(UroToday.com) The 2024 ESMO annual meeting included a session on addressing uncertainties in the management of urothelial and renal cell carcinomas, featuring a presentation by Dr. Debbie Robbrecht discussing how to manage patients with durable response on systemic therapy and whether there is a role in de-escalation. Dr. Robbrecht started by highlighting 8 patient scenarios from her clinical practice whereby patients may have been candidates for de-escalation of therapy:
Thus, the question is: is longer better than shorter in a responding patient? In an analysis of KEYNOTE-0451 and KEYNOTE-052,2 the median duration of response with first line pembrolizumab was 33.4 months, whereas for second line therapy was 29.7 months. However, Dr. Robbrecht cautions that the association between duration of response and duration of therapy is somewhat unclear:
Regarding retreatment, there appears to be some feasibility in KEYNOTE-045 and KEYNOTE-052. In KEYNOTE-045 the treatment free interval was 7.7 months, compared to 13 months for KEYNOTE-052, with a 45% complete/partial response rate after a second course of pembrolizumab in KEYNOTE-045 and a 50% complete/partial response rate in KEYNOTE-052 after retreatment. Dr. Robbrecht notes that there is good data in the NSCLC literature for de-escalation, with no difference in patients treated with a fixed duration of 2 years of nivolumab versus indefinite nivolumab therapy.
In the JAVELIN Bladder 100 trial3 of maintenance avelumab for advanced urothelial carcinoma, there is a suggestion for a window of de-escalation of therapy, particularly with those patients that had >= 12 months of treatment (median PFS 26.7 months, 95% CI 19.4-32.2). Considerations for de-escalation are also important in the context of toxicity after >=12 months of therapy.
Providers are also willing to consider de-escalation in appropriately selected patients. For example, in the NSCLC literature for patients receiving immune checkpoint inhibitors, 45% of providers would favor a shorter duration of treatment for their patients. In a 2022 survey of metastatic cancer patients assessing factors in optimal cancer care, key aspects that were important to patients were:
- A chance of eliminating all evidence of disease
- Duration of therapy
- Improvement in quality of life
- The ability to get off therapy
Among RCC patients specifically, lessons learned from a questionnaire regarding when there is an opportunity to interrupt therapy based on appropriate response, 58% of patients were anxious about this decision, 80% agreed, and 12% felt safer (avoiding future side effects).
There are two key trials assessing a shorter course of IO include:
- The IMAGINE trial: a phase 3 trial of continuing versus stopping IO therapy after 12-15 months in the absence of progressive disease. This trial has unfortunately closed secondary to poor accrual
- The AVE-SHORT trial: a phase 2 trial of 6 months avelumab maintenance for metastatic urothelial carcinoma, which is currently ongoing. At the time of an interim analysis for this trial, the median overall survival was 22.3 months (95% CI 19.9-24.7)
How do we identify/predict patients with urothelial carcinoma with a durable response? Currently, there are no clear predictive factors and an inability to predict the chance of being a ‘responder’. However, ctDNA clearance during treatment may eventually prove to be beneficial [4]
Dr. Robbrecht concluded her presentation discussing how to manage patients with durable response on systemic therapy and whether there is a role in de-escalation by noting that biomarkers (for example, ctDNA) will continue to play a key role in appropriately selecting these patients.
Presented by: Debbie Robbrecht, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024.
References:
- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.
- Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18(11):1483-1492.
- 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.
- Tolmeijer SH, van Wilpe S, Geerlings MJ, et al. Early on-treatment circulating tumor DNA measurements and response to immune checkpoint inhibitors in advanced urothelial carcinoma. Eur Urol Oncol. 2024 Apr;7(2):282-291.