(UroToday.com) The 2024 GU ASCO annual meeting featured a urothelial carcinoma session and a presentation by Dr. Michal Sternschuss discussing neoadjuvant nivolumab + ipilimumab in cisplatin-ineligible patients with upper tract urothelial cancer. Perioperative platinum-based chemotherapy for upper tract urothelial cancer improves pathologic responses and disease-free survival.1 However, up to 50% of patients are ineligible for cisplatin-based chemotherapy. The 3-year disease free survival of 50% in the control arm of the POUT trial highlighted the poor outcomes of surgery alone. Hence, perioperative treatment alternatives remain an area of unmet need in this population. Of note, the PURE-02 trial with single agent neoadjuvant pembrolizumab did not show encouraging results in upper tract urothelial cancer. At the GU ASCO 2024 annual meeting, Dr. Sternschuss reported the updated results from their ongoing phase II neoadjuvant trial of nivolumab + ipilimumab for cisplatin-ineligible patients with upper tract urothelial cancer.
Cisplatin-ineligible patients with histologically confirmed high-grade upper tract urothelial cancer and/or radiographically invasive upper tract urothelial cancer with positive selective urine cytology were eligible for this trial. Patients were treated with ipilimumab 3mg/kg + nivolumab 1mg/kg (weeks 0, 6), and nivolumab 3mg/kg (week 3) prior to radical nephroureterectomy:
The primary endpoint was pathologic complete response (ypT0pN0) and secondary primary endpoints included <ypT2pN0 rate, disease-free survival, and toxicity. Next generation sequencing of pre-treatment tumors was correlated with pathologic response.
Seventeen patients (76% male) were enrolled between February 2021 and June 2023 with a median age of 73 (range 59-85) years. Primary sites included ureter in 10 patients, renal pelvis in 5 and both sites in 2 patients. The median tumor diameter was 3.0 cm, (range: 1.5 - 4.2 cm), with 8 patients (47%) having hydronephrosis:
To date, 11 patients (65%) have received all planned treatment, 6 patients had nivolumab +/- ipilimumab stopped early due to treatment-related toxicities, 15 patients have undergone radical nephroureterectomy (median interval from last treatment to surgery: 1.9 months, range 0.5-5.5 months), one declined surgery, and another progressed on nivolumab + ipilimumab.
A pathologic complete response was seen in 5/15 patients (29%) and <ypT2pN0 in 10/15 (59%). Four patients developed metastatic recurrence at 3.9, 8.2, 10.3, and 15.6 months after treatment initiation. CTCAE grade ≥3 treatment-related adverse events occurred in 5 patients (29%). Four patients died during follow up: two of metastatic disease, one of complications related to a bowel leak (7.2 months after nivolumab + ipilimumab initiation and 4.7 months after radical nephroureterectomy), and one from complications of a fall unrelated to disease or treatment (9.2 months after nivolumab + ipilimumab initiation and 4.7 months after radical nephroureterectomy). Patient outcomes for these first 17 patients are as follows:
The median tumor mutational burden in nine patients with pre-treatment sequencing was 13.2 mutations/mb (range 4.1-106.3), with 4/5 patients with tumor mutational burden >10 <ypT2pN0 at radical nephroureterectomy. Pathogenic germline variants in mismatch repair genes were confirmed in four patients (MSH2 in 3, MLH1 in 1) and MSI-high tumors without germline alterations in two patients, with all six completing radical nephroureterectomy. All of these patients achieved pathologic complete response (n=4) or ypTaN0 (n=2) and remained alive and disease-free at last follow-up.
Dr. Sternschuss concluded his presentation by discussing neoadjuvant nivolumab + ipilimumab in cisplatin-ineligible patients with upper tract urothelial cancer with the following take-home points:
- Updated findings from an ongoing phase II trial of cisplatin-ineligible patients with upper tract urothelial cancer receiving neoadjuvant nivolumab + ipilimumab show clinical activity in line with our initial results
- All patients with pathogenic germline variants in mismatch repair genes or MSI-high tumors without germline alteration who underwent radical nephroureterectomy achieved <ypT2pN0 and remain free of disease
Presented by: Michal Sternschuss, Memorial Sloan Kettering Cancer Center, New York, NY
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 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
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.