Durvalumab Combo Shows Encouraging Preliminary Data in High-Risk UTUC

"Although the study was considered as negative, this neoadjuvant combination regimen increased the rate of low-risk residual tumors, with a good safety profile and without increasing the surgical risk, especially when cisplatin could be used," according to the study authors.

Although neoadjuvant durvalumab (Imfinzi) plus chemotherapy did not reach the primary end point of pathologic complete response (pCR; ypT0) among patients with operable high-risk upper tract urothelial carcinoma (UTUC), the combination demonstrated promising results with respect to downstaging, according to findings from the phase 2 iNDUCT-GETUG V08 trial (NCT04617756).¹

Overall, ypT0 tumors were reported in 13% of patients who received durvalumab plus gemcitabine/cisplatin in cohort 1 and in 5% of those who received durvalumab plus gemcitabine/carboplatin in cohort 2. These outcomes did not meet the trial’s primary end point, as pT0 rates fell below the working hypothesis of 25% in cohort 1 and 21% for cohort 2.

Study investigators noted that most patients had low-risk residual disease following treatment. Nearly all patients with residual disease had pure urothelial carcinoma histology, although 1 patient in cohort 1 had mixed tumor histology.

“The results of our study did not meet the primary end point in either cohort as pT0 rates were below our working hypothesis,” lead study author Nadine Houédé, MD, PhD, from the Department of Oncology at CHU Nîmes and from INSERM U1194 at Montpellier University, both in France, wrote with coauthors.¹ “Although the study was considered as negative, this neoadjuvant combination regimen increased the rate of low-risk residual tumors, with a good safety profile and without increasing the surgical risk, especially when cisplatin could be used.”

Investigators of the open-label, multicenter phase 2 iNDUCT-GETUG V08 study assigned 49 patients to either cohort 1 (n = 30) or cohort 2 (n = 19) based on renal function status. Those with an estimated glomerular filtration rate (EGFR) of at least 60 mL/min/1.73 m² received durvalumab at 1500 mg intravenously on day 1 plus gemcitabine at 1000 mg/m² intravenously on days 1 and 8 plus cisplatin at 70 mg/m² on day 1 in cohort 1. In cohort 2, patients with an EGFR of 40 mL/min/1.73 m² or higher but less than 60 mL/min/1.73 m² received durvalumab plus gemcitabine and carboplatin at area under the curve of 4.5.

Neoadjuvant treatment occurred once every 3 weeks for 4 cycles before surgery.

The trial’s primary end point was pCR or ypT0 incidence at the time of surgery following neoadjuvant therapy. Secondary end points included partial response rate, safety, and tolerability.

Patients 18 years or older with histologically confirmed high-grade UC of the renal pelvis or ureter and presence of high-grade disease on ureteroscopic tumor biopsy results or high-grade disease on urine cytology results and infiltrative aspect of renal pelvis or the ureteral wall on CT scan were eligible for enrollment in the trial.² Other eligibility criteria included having no prior systemic therapies, an ECOG performance status of 0 or 1, and a life expectancy of 12 weeks or longer.

The median age across the entire study population was 68 years (range, 38-79), and 41% of patients were women. Additionally, most patients had current or former smoking status (55%), an ECOG performance status of 0 (65%), pyelocaliceal tumors (63%), T2 disease (37%), and N0 nodal involvement (80%).

The most common treatment-related adverse effects of any grade included asthenia (59%), nausea (53%), creatinine increases (47%), anemia (45%), and neutropenia (20%). Investigators observed no grade 5 events or serious grade 3/4 immunotherapy-related toxicities.

The neoadjuvant regimen did not confer any strong effects on kidney function. Additionally, significant loss of kidney function was reported in 1 patient in cohort 1. Renal function improved or remained stable for 9 patients in cohort 2.

References

1. Houédé N, Chevallier T, Audenet F, et al. Safety and efficacy of neoadjuvant durvalumab plus gemcitabine/cisplatin or carboplatin in patients with operable high-risk upper tract urothelial carcinoma: the iNDUCT-GETUG V08 trial. J Clin Oncol. Published online February 14, 2025. doi:10.1200/JCO-25-00179
2. Safety & efficacy of durvalumab+neoadjuvant chemotherapy for high-risk urothelial carcinoma of the upper urinary tract (iNDUCT). ClinicalTrials.gov. Updated May 30, 2023. Accessed April 4, 2025. https://tinyurl.com/mry7f82d