# Long-term Real-world Survival Outcomes with Dual Immune Checkpoint Blockade in Synchronous Metastatic Renal Cell Carcinoma: Implications for the Design of Prospective Cytoreductive Nephrectomy Trials

## TL;DR

Immunotherapy with nivolumab and ipilimumab for metastatic kidney cancer shows good survival, especially for those with strong responses, regardless of later surgery.

## Contribution

Shows real-world long-term survival data and challenges assumptions for clinical trial design in metastatic renal cell carcinoma.

## Key findings

- Median overall survival was 29.0 months in the overall cohort, with 49.8 months for intermediate-risk patients.
- Complete or near-complete responders had similar survival whether or not they had delayed surgery.
- IMDC risk was the strongest predictor of survival and progression-free survival.

## Abstract

Real-world treatment of synchronous metastatic renal cell carcinoma with nivolumab + ipilimumab yields encouraging overall survival. Exceptional responders show excellent survival, even without deferred cytoreductive nephrectomy. Currently recruiting trials of deferred cytoreductive nephrectomy are likely to underestimate eventual survival in their control arms.

Patients with synchronous metastatic renal cell carcinoma (s-mRCC) increasingly undergo systemic therapy with their primary tumour in situ. We report long-term survival outcomes and deferred cytoreductive nephrectromy (dCN) rates in an unselected real-world s-mRCC cohort of patients treated with nivolumab + ipilimumab.

This was a retrospective cohort study of 287 patients with s-mRCC treated with nivolumab + ipilimumab between 2018 and 2024 at five European institutions. Data were collected for International mRCC Database Consortium (IMDC) risk, overall survival (OS), progression-free survival (PFS), treatment responses, and dCN rates.

At median follow-up of 23.5 mo, median OS was 29.0 mo (95% confidence interval [CI] 20.1–36.2) for the overall cohort (n = 287), and 49.8 mo (95% CI 33.1–not reached) for the intermediate-risk group (n = 144, 50%) versus 16.3 mo (95% CI 13.5–26.3) for the poor-risk group (n = 143, 50%; hazard ratio [HR] 0.50, 95% CI 0.35–0.71; p < 0.001). IMDC risk was the only significant baseline multivariable predictor for both OS and PFS. Among patients with a complete or near-complete response (CR/nCR) at metastatic sites, there was no significant difference in OS between subgroups with dCN owing to the depth of response (n = 27) and without dCN (n = 23; HR 1.00, 95% CI 0.29–3.47; p > 0.9).

Real-world treatment of s-mRCC with nivolumab + ipilimumab yields encouraging OS, especially in patients with intermediate IMDC risk and CR/nCR at metastatic sites. Trials investigating dCN following immunotherapy may be impacted by this lower-than-expected event rate, which could potentially affect their estimated sample sizes.

We looked at outcomes for patients with metastatic kidney cancer who were treated with immunotherapy while their kidney tumour was still in place. Patients who responded well to immunotherapy were likely to survive for a long time, whether or not they then had surgery to remove their kidney tumour. Our results will help in the design of analyses for clinical trials that are already testing the role of delayed surgery for metastatic kidney tumours.