ASCO Guidelines Aim to Outline Updated Recommendations for ccRCC Management

The American Society of Clinical Oncology (ASCO) has released new guidelines concerning recommendations for the optimal treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC) following a systematic literature review by an expert panel.

Treatment options are quickly evolving as findings from phase 3 studies of therapeutic options for ccRCC, the most common subtype of RCC continue to be reported.

Data compiled from randomized clinical trials, other relevant study designs, clinical experience, and systematic reviews with or without the inclusion of a meta-analysis informed the guidelines. Six clinical questions related to ccRCC were addressed by the panel as follows:

• How is it defined and how is it diagnosed?
• What is the role of cytoreductive nephrectomy?
• What are the preferred options for first-line systemic treatment?
• What is the optimal second- or later-line systemic treatment?
• What is the optimal application of metastasis-directed therapy?
• What considerations should be applied to treatment of special ccRCC subsets?

Clinical trial participation was generally encouraged for patients with metastatic ccRCC. According to the guidelines, quality of life continues to be an important focus and shared decision-making between physicians and patients remains crucial because of high levels of uncertainty in treatment. There should also be communication from multidisciplinary team members when caring for mRCC patients as well, the panel wrote.

A diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis, the guideline authors wrote. Additionally, treatment decisions should consider the International Metastatic RCC Database Consortium risk criteria.

Further recommendations from the panel suggest that select patients can be offered initial active surveillance strategy for first-line treatment and all patients should undergo risk stratification. Select patients with kidney-in-place and favorable- or intermediate-risk disease can be offered cytoreductive nephrectomy and a period of active surveillance can be offered to those who have undergone prior nephrectomy if the patient is asymptomatic with a low burden of disease.

Patients with favorable-risk disease who require systemic therapy can be treated with an immune checkpoint inhibitor (ICI) in combination with a VEGFR-directed tyrosine kinase inhibitor (TKI). Recommendations stated that patients with intermediate- or poor-risk disease should be given a doublet regimen but did not specify on what the regimen should be in terms of multiple ICIs vs an ICI plus a VEGFR TKI. Moreover, select patients can either receive an ICI or VEGFR TKI monotherapy depending on comorbidities. IL-2–directed agents are also an option, although the panel could not provide recommendations for selection criteria.

Second- or later-line systemic treatment for patients who progressed on a VEGFR TKI alone should consist of nivolumab (Opdivo) or cabozantinib (Cabometyx), guideline authors wrote. Patients who have experienced disease progression after treatment with combination immunotherapy should receive a VEGFR TKI. If a patient progresses after initial therapy that combines a VEGFR TKI and an ICI, an alternate VEGFR TKI can be offered as monotherapy. Finally, patients on immunotherapy with limited disease progression may be offered local therapy with the continuation of immunotherapy.

Metastasis-directed therapy for patients will low volume disease can include metastasectomy, ablative measure, or radiotherapy. Patients undergoing a complete metastasectomy should not receive a subsequent TKI.

The guidelines advised clinicians to treat patients with bone metastases with a bone resorption inhibitor when concern for skeletal-related events is present. Patients with symptomatic bone metastases should receive bone-directed radiation. Although regimens containing cabozantinib are preferred, there was no recommendation for optimal systemic therapy for patients who also have brain metastases. Patients with disease displaying sarcomatoid features should receive a first-line ICI-based combination treatment or either ipilimumab (Yervoy) plus nivolumab or an ICI plus a TKI.

The authors acknowledge that personalized treatment regimens need to be improved and more clinical trials are necessary to define predictive and prognostics biomarkers. Additionally, the ASCO guidelines are broad and data for patients with multiple chronic conditions are lacking as many clinical trials exclude these complex subgroups. Disparities in access to care must be considered as well along with financial toxicity.

The updated guidelines are exclusively for patients with ccRCC. Because most clinical trials only include patients with clear cell histology, which applies to approximately 70% of patients, there is an unmet need among patients with non-ccRCC. Furthermore, a lack of a universal standard for comparison was a limitation; most trials the guidelines are based on had sunitinib (Sutent) as a standard of care for first-line treatment, which has been evolving. The criteria for defining patients for risk for recurrence, response, or death from RCC is also outdated as it does not include immunotherapies and is based on treatments with only TKIs or earlier.

A first draft of the recommendations was made available from January 18, 2022, to February 2, 2022, for comment from the public. There were 59 written comments from 23 responders. Five of the 20 recommendations were revised after 25% of responders noted disagreements with the guidelines.

Reference

Rathmell WK, Rumble RB, Van Veldhuizen PJ, et al. Management of metastatic clear cell renal cell carcinoma: ASCO guideline. J Clin Oncol. 2022;40(25):2957-2995. doi:10.1200/JCO.22.00868