2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Renal Cancer

How to Optimize the Use of Adjuvant Pembrolizumab in Renal Cell Carcinoma: Which Patients Benefit the Most? - Beyond the Abstract

The Keynote-564 set a paradigm shift for kidney cancer patients, demonstrating the benefit of the use of pembrolizumab vs. placebo as an adjuvant treatment for patients with intermediate and high-risk kidney cancer.1 Adjuvant Pembrolizumab use is now recommended by major national and international guidelines.2,3 These results have been further supported by the recent publication of the 30-month follow-up, where disease free survival (DFS) was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]).4

Overall survival data are still immature. In the meantime, the CheckMate-914 and the IMmotion010 trials failed to prove evidence of a benefit in terms DFS for adjuvant nivolumab plus ipilimumab vs. placebo and atezolizumab vs. placebo, respectively.5,6 In this context, the inconsistent success of trials on adjuvant immunotherapy may be addressed to different causes such as increased toxicity, different pharmacodynamics or pharmacokinetics of the immunotherapies, different trial design, and patient selection.

We tried to address this latest issue by comparing baseline characteristics and oncologic outcomes of patients potentially eligible for adjuvant pembrolizumab in the off-trial setting (San Raffaele Hospital prospectively maintained database) with those in the placebo arm of the Keynote -564 and by identifying those patients who may benefit the most from adjuvant treatment according to the risk of disease progression at 1-year. We chose 1-year risk of progression as a meaningful cut-off to consider patient suitable for adjuvant treatment, with the idea that adjuvant treatment should be recommended to those with a high-risk of early recurrence while it can be spared, in favor of salvage treatment, to those with a low risk of early recurrence.

We found that patient potentially eligible for adjuvant pembrolizumab in the off-trial setting, i.e. with the same inclusion and exclusion criteria of the Keynote-564, were more frequently less fit and with more aggressive kidney cancer compared to those included in the placebo arm of the trial. Interestingly, by applying a regression tree analysis, we found that patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95%CI 20.2-40.3]); patients without LNI but necrosis were at intermediate risk (1-year DFS 62.5% [95%CI 56.9-68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95%CI 79.1-88.9]) (Figure 1). The Kaplan-Meier curves shows how well DFS is stratified into these three groups (Harrel’s C-index for DFS 73.3%) and graphically compared DFS to that of the placebo arm of the Keynote-564.

Risk_stratification_a.png
Risk_stratification_b.png
Figure 1: A) Risk stratification tree assessing 1-year recurrence for patients with renal cell cancer potentially eligible for adjuvant pembrolizumab according to the KEYNOTE-564 inclusion criteria. B) Kaplan-Meier curves of the three risk categories and a digitalized and reconstructed Kaplan-Meier curve for DFS in the KEYNOTE-564 placebo arm

This study should be taken as hypothesis generating and should promote discussion on the important topic of trial design for adjuvant treatment of kidney cancer and on the indication for the use of adjuvant treatment in off-trial setting. Some key questions arise from our work and need urgent answers:

  • Have trials on adjuvant treatment for kidney cancer failed because of the inclusion of too many low-risk or understaged patients?
  • Should we restrict the use of adjuvant treatment to more aggressive kidney cancer, i.e. those with a higher 1-year risk of progression?
  • Will the effect of pembrolizumab be confirmed also in off-trial setting?
  • Should we rethink the importance of surgical lymph-node staging for high-risk kidney cancer patients?
Written by: Giuseppe Fallara, MD & Umberto Capitanio, MD

Division of Experimental Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy

References:

  1. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang Y-H, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. New Engl J Med 2021;385(8):683–94.
  2. Bedke J, Albiges L, Capitanio U, Giles RH, Hora M, Lam TB, et al. 2021 Updated European Association of Urology Guidelines on the Use of Adjuvant Pembrolizumab for Renal Cell Carcinoma. Eur Urol 2021;81(2):134–7.
  3. Powles T, Albiges L, Bex A, Grünwald V, Porta C, Procopio G, et al. ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma. Ann Oncol 2021;32(12):1511–9.
  4. Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022;23(9):1133–44.
  5. Bristol Myers Squibb Provides Update on CheckMate -914 Trial Evaluating Opdivo (nivolumab) Plus Yervoy (ipilimumab) as Adjuvant Treatment of Localized Renal Cell Carcinoma [Internet]. Bristol Myers Squibb Provides Update on CheckMate -914 Trial Evaluating Opdivo (nivolumab) Plus Yervoy (ipilimumab) as Adjuvant Treatment of Localized Renal Cell Carcinoma. 2022 [cited 2022 Aug 16];Available from: https://news.bms.com/news/details/2022/Bristol-Myers-Squibb-Provides-Update-on-CheckMate--914-Trial-Evaluating-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-as-Adjuvant-Treatment-of-Localized-Renal-Cell-Carcinoma/default.aspx
  6. Pal SK, Uzzo R, Karam JA, Master VA, Donskov F, Suarez C, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2022. 
Read the Abstract