The Society for Immunotherapy of Cancer (SITC) maintains a clinical practice guideline on immunotherapy for the treatment of renal cell carcinoma (RCC), which they originated in 2016 to provide clinicians with evidence-based recommendations on integrating immunotherapies into practice. The recently updated SITC clinical practice guideline on immunotherapy for the treatment of renal cell carcinoma (RCC), features many new recommendations, showcasing just how far the guideline has evolved over the years.
Today, we are taking a look at the latest version of SITC’s guideline, Immunotherapy for the Treatment of Renal Cell Carcinoma, and comparing it to the 2016 original version of the guideline.
Guidelines Referenced:
Immunotherapy for the Treatment of Renal Cell Carcinoma
Immunotherapy for the Treatment of Renal Cell Carcinoma
- November 2016
- Full Text
Key Takeaways (2016 - 2026)
The following table reflects the latest recommendations included in the 2026 update. To view the complete guideline, along with the recommendations themselves, view the full-text versions using the links featured above.
Overall, the 2026 guideline features many recommendations on patient education and quality of life, special considerations for immune checkpoint inhibitor (ICI) treatment, early-stage RCC, and diagnostic tests that the 2016 version does not address. The 2026 guideline highlights the continued importance of immunotherapy for the treatment of RCC and reflects the expanding role of ICIs more recently.
Comparison of Recommendations
| Topic | 2026 | 2016 |
|---|---|---|
| Diagnostic Tests and Biomarkers | For patients with suspected RCC, pathology should confirm the diagnosis. For patients with sarcomatoid/rhabdoid differentiation/features, patients may have improved outcomes to immunotherapy and should be considered for immune-based regimens. For patients with RCC, TMB, MSI/MMR status, PD-L1 expression, and/or specific genetic mutations (e.g., PBRM1) are not recommended for patient selection for immunotherapy. | N/A |
| Stage II, Stage III, and Stage IV RCC Amenable to Metastasis-Directed Therapy | Use of validated nomograms (e.g., ASSURE, Mayo Clinic, UISS) may be useful to further guide consideration for use of adjuvant pembrolizumab for patients who are eligible. For patients with resected RCC, clinical trial enrollment for adjuvant therapy should be offered when available. For patients with resected RCC who are eligible, discussion of treatment risks and benefits of adjuvant ICI therapy is recommended. For patients with resected RCC who have pT2 with Fuhrman grade 4 or sarcomatoid differentiation, pT3 or higher, regional lymph node metastasis, or M1 NED, adjuvant pembrolizumab should be considered. For patients with resected RCC who are starting adjuvant systemic therapy, imaging should be obtained within 3 months prior to initiation. For patients with resected RCC who will be receiving adjuvant pembrolizumab, treatment should be initiated within 3–4 months of surgery and should be continued for 1 year. For patients with resected RCC who experience disease progression during or within 1 year after receiving adjuvant pembrolizumab, there is currently no level one evidence to guide standard treatment. For patients with resected RCC who experience disease progression during or within 1 year after receiving adjuvant pembrolizumab, although the data are limited, metastasectomy, ablation, or radiotherapy may be considered for limited recurrence. For patients with resected nccRCC, there is no SOC adjuvant therapy, and clinical trial enrollment is recommended, when available and appropriate. There is no standard neoadjuvant regimen for patients with non-metastatic localized RCC, and a multidisciplinary consultation should be considered to determine the best management strategy for these patients. | The current standard of care in the adjuvant setting is either observation or enrollment in a clnical trial. Do not use IFN, even in combination with bevacizumab and even at lower IFN doeses. |
| Stage IV RCC | ||
| Initial Assessment | For patients who are candidates for immunotherapy with metastatic RCC, the role of cytoreductive nephrectomy or SBRT to the renal primary is under active investigation. In the absence of definitive prospective data, a multidisciplinary approach is recommended for consideration of cytoreductive nephrectomy either in an immediate or deferred fashion. For patients eligible for systemic therapy, an immunotherapy-based approach is recommended. A subset of patients with asymptomatic, low-volume, and slow-growing disease could be candidates for active surveillance or metastases-directed therapy. | Nephrectomy remains an important component of management of patients with mRCC. Selected patients with mRCC who have undergone nephrectomy should be referred to a center of excellence for further discussion, as appropriate. Evidence regarding management of CNS metastases in inconclusive. Therefore, preoceeding with HD IL-2 in this setting should be individualized, based on clinical judgement. Prognostic categories developed to predict survival in patients with mRCC are used to guide treatment decisions. Only patients with clear cell histology should be considered for HD IL-2. There is limited to no role for low dose IL-2 as a single agent, with the possible exception of patients with impaired organ function. Efficacy data favor HD IL-2 compared to low dose IL-2. |
| Available Immunotherapy for Treatment-Naive ccRCC | For patients with sarcomatoid features with RCC, ipilimumab plus nivolumab is a preferred option. For patients being considered for an immunotherapy-based approach, four regimens (nivolumab plus ipilimumab; pembrolizumab plus axitinib; nivolumab plus cabozantinib; pembrolizumab plus lenvatinib) have been shown to improve OS. In the absence of head-to-head comparisons any of these options is recommended. For patients with treatment-naïve metastatic RCC, clinical trial enrollment should be encouraged, when available. | HD IL-2 should be reserved for patients with clear cell RCC. |
| Available Therapy for Previously Treated Disease | For patients with ICI-refractory metastatic RCC, a TKI-based regimen or belzutifan (in the setting of prior TKI) is recommended. If the patient previously received an ICI plus TKI combination, treatment with a different TKI should be selected. There is no proven role for sequential anti-PD-(L)1 regimens for patients with previously treated metastatic RCC. For patients with previously treated metastatic RCC, clinical trial enrollment should be encouraged. | Give a second two-week course of therapy to those patients with responding or stable disease 12 weeks following HD IL-2. Continue to observe, especially in patients with stable disease, undil progression is documented, and then start another treatment. Even if response to HD IL-2 lasts at least six months, proceed to another therapy. Following initial anti-VEGF TKI, anti-PD-1 agents are the preferred second-line immunotherapy. Preferred treatment for patients who progress on anti-VEGF TKI therapy but have good eCOG PS (≤1): anti-pd-1 agents in clinical trials or as commercial agent, if available. If anti-PD-1 agents are not available, HD IL-2 should be considered as second-line therapy after a washout period, in appropriate patients. HD IL-2 could be used after anti-PD-1 therapy based on the lower risk of persistent immune-related adverse events with anti-PD-1 agents compared with other checkpoint inhibitors (e.g., anti-CTLA-4 agents). |
| Available Immunotherapy for Treatment-Naive nccRCC | For patients with treatment-naïve nccRCC, enrollment on a clinical trial is recommended when available. | N/A |
| Special Considerations for ICI Treatment | Local therapy should be considered for patients with RCC with oligometastatic disease. Local therapy for oligometastatic RCC does not require interruption of systemic immunotherapy. For patients with RCC and brain metastases, consider local therapy with or without systemic therapy whenever feasible. Local therapy should not interrupt immunotherapy. For patients with RCC with oligoprogressive disease, stereotactic radiation therapy should be considered. For patients with advanced RCC with radiographic progression but who remain clinically stable and are tolerating therapy, continuation of systemic immunotherapy with close monitoring may be considered. For patients receiving immunotherapy for metastatic RCC, the best available evidence supports 2 years of ICI treatment; however, treatment could be continued beyond 2 years as personalized to the patient. For patients who have received local therapies to all sites of metastatic disease within 1 year of nephrectomy, adjuvant pembrolizumab treatment for 1 year can be considered. For patients with pre-existing significant autoimmune disease or solid organ transplant, avoiding ICI therapy initially and consulting with a specialist is recommended. For patients being considered for treatment with ICIs, HIV is not a contraindication. For patients being considered for treatment with ICIs, older age is not a contraindication. Geriatric assessment before initiation of ICIs therapy can be considered to determine if patients will be able to tolerate the treatment. | N/A |
| Patient Education and QOL | For patients with RCC receiving immunotherapy, providing educational materials about therapy risk and benefit is recommended. For patients with RCC receiving immunotherapy, discussion about the risks and benefits of treatment is recommended. For patients with a decline in QOL or physical functioning, ensure appropriate diagnostic workup for immune-mediated toxicity, disease progression, or alternative causes. For patients with RCC receiving immunotherapy, assessment of emotional wellbeing and referral to appropriate specialists is recommended at initial diagnosis, disease progression, and for those with long-term irAEs. | N/A |
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