2015 1

Non-Clear Cell RCC

Checkpoint blockade has demonstrated encouraging anti-tumor activity in non-clear cell RCC, and these patients should not be excluded from immunotherapy consideration. 1

Pembrolizumab Monotherapy Data (KEYNOTE-427 Cohort B):

• ORR of 24.8% (95% CI: 18.5-32.2) across non-clear cell histologies 1
• Papillary histology: ORR 25.4% 1
• Unclassified histology: ORR 34.6% 1
• Chromophobe histology: ORR 9.5% 1
• Higher response rates in PD-L1+ tumors (CPS ≥1): ORR 33.3% versus 10.3% for CPS <1 1

Adjuvant Setting

Adjuvant pembrolizumab 200 mg IV every 3 weeks for up to 17 cycles (approximately 12 months) is recommended for intermediate- and high-risk clear cell RCC after nephrectomy, initiated within 12 weeks of surgery. 4

Eligible patients include: 4

• Intermediate risk: pT2 grade 4 or sarcomatoid N0M0, or pT3 any grade N0M0
• High risk: pT4 any grade N0M0, or any pT with N+ M0
• M1 NED after complete resection within 1 year of nephrectomy

Critical caveat: Extensive counseling is mandatory before initiating adjuvant therapy, as a substantial proportion of patients are cured by surgery alone and may receive unnecessary treatment with potential long-term toxicity 4

Key Clinical Considerations

Treatment Selection Algorithm:

1. Determine histology (clear cell versus non-clear cell) and presence of sarcomatoid features 1

2. Assess IMDC risk category (favorable, intermediate, poor) for clear cell RCC 1

3. For sarcomatoid features: Choose nivolumab + ipilimumab 1

4. For intermediate/poor-risk clear cell: Choose any approved IO/TKI combination or nivolumab + ipilimumab 1

5. For favorable-risk clear cell: IO/TKI combinations are recommended, though OS benefit versus sunitinib is not yet mature 1

6. For non-clear cell: Consider pembrolizumab monotherapy, particularly for papillary or unclassified histology 1

Important Pitfalls:

PD-L1 testing is NOT required for treatment selection in RCC - unlike non-small cell lung cancer where PD-L1 ≥50% is required for pembrolizumab monotherapy 3. All approved IO combinations for RCC can be initiated without waiting for PD-L1 results 3

Toxicity management is critical: Pembrolizumab + lenvatinib required dose reductions in 68.8% of patients with 82.4% experiencing grade 3-4 adverse events 3. Grade 3-5 treatment-related adverse events occurred in 11% of patients receiving pembrolizumab monotherapy for non-clear cell RCC 1

Salvage potential after first-line IO: Patients progressing on first-line IO/IO can achieve ORR of 47% with second-line TKI, compared to 13% ORR with second-line therapy after TKI/IO, though PFS-2 and OS were not significantly different between strategies 5