ESMO 2021: Are Adjuvant Immune Checkpoint Inhibitors a Standard of Care for Operable High-Risk Urothelial and Kidney Cancer? Yes

(UroToday.com) 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. Thomas Powles discussed that yes, adjuvant immune checkpoint inhibitors are standard of care. At the moment, there is no approved neoadjuvant or adjuvant therapy for patients with high-risk kidney cancer, but there are several scoring systems to risk-stratify patients. The KEYNOTE-564 trial1 is the first adjuvant checkpoint inhibitor in the adjuvant disease space. Patients randomized to pembrolizumab had a significant disease-free survival benefit compared to those treated with placebo in the intention-to-treat population (HR 0.68, 95% CI 0.53-0.87):


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Dr. Powles notes that the overall survival results from KEYNOTE-564 are trending in the correct direction, but are only based on 51 events: 

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The health-related quality of life data was presented earlier at ESMO 2021 by Dr. Toni Choueiri, noting that 20% of patients discontinued therapy with 7% requiring high-dose steroids. According to Dr. Powles, this is likely secondary to patients have less acceptance of adverse events in the adjuvant setting. Based on the available tools used in this trial (FKSI-DRS, QLQ-C30 GHS/QoL, and QLQ-C30 physical conditioning), there were no glaring differences in quality of life between the two arms:

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Based on no OS signal in any of the adjuvant TKI trials, according to Dr. Powles, assuming VEGF TKI and immune therapy will have the same effect on OS is like comparing a bus and a tree. The hypothesis for generating a long-term signal and cure is present for immunotherapy, which is not the case for the VEGF TKI therapies.

Switching to bladder cancer, Dr. Powles highlights that this is a more nuanced approach given that we give chemotherapy for MIBC with level 1 evidence in the neoadjuvant setting, as well as occasionally giving chemotherapy in the adjuvant setting, with a 5-13% reduction in disease recurrence. The CheckMate 274 trial testing adjuvant nivolumab in high-risk MIBC was recently published,2 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): 

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Similar to the KEYNOTE-564 trial in RCC, quality of life data for nivolumab versus placebo in CheckMate 274 showed very few differences in quality of life between the two arms. Dr. Powles emphasized that it is important to remember that we have not seen any OS data, and the question remains as to why there was no PFS or OS advantage for atezolizumab? Why didn’t the PD-L1 biomarker work for atezolizumab? Importantly, ctDNA appears prognostic and predictive of OS with atezolizumab in adjuvant urothelial cancer, with exploratory analyses suggesting that ctDNA positive patients may benefit from adjuvant atezolizumab. 

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Currently, the IMvigor011 trial is testing adjuvant atezolizumab versus placebo in high-risk MIBC who are ctDNA positive following radical cystectomy:

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As follows is Dr. Powles’ ‘reasonable’ position for adjuvant therapy for RCC and urothelial carcinoma:

  • These adjuvant immune checkpoint inhibitor data sets are not mature, which does create uncertainty
  • Patients need to be actively involved in these decisions with all of the information. Treatment has risk with no proven OS benefit as of yet
  • For adjuvant pembrolizumab for high-risk kidney cancer:
    • As it stands, the efficacy and toxicity indicators are pointing in the right direction
    • Adjuvant pembrolizumab is reasonable for informed and willing patients with intermediate and high-risk clear cell RCC
    • If the facts change we can change our opinion
  • Adjuvant nivolumab for high-risk bladder cancer:
    • The story is more complex in urothelial carcinoma with conflicting indicators from other immune checkpoint inhibitors and no OS data for nivolumab
    • It is likely that patient selection will be required (PD-L1 or ctDNA) and/or an OS indicator (even if immature)
    • While some patients will want adjuvant nivolumab, it is harder to recommend with all of the uncertainty


Presented by: Thomas Powles, MD, Department of Genitourinary Oncology, Barts Cancer Institute, Queen Mary University of London, St Bartholomew’s Hospital, London, UK


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.

References:

  1. 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.
  2. 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.
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