ESMO 2021: Are Adjuvant Immune Checkpoint Inhibitors a Standard of Care for Operable High-Risk Urothelial and Kidney Cancer? No

( The European Society of Medical Oncology (ESMO) 2021 annual congress included a controversial session highlighting ‘Are adjuvant immune checkpoint inhibitors a standard of care for operable high-risk urothelial and kidney cancer?’ Dr. Michiel van der Heijden discussed that no, adjuvant immune checkpoint inhibitors are not standard of care. Dr. van der Heijden started by highlighting that spring 2021 was a happy time: the daily COVID numbers were decreasing, KEYNOTE-564 was presented at ASCO, and CheckMate 274 was published in the New England Journal of Medicine.1 Taking a step back, it is important to remember that the goal of adjuvant therapy is to prevent disease recurrence and death, with the knowledge that a proportion of patients will be treated for a disease that was cured with surgery alone. As such, disease-free survival does not necessarily mean a survival benefit just that the time to disease recurrence was delayed.

Dr. van der Heijden notes that the benchmark in bladder cancer is chemotherapy. There have been several randomized clinical trials in the adjuvant setting, but the most recent and clinically relevant is the EORTC 30994 trial,2 which tested immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse. After a median follow-up of 7.0 years (IQR 5.2-8.7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0.54, 95% CI 0.4-0.73, p<0.0001): 


Importantly, there was no meaningful subsequent therapy available in this era. 

Looking at adjuvant immunotherapy studies in bladder cancer, there have been three assessing DFS, including IMvigor010 (atezolizumab, n=800 - negative),3 Ambassador (pembrolizumab, n=739 – no results yet) and CheckMate 274 (nivolumab, n=700 - positive).1 All these trials had a similar trial design:


Looking first at the IMvigor010 trial,3 patients were randomly assigned (1:1) to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Over a median follow-up of 21.9 months (IQR 13.2-29.8), the median DFS was 19.4 months (95% CI 15.9-24.8) with atezolizumab and 16.6 months (11.2-24.8) with observation (stratified HR 0.89, 95% CI 0.74-1.08). As such, this was a completely negative study. The CheckMate 274 trial testing adjuvant nivolumab in high-risk MIBC,1 noting a significant DFS benefit versus placebo in the intention-to-treat population (HR 0.70, 98.31% CI 0.54-0.89), as well as in the PD-L1 >=1% cohort (HR 0.53, 98.87% CI 0.34-0.84). Looking at the forest plot of CheckMate 274, Dr. van der Heijden highlights the impact of previous neoadjuvant chemotherapy, which was associated with a DFS benefit for nivolumab of HR 0.52 (95% CI 0.38-0.71).

Dr. van der Heijden’s conclusions for adjuvant bladder therapy are as follows:

  • DFS is promising for nivolumab, especially in the PD-L1+ population
  • However, (i) OS is still missing and should be available soon, (ii) OS should be judged separately for PD-L1+ and PD-L1 negative subgroups, (iii) it is possible that the DFS curves will converge further in the intention-to-treat group, and (iv) discrepant results with IMvigor010 warrant caution

Looking at adjuvant immunotherapy for RCC, Dr. van der Heijden notes that there are four studies including three that are still awaiting reporting (IMmotion010 – atezolizumab; CheckMate914 – nivolumab + ipilimumab; Rampart – durvalumab +/- tremilimumab) and the recently reported and published KEYNOTE-564 trial.4 In the KEYNOTE-564 trial, patients were randomized to pembrolizumab versus placebo, with pembrolizumab having a DFS benefit in the intention-to-treat population (HR 0.68, 95% CI 0.53-0.87), with an early signal but too early to characterize OS benefit (HR 0.54, 95% CI 0.30-0.96):


In this trial, 5.8% were M1 NED (requiring a metastasectomy within the first year after nephrectomy). If these patients are removed (ie. just assess M0 patients), the DFS benefit is less impressive than the intention-to-treat population at HR 0.74, 95% CI 0.57-0.96. Given that there are several options in the M+ setting, these combination regimens should be the standard in M+ disease and it is possible that these highly efficacious combinations may not be as effective (or possible) after adjuvant checkpoint inhibitor therapy.

Dr. van der Heijden’s conclusions for adjuvant pembrolizumab in RCC are as follows:

  • For M0 disease, the HR of 0.74 is promising but needs OS confirmation. From this population, 70% may not need adjuvant treatment and there will likely be a degree of toxicity for all that receive treatment. Also, adjuvant therapy may impact efficacy of metastatic therapy
  • For M+ NED, it is questionable if this group should be included. Is metastasectomy really the standard of care in patients recurring <1 year after nephrectomy? The real comparison for these patients should be first-line systemic therapy (TKI + IO or Nivo/Ipi) versus metastasectomy. Including this group may be seen as encouragement for doing a metastasectomy
  • The M+ outcome may be responsible for the early OS signal

Presented by: Michiel S. Van der Heijden, MD, PhD, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands 

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 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.


  1. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114.
  2. Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+M0 urothelial carcinoma of the bladder (EORTC 30994): An intergroup, open-label, randomized phase 3 trial. Lancet Oncol. 2015 Jan;16(1)76-86.
  3. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): A multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):525-537.
  4. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694.