(UroToday.com) The 2025 GU ASCO annual meeting featured a urothelial carcinoma session and a presentation by Dr. Nadine Houede discussing safety and efficacy of neoadjuvant immunotherapy with durvalumab in combination with neoadjuvant chemotherapy in patients with operable high-risk upper tract urothelial carcinoma.
Upper tract urothelial carcinoma is a rare disease with a poor prognosis for which radical nephroureterectomy remains the gold standard for high risk localized upper tract urothelial carcinoma without evidence of metastasis. The POUT trial1 is the only phase 3 trial available in the adjuvant setting, which showed a disease free survival benefit of 62% versus 45% for high risk patients receiving perioperative chemotherapy.
As such, additional systemic therapy in a neoadjuvant setting may prolong survival for upper tract urothelial carcinoma patients, especially those after radical nephroureterectomy who are ineligible to receive nephrotoxic chemotherapy. There is rationale for interest in immunotherapy, given the recent data from NIAGARA in bladder cancer showing an estimated event free survival of 67.8% in the durvalumab group versus 59.8% in the comparison group (HR 0.68, 95% CI 0.56-0.82).2 However, there is limited data for immunotherapy in upper tract urothelial carcinoma – the PURE-02 trial assessed 10 patients treated with pembrolizumab, resulting in one ypT0.
iNDUCT (GETUC V 08) was a phase 2 clinical trial (NCT04617756) conducted in 10 French centers. Eligible patients had non metastatic, high-grade disease on ureteroscopic tumor biopsy or on urine cytology and infiltrative aspect of renal pelvis/ureteral wall on CT imaging. Subjects received a combination of: durvalumab/gemcitabine/cisplatin (cohort 1) or carboplatin (cohort 2) every 3 weeks for a total of 4 cycles based on glomerular filtration rate, prior to radical nephroureterectomy:
The primary objective was to assess the pathological complete response (ypT0) rate of each combination.
A total of 50 patients were enrolled between 2021 and 2023 (30 in cohort 1 – cisplatin/gemcitabine + durvalumab; 19 in cohort 2 – carboplatin/gemcitabine + durvalumab; 1 patient withdrew consent). The median age was 68 years of age (range 38-79) and 59% were males. Overall, 90% of patients (n = 44) received 4 cycles of treatment, 3 patients received 3 cycles, and 2 patients received 2 cycles. Five patients switched to carboplatin during chemotherapy. The results for the pre-trial histologic diagnosis are highlighted as follows:
A secondary endpoint was safety, and no immunotherapy-mediated adverse events were observed. Two patients had Grade 3 neutropenia, 1 grade 4, 1 patient had grade 3 thrombocytopenia, and 1 grade 3 anemia:
Kidney function at baseline and at cycle 4 are noted in the following table:
The pathologic complete response rate was 13% (95% CI 5%-30%) in cohort 1 and 5% (95% CI 1%-25%) in cohort 2. The complete pathological response outcomes are as follows:
Dr. Houede noted several limitations of this trial:
- Biopsy was not mandatory and only completed in 50% of patients
- There was no control arm with cisplatin-based chemotherapy alone
- These are preliminary results, with the 2 year disease free survival data pending
Dr. Houede concluded her presentation discussing safety and efficacy of neoadjuvant immunotherapy with durvalumab in combination with neoadjuvant chemotherapy in patients with operable high-risk upper tract urothelial carcinoma with the following take-home points:
- This is the first completed neoadjuvant phase 2 clinical trial in upper tract urothelial carcinoma combining immunotherapy and platinum-based chemotherapy
- This combination is safe and did not impact surgery negatively
- These are encouraging results in terms of residual disease, mainly when cisplatin-based chemotherapy was used
- A randomized phase 3 study comparing neoadjuvant chemotherapy with chemotherapy combined with immunotherapy in patients with high-risk localized upper tract urothelial carcinoma (iNDUCT-3) will open soon to validate these results.
Presented by: Nadine Houede, Institut de Cancérologie du Gard, Oncology Department, Montpellier University, Montpellier, France
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
References:
- Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): A phase 3, open-label, randomized controlled trial. Lancet 2020 Apr 18;395(10232):1268-1277.
- Powles T, Catto JWF, Galsky MD, et al. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. N Engl J Med. 2024 Nov 14;391(1):1773-1786.