EAU 2021: Cytoreductive Nephrectomy in the Management of Metastatic Clear Cell RCC: Systemic Treatment Without or with Delayed Nephrectomy - When and How?

(UroToday.com) Dr. Axel Bex presents his take on the management of metastatic clear cell RCC with systemic therapy, with or without delayed nephrectomy – specifically focusing on the when and how. As the primary author of the SURTIME Study,1 he can speak to the literature with great authority.

First, based on the CARMENA2 and SURTIME1 study results, the current ESMO and EAU guidelines recommend against cytoreductive nephrectomy in MSKCC/IMDC intermediate/poor-risk patients with asymptomatic primary tumors when medical treatment is required. So ultimately if the patient needs systemic therapy, they should get systemic therapy upfront.

He notes that both of the above studies with using sunitinib (TKI) as the systemic therapy.

However, the standard of care has changed. IO/IO combination or IO/TKI combination have become standard of care. He then looked at the current status of metastatic clear cell RCC management with IO therapy. Below, he summarizes the outcome of most of the major trials in this disease space:

SURTIME.png

In these studies, between 11-30% of patients were treated with the primary tumor in place. And, in those patients, when treated with ICI based combination therapy, they have better PFS and OS in exploratory analyses compared to treatment with sunitinib.

So, when treated with an IO combination with the primary tumor in place, the question becomes when to do delayed nephrectomy? There are a few clinical scenarios highlighted below:

IO_combination.png

The chance of complete response (CR) of the primary tumor is unlikely – but likely still warrants deferred CN, as imaging is not ideal to confirm pathologic CR.

If the patient had CR in all metastatic sites, we have a moral obligation to proceed with CN in these patients as they have a potential for durable long-term cure – and may allow cessation of systemic therapy.

Most likely is that there is stable disease or partial response – and deferred CN may be beneficial in both settings.

There are 2 planned phase 3 clinical trials involving CN in the IO combinations: NORDIC-SUN and PROBE. These may help address the question of the role of CN, as patients are randomized to either CN or continued systemic therapy.

However, there have been some institutional data to suggest some response. He presented some multi-institutional data that includes his own institution.

As seen below, in patients treated with Nivo/Ipi with primary tumor in place, there is generally a trend to partial or complete response:

NORDIC-SUN.png

In their experience, patients had CR at all metastatic sites in only 1.7% of patients. But partial response rates were high.

Of 20 patients who underwent deferred CN, 3 had complete pathological response. No surgical complications due to prior therapy. The relative downsizing of tumors with therapy and the degree of fibrosis is noted below:

A_Bex.png

He then concluded with the following statements:

  1. Patients who require systemic therapy should receive immune checkpoint inhibitor combination therapy first in analogy to CARMENA/SURTIME, as these are the new standard of care
  2. There is currently no level one evidence that deferred CN in patients with response at metastatic sites in the era of ICI improve survival, but clinical trials are planned
  3. In the meantime, deferred CN may provide benefits for patients in certain clinical scenarios.

Presented by: Axel Bex, MD, PhD, Royal Free NHS Foundation Trust, London, UK

Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

References:

  1. Bex A, Mulders P, Jewett M, Wagstaff J, van Thienen JV, Blank CU, van Velthoven R, Del Pilar Laguna M, Wood L, van Melick HHE, Aarts MJ, Lattouf JB, Powles T, de Jong Md PhD IJ, Rottey S, Tombal B, Marreaud S, Collette S, Collette L, Haanen J. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol. 2019 Feb 1;5(2):164-170. doi: 10.1001/jamaoncol.2018.5543. Erratum in: JAMA Oncol. 2019 Feb 1;5(2):271. PMID: 30543350; PMCID: PMC6439568.
  2. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. New England Journal of Medicine 2018;379:417-27.
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