AUA 2021: The Future of Neoadjuvant Therapy in Bladder Cancer 

(UroToday.com) The Society of Urologic Oncology (SUO) session at the 2021 American Urological Association, (AUA) virtual annual meeting included a presentation by Dr. Elizabeth Kessler discussing the future of neoadjuvant therapy in bladder cancer.

Dr. Kessler notes that 20% of patients present with muscle-invasive bladder cancer, with 50% of patients recurring despite radical cystectomy and pelvic lymph node dissection. As such, systematic therapy may improve the outcomes provided by local therapy alone. Based on the key neoadjuvant chemotherapy trials,1-2 neoadjuvant chemotherapy downstages the tumor, improves disease specific survival, and improves overall survival. However, unfortunately, there has been historically poor uptake of neoadjuvant chemotherapy, as noted in the following figure of neoadjuvant chemotherapy utilization over time:

 

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Dr. Kessler notes that the reason for poor uptake of neoadjuvant chemotherapy is likely multifactorial, but at the root of the problem is that these patients are complicated, as well as being entangled in a complicated health care system. Perhaps we are able to learn from the metastatic setting, given that in advanced urothelial carcinoma there have been several approvals for immunotherapy, antibody drug conjugates, and targeted agents. Evolving strategies include:

  • Novel drugs and novel drug combinations, such as immunotherapy, targeted, and metabolic options
  • Time of therapy, whether in the neoadjuvant, perioperative, or adjuvant setting, with the importance of avoiding delay
  • Risk stratification, using new modalities such as circulating tumor cells, tumor infiltrating lymphocytes, and tumor gene signatures

Dr. Kessler emphasized that the future may still be chemotherapy, however it is crucial to identify which patients are most likely to benefit. The TCGA subtypes suggest that basal tumors are more aggressive and more likely to invade, whereas luminal tumors have a better prognosis regardless of neoadjuvant chemotherapy utilization. Predictors of response are available as well, such as ERCC2, DNA damage repair mutations, and COXEN. According to Dr. Kessler, the future landscape may be as follows:

 

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With regards to immunotherapy, Dr. Kessler emphasized that we can adapt from the activity observed in the advanced disease, noting that this is already an immune responsive disease. Recently, we have seen an expanded role for immunotherapy including maintenance avelumab after first-line platinum chemotherapy in the JAVELIN Bladder 100 trial3 and adjuvant nivolumab after surgery in the CheckMate-274 trial.4 Additionally, there is much work ongoing with many phase 2 and 3 trials ongoing and future trials planned.

Antibody drug conjugates have also emerged onto the landscape, notably enfortumab vedotin and sacituzumab govitecan. The EV-103 trial was first presented at ASCO 2021, a study evaluating the safety/activity of enfortumab vedotin + pembrolizumab (Dose Escalation/Cohort A). At the time of data cutoff, the median follow-up for the 45 first-line locally advanced or metastatic urothelial carcinoma patients was 24.9 months. The median number cycles of enfortumab vedotin + pembrolizumab was 9 (range 1-34). Confirmed objective response rate was 73.3% (95% CI 58.1 to 85.4) including 17.8% complete response and an objective response rate of 57.1% (8/14) in patients with liver metastasis. There are also several ongoing and futures studies for antibody drug conjugate therapy:

  • The SURE trial: sacituzumab +/- pembrolizumab
  • KEYNOTE-B15: enfortumab vedotin plus pembrolizumab versus chemotherapy alone
  • KEYNOTE-905: enfortumab vedotin plus pembrolizumab versus cystectomy alone

Dr. Kessler concluded her presentation with the following take home messages:

  • We take care of a complex patient population, and the treatment options will likely increase the pool of people potentially eligible for neoadjuvant therapy
  • The future will help us decide when, what and why to treat patients

 

Presented by: Elizabeth Kessler, MD, Medical Oncologist, University of Colorado, Aurora, CO

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 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.

References:

  1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
  2. Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long term results of the BA06 30894 trial. J Clin Oncol 2011;29(16):2171-2177.
  3. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020 Sept 24;383(13):1218-1230.
  4. 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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