Durvalumab Plus Chemo May be Promising Neoadjuvant Option in UTUC

The first completed neoadjuvant phase 2 study combining immunotherapy with platinum-based chemotherapy in patients with upper tract urothelial carcinoma (UTUC) showed that durvalumab (Imfinzi) plus chemotherapy was safe and yielded encouraging residual disease outcomes, according to data from the phase 2 iNDUCT trial (NCT04617756).1

Findings from iNDUCT presented at the 2025 Genitourinary (GU) Cancers Symposium showed that patients in cohort 1 who received durvalumab plus cisplatin (n = 30) vs patients in cohort 2 who received durvalumab plus carboplatin (n = 19) had kidney function levels at baseline (creatine clearance) of greater than 60 mL/min (87% vs 47%), 40 to 60 mL/min (13% vs 69%), and less than 40 mL/min (0% vs 13%). At cycle 4, kidney function was greater than 60 mL/min (80% vs 32%), 40 to 60 mL/min (13% vs 47%), less than 40 mL/min (3% vs 5%), and data were missing for 1 vs 3 patients, respectively.

Additionally, patients had the following pathological tumor stages at surgery in cohort 1 vs cohort 2: ypT0 (13% vs 5%), ypTis/ypTA (17% vs 31%), ypT1 (34% vs 12%), ypT2 (3% vs 16%), ypT3 (20% vs 26%), ypT4 (3% vs 5%), renal cell carcinoma (RCC; 3% vs 0%), and no surgery (7% vs 5%). Nodal status at surgery was Nx (30% vs 39%), N0 (67% vs 50%), N1 (0% vs 11%), and N2 (3% vs 0%), respectively.

“The combination is safe, and [does] not negatively impact surgery,” Nadine Houede, MD, of Institut de Cancérologie du Gard, Oncology Department, at Montpellier University in France, said during a presentation of the data. “Encouraging results [were seen] in terms of residual disease, mainly when cisplatin-based chemotherapy [was] used.”

Following these data, the phase 3 iNDUCT-3 trial is planned to compare chemotherapy alone vs chemotherapy plus immunotherapy in patients with UTUC.

Examining iNDUCT, Patients Enrolled, and Safety

As UTUC is a rare disease with a poor prognosis and radical nephroureterectomy (RNU) is the standard for those with high-risk disease who don’t have metastasis, Houede and coauthors noted an argument can be made for neoadjuvant treatment because it may result in better renal function ahead of RNU. Moreover, treatment of micrometastases and downstaging of the tumor may be beneficial in the neoadjuvant setting. Notably, Houede added that patients with upper tract disease were excluded from the phase 3 NIAGARA trial (NCT03732677), which examined durvalumab in combination with gemcitabine and cisplatin as neoadjuvant treatment and durvalumab monotherapy for adjuvant treatment in muscle-invasive bladder cancer.

iNDUCT enrolled patients with high-grade UTUC per tumor biopsy or urine cytology and/or those with an infiltrative aspect of the renal pelvis/ureteral wall on imaging with negative cystoscopy. The primary end point of the study was rate of ypT0. Patients had an ECOG performance status of 0 or 1, M0 disease, and cTNM of T3 or less and N1 or less. They received durvalumab plus gemcitabine/cisplatin or gemcitabine/carboplatin every 3 weeks for 4 cycles prior to surgery. Of the 50 patients enrolled, 49 were allocated to treatment. In the cisplatin group, 30 patients were planned to undergo therapy, but 1 patient withdrew consent and 1 experienced disease progression; 28 patients proceeded to RNU and 1 patient experienced RCC. In the carboplatin group, 19 patients planned to undergo therapy, but 1 had metastases at diagnosis; 18 patients proceeded to and completed RNU.

In the total population (n = 49), the median age was 68 years (range, 38-79) and 41% of patients were female. Most patients had an ECOG performance score of 0 (65%), had cytology performed (59%), had N0 disease (80%), and 39% underwent a biopsy. In the cisplatin vs carboplatin cohorts, the median tumor size was 33.4 mm (range, 11-80) vs 49.6 mm (range, 2-140) and most tumors were pyelocaliceal (60% vs 69%).

Among all patients, low- and high-grade histology was as follows for those who underwent cytology (n = 15; 47% and 53%, respectively), biopsy (n = 5; 40% and 60%), and both cytology and biopsy (n = 14; 14% and 21%). Houede and investigators pointed out the discordance between high-grade and low-grade disease with the different histological staging systems.

Additionally, Houede noted limitations of the study, which included that biopsies were not mandatory and conducted in less than 50% of patients. Additionally, there was no control arm with platinum-based chemotherapy alone and these are primary results as disease-free survival data are not yet available.

Moreover, safety data revealed that the most common adverse effects (AEs) patients treated in either cohort experienced were asthenia (any-grade, 59%; grade 3, 4%), nausea (53%; 4%, respectively) increased creatine levels (47%; 4%), anemia (45%; 8%), neutropenia (20%; 8%), diarrhea (16%; 2%), tinnitus (12%; 0%), and mucositis (12%; 2%). Grade 4 AEs included neutropenia and thrombocytopenia, which each occurred in 1 patient. Notably, no grade 3 or 4 immune-related AEs were reported.

Reference

1. Houede N, Chevallier T, Loic J, et al. Safety and efficacy of neoadjuvant immunotherapy with durvalumab (MEDI 4736) in combination with neoadjuvant chemotherapy (gemcitabine/cisplatin or carboplatin) in patients with operable high-risk upper tract urothelial carcinoma. J Clin Oncol. 2025;43(suppl 5):661. doi:10.1200/JCO.2025.43.5_suppl.661