Safety and efficacy of neoadjuvant durvalumab plus gemcitabine/cisplatin or carboplatin in patients with operable high-risk upper tract urothelial carcinoma: the iNDUCT trial.

Purpose: After radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), prognosis is poor for high-risk patients. This study evaluated safety and efficacy of neoadjuvant chemotherapy (cisplatin or carboplatin + gemcitabine) in combination with durvalumab in these patients.

Patients and methods: This phase II trial (NCT04617756) included patients with non-metastatic, high-grade UTUC, based on the ureteroscopic biopsy or urine cytology, and/or infiltrative aspect of the renal pelvis/ureteral wall by CT imaging. Before RNU, patients received durvalumab plus gemcitabine/cisplatin (cohort 1) or durvalumab plus gemcitabine/carboplatin (cohort 2) every 3 weeks for a total of four cycles (cohort choice based on the glomerular filtration rate). The primary objective was the pathological complete response (ypT0) rate in each cohort.

Results: Fifty patients were enrolled between 2021 and 2024 (31 in cohort 1; 19 in cohort 2). Median age was 68 years (range 38-79), 59% were men. Forty-five patients received 4 cycles of treatment, three patients 3 cycles, and one patient 2 cycles. Five patients switched to carboplatin during treatment. At surgery (n=45 patients), rates of pT0 were 13% (4/29) in cohort 1 and 5% (1/19) in cohort 2. Fifty percent (15/29) of patients were pTa /pT1 in cohort 1, and 42% (8/19) in cohort 2. No severe immunotherapy-mediated toxicity was observed. Four patients had chemotherapy-related grade 3 neutropenia, one grade 4; one patient had grade 3 thrombopenia, one grade 4; four patients had grade 3 anemia.

Conclusion: While our negative study did not meet its primary endpoint in either cohort, the combination of durvalumab and platin-based chemotherapy, especially cisplatin, showed promising results in terms of downstaging. The safety profile was good and the surgical risk was not increased.