SIU 2021: What Trials Do We Need in Advanced Renal Cell Carcinoma to Improve Outcomes  

(UroToday.com) The Société Internationale D’Urologie (SIU) 2021 annual meeting included a master class on advanced kidney cancer with a presentation by Dr. Axel Bex discussing the trials we need in advanced renal cell carcinoma (RCC) to improve outcomes. Dr. Bex started his talk by highlighting the danger of radiological window dressing noting that there are two important clinical scenarios when discussing treatment and time after nephrectomy:



  1. A patient on adjuvant treatment after a radical nephrectomy that moves through the invisible phase to the asymptomatic visible phase to disease recurrence at a later date
  2. A patient on placebo after a radical nephrectomy that has a recurrence earlier than someone on adjuvant therapy.

However, is there really a difference between these two scenarios and the onset of a symptomatic recurrent phase?

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There are several rationales for neoadjuvant therapy for patients with RCC, as follows:

  • Downsizing of the renal mass:
    • Locally confined renal masses for nephron-sparing surgery that would otherwise be candidates for radical nephrectomy
    • Locally advanced renal tumors to allow complete surgical resection
  • Downstaging of the disease: Reduce the extent of locoregional disease and micrometastasis before surgical resection
  • Improve outcome parameters: Prolong the disease-free and overall survival in renal tumors at high risk of disease recurrence
  • Translational research: To understand mechanisms of resistance to therapy and identify patients who will benefit from this approach

Dr. Bex notes that there is the variability of inter-observer agreement on the feasibility of partial nephrectomy before and after neoadjuvant therapy. Among 22 patients with clear cell renal cell carcinoma in a phase II neoadjuvant axitinib trial, the median RENAL nephrometry score changed from 11 before treatment to 10 after treatment.1 Of 17 tumors with high complexity before axitinib treatment, three became moderate complexity after treatment. The overall κ statistic was 0.611. Moderate-complexity κ was 0.611 versus a high-complexity κ of 0.428. Before axitinib treatment, the κ was 0.550 versus 0.609 after treatment. After treatment with axitinib, all five reviewers in this study agreed that only five patients required radical nephrectomy (instead of eight before treatment) and that 10 patients could now undergo partial nephrectomy (instead of three before treatment).

In the NAXIVA phase 2 trial of neoadjuvant axitinib for reducing the extent of venous tumor thrombus, first presented at GU ASCO 2021, the primary endpoint was the percentage of evaluable patients with an improvement in venous tumor thrombus according to the Mayo classification (assessed using MRI abdomen scans at screening and week 9, prior to surgery). Among 21 patients enrolled in the trial, there were 11 patients that were M0 and 10 M1 patients. The percentage of evaluable patients with an improvement in venous tumor thrombus according to the Mayo classification was 31.3% (80% confidence interval [CI] 19.6%-44.8%):
 
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Ultimately, 17 patients proceeded to surgery of which 7 (41.1%) had a change in the surgical approach to a less invasive option. There was a median percentage reduction in venous tumor thrombus height observed in 5 out of 17 patients (29.4%), and no patients had deterioration in “level of control” of the inferior vena cava (IVC)/renal vein.

Dr. Bex then discussed the ADAPTeR trial, which was a phase II study of nivolumab in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell RCC aiming to understand the mechanism underpinning therapeutic response.2 T-cell receptor analysis revealed a significantly higher number of expanded T cell clones pre-treatment in responders, suggesting pre-existing immunity. Furthermore, data suggest that nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response.

There are several planned phase 3 trials involving cytoreductive nephrectomy in the era of immune checkpoint inhibition. The NORDIC-SUN (NCT03977571) trial is an open label phase 3 randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic RCC receiving checkpoint inhibitors. Approximately 400 patients will be randomized to surgery after induction therapy (nivolumab + ipilimumab) followed by maintenance nivolumab versus induction therapy (nivolumab + ipilimumab) followed by maintenance nivolumab (no surgery). The primary outcome for this trial is overall survival over a minimum of three years of follow-up. The PROBE trial will include patients with metastatic RCC treated with an immunotherapy-based regimen who had stable disease/partial response/complete response who will then be randomized 1:1 to cytoreductive nephrectomy versus a continued immunotherapy-based regimen. Importantly, both of these trials compare the former experimental arms from CARMENA (systemic therapy only) and SURTIME (upfront systemic therapy followed by cytoreductive nephrectomy in the absence of progression).

Dr. Bex concluded his presentation with the following take-home messages:

  • Adjuvant trials should either have symptomatic disease progression or OS as a primary endpoint or should at least be powered to have OS outcome data as a secondary endpoint
  • Neoadjuvant trials with strong translational endpoints are needed to understand the mechanism of response and resistance
  • Trials investigating cytoreductive nephrectomy should be designed taking longer PFS and OS with current combinations into account
  • With unproven superiority of any combination over the other the efficacy of systemic therapy as a component of cytoreductive nephrectomy trials should be regarded as a ‘class-effect’

Presented by: Axel Bex, MD, Division of Surgery and Interventional Science, The Royal Free London NHS Foundation Trust and UCL, London, United Kingdom

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 Société Internationale D’Urologie (SIU) Hybrid Annual Meeting, Wed, Nov 10 – Sun, Nov 14, 2021.

References:

  1. Karam JA, Devine CE, Fellman BM, et al. Variability of inter-observer agreement on feasibility of partial nephrectomy before and after neoadjuvant axitinib for locally advanced renal cell carcinoma (RCC): Independent analysis from a phase II trial. BJU Int. 2016 Apr;117(4):629-635.
  2. Au L, Hatipoglu E, de Massy MR, et al. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. Cancer Cell. Nov 8;39(11):1497-1518.
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