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Response Assessment of Patients with Locally Advanced Renal Cell Carcinoma Receiving Prior Systemic Therapy - Beyond the Abstract

Surgical treatment of locally advanced renal cell carcinoma (RCC), especially in the presence of venous tumor thrombus, remains challenging. While checkpoint inhibitor (CPI)– and tyrosine kinase inhibitor (TKI)–based combinations are standard in metastatic RCC, their role in the neoadjuvant setting for non-metastatic disease is still evolving. In our retrospective single-center study, we assessed radiographic response, pathological outcomes, and surgical feasibility following preoperative systemic therapy in patients with locally advanced RCC.

Our cohort included 17 non-metastatic RCC patients, most with high-risk features and venous tumor thrombus. The majority received CPI+TKI combinations, predominantly lenvatinib plus pembrolizumab. After a median of seven months of treatment, median radiographic tumor reduction was 27%, comparable to or exceeding reductions reported in prospective neoadjuvant CPI+TKI trials1,2 and clearly superior to CPI monotherapy, which has shown minimal primary tumor shrinkage.3

Importantly, our results demonstrate a disconnect between radiographic and pathological response. More than half of patients experienced pathological T-stage downstaging, and 17.6% achieved a complete pathological response (ypT0), despite no correlation between imaging response and residual viable tumor—consistent with findings from NEOAVAX.4 These data highlight that stable disease on imaging does not preclude meaningful biological treatment effects.

Venous tumor thrombus response was clinically relevant: 50% of patients with vena cava involvement experienced a reduction in Mayo thrombus level, with no progression observed. This aligns with prior prospective studies showing thrombus downstaging after neoadjuvant TKI or CPI+TKI therapy and supports consideration of induction therapy in patients with extensive venous involvement.5,6

From a surgical perspective, nephrectomy and thrombectomy were feasible in all patients, with acceptable perioperative morbidity. Major complications were limited and occurred primarily in complex thrombus cases.

Clinical Take-Home Message

Our results support neoadjuvant CPI+TKI therapy as a useful downstaging and surgical facilitation strategy in selected patients with locally advanced, non-metastatic RCC—particularly those with venous tumor thrombus. Radiographic response alone should not guide decision-making, as meaningful pathological responses may occur despite limited tumor shrinkage. Until randomized trials define a survival benefit, neoadjuvant therapy should be considered within multidisciplinary decision-making to optimize surgical outcomes.

Written by: Konstantin E. Seifert, Department of Urology, University Hospital Münster, Münster, Germany

References:

  1. Karam JA, Msaouel P, Haymaker CL, Matin SF, Campbell MT, Zurita AJ, Shah AY, Wistuba II, Marmonti E, Duose DY, Parra ER, Soto LMS, et al. Phase II trial of neoadjuvant sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced clear cell renal cell carcinoma. Nat Commun 2023;14.
  2. Bex A, Abu-Ghanem Y, Van Thienen J V., Graafland N, Lagerveld B, Zondervan P, Beerlage H, van Moorselaar J, Kockx M, Van Dam P-J, Szabados B, Blank CU, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). Journal of Clinical Oncology 2022;40:289–289. https://doi.org/10.1200/JCO.2022.40.6_suppl.289
  3. Carlo MI, Attalla K, Mazaheri Y, Gupta S, Yildirim O, Murray SJ, Coskey DT, Kotecha R, Lee CH, Feldman DR, Russo P, Patil S, et al. Phase II Study of Neoadjuvant Nivolumab in Patients with Locally Advanced Clear Cell Renal Cell Carcinoma Undergoing Nephrectomy. Eur Urol 2022;81:570–3.
  4. Bex A, Cornelis van der Mijn J, Graafland N, van Thienen J V, Wilgenhof S, Lagerveld B, Zondervan P, Jeroen Van Moorselaar RA, Kockx M, Van Dam P-J, Mestdagh P, Emma Szabados B, et al. Exploratory analysis from NEOAVAX, a neoadjuvant trial of avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy. 2025
  5. Stewart GD, Welsh SJ, Ursprung S, Gallagher FA, Jones JO, Shields J, Smith CG, Mitchell TJ, Warren AY, Bex A, Boleti E, Carruthers J, et al. A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA). Br J Cancer 2022
  6. Gu L, Peng C, Liang Q, Huang Q, Lv D, Zhao H, Zhang Q, Zhang Y, Zhang P, Li S, Xu J, Chen L, et al. Neoadjuvant toripalimab plus axitinib for clear cell renal cell carcinoma with inferior vena cava tumor thrombus: NEOTAX, a phase 2 study. Signal Transduct Target Ther 2024;9:264.
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