(UroToday.com) The 2022 American Urological Association (AUA) Annual Meeting included the Society of Urologic Oncology (SUO) session and a presentation by Dr. Sima Porten discussing adjuvant therapy after nephroureterectomy for high-risk upper tract urothelial carcinoma. Dr. Porten notes that upper tract urothelial carcinoma makes up 5-10% of all urothelial carcinoma, with a 2:1 incidence of males to females, and an association with environmental exposures (smoking, aristolochia, arsenic, etc). Furthermore, upper tract urothelial carcinoma is associated with familial syndromes such as Lynch syndrome (and the inherent microsatellite instability). These patients are typically difficult to clinically stage and are more likely to present at invasive or advanced stages of disease (56%). Recent work has highlighted that FGFR3 alterations have a dominant role in upper tract urothelial carcinoma, as well as luminal molecular subtype.
Dr. Porten then highlighted a case presentation of a 60 year old male who presented with right flank pain and hematuria, which was initially thought to be renal colic from stone disease. The initial workup with cystoscopy that was normal, however imaging was consistent with right upper tract urothelial carcinoma (no lymphadenopathy, no metastasis). His history was pertinent for a 15 pack year smoking history, eGFR or 60, and a hemoglobin of 10. His ureteroscopy/biopsy was consistent with high grade Ta/T1 in the renal pelvis:
This patient subsequently underwent a radical nephroureterectomy with lymphadenectomy, demonstrating pT3N0 high-grade urothelial carcinoma involving the renal pelvis and proximal ureter (0/16 nodes involved). The risk of recurrence/relapse is high in the non-urothelial tract for this patient, thus there should be consideration of adjuvant therapy. Dr. Porten notes that based on the Krabbe nomogram high risk patients should have strong consideration for adjuvant therapy, and these include patients with (i) pT2-pT4 (N any), (ii) N1-3 disease (pT any), or (iii) high grade, urothelial predominant histology.
Dr. Porten then discussed the POUT trial,1 which was a phase 3 randomized clinical trial done at 71 NHS hospitals in the United Kingdom. Eligible patients were ≥16 years, had received a radical nephroureterectomy for UTUC, were postoperatively staged with either muscle-invasive (pT2–pT4, pNany) or lymph node-positive (pTany, pN1–3) M0 disease with predominantly transitional cell carcinoma histology, and were fit to receive adjuvant chemotherapy within 90 days of surgery. Patients also had to have a GFR of ≥30 mL/min and were randomized 1:1 to receive either surveillance or adjuvant chemotherapy: four 21-day cycles of platinum-based chemotherapy (cisplatin 70 mg/m2) within 14 days of randomization; gemcitabine (1000 mg/m2) given on days 1 and 8 of each cycle. Patients with impaired renal function (GFR ≥30 mL/min but <50 mL/min) received carboplatin rather than cisplatin. The trial schema of POUT is as follows:
The primary endpoint of this trial was DFS defined as time from randomization to either first recurrence in the tumour bed, first metastasis, or death from any cause. Secondary endpoints included metastasis-free survival, overall survival, treatment compliance, acute toxicity, late toxicity, and patient-reported quality of life. There were 261 patients included in the trial between June 19, 2012 and November 8, 2017, including 129 patients randomized to surveillance and 132 to chemotherapy; 260 patients were included in the intention to treat analysis. Included patients were a median 68.5 years of age (IQR 62.0-74.1 years). With respect to tumor characteristics, 94% patients had pT2-T3 disease and 91% were N0. The median follow-up was 30.3 months (IQR 18.0-47.5 months). There were 7 of 131 patients allocated to chemotherapy that did not start treatment and 75% of those that started chemotherapy received four cycles. There were 60 (47%) DFS events in the surveillance cohort and 35 (27%) in the chemotherapy cohort; as such, the unadjusted HR was 0.45 (95%CI 0.30-0.68) in favor of chemotherapy (log-rank p = 0.0001):
The three year disease-free survival rate was 46% for surveillance (95% CI 36-56) and 71% for chemotherapy (95% CI 61-78). Metastasis free survival also favored chemotherapy, with a HR of 0.48 (95%CI 0.31-0.74, log-rank p = 0.0007), and the three-year event-free rates were 53% (95% CI 42-63) for those on surveillance and 71% (95% CI 60-79) for those receiving chemotherapy. The subgroup analysis from POUT is as follows:
With regards to adjuvant immunotherapy, there have been three trials, of which upper tract urothelial carcinoma was included with MIBC patients. The IMvigor 010 trial2 tested adjuvant atezolizumab versus observation and was a negative trial, and the AMBASSADOR trial tested adjuvant pembrolizumab versus observation and has results pending. CheckMate 2743 tested adjuvant nivolumab versus placebo, and is now FDA approved in this disease space. More, specifically, CheckMate 274 was a phase 3, randomized, double-blind, multicenter trial comparing nivolumab and placebo in a 1:1 randomized fashion among patients with high-risk muscle-invasive urothelial carcinoma (with primary tumor sites including bladder, ureter, or renal pelvis) after radical surgery:
Patients randomized to receive nivolumab were administered nivolumab 240mg every 2 weeks for up to 1 year of adjuvant therapy. All patients had to have radical surgery (cystectomy or nephroureterectomy) within 120 days of randomization. Patients were allowed but not required to have received neoadjuvant cisplatin, and patients who were ineligible for or declined cisplatin-based chemo were also included. Additionally, patients were required to have urothelial histology and be at high risk of recurrence based on pathologic staging and be disease-free based on imaging prior to randomization. The primary outcomes of interest were DFS in all randomized patients (ITT population) and in patients with tumor PD-L1 expression ≥ 1%. CheckMate 274 accrued 709 patients, of whom 353 were randomized to nivolumab (of whom, 140 had PD-L1 ≥ 1%) and 356 were randomized to placebo (of whom 142 had PD-L1 ≥ 1%). Of note, 21% of these patients had upper tract urothelial carcinoma. Over a median follow-up of 20 months, median disease-free survival was significantly longer for patients receiving nivolumab (21 months) compared to placebo (11 months; HR 0.70, 95% CI 0.54-0.89):
A similar effect was observed in the PD-L1 ≥ 1% population (HR 0.53, 95% CI 0.34-0.84).
Dr. Porten notes that future directions in adjuvant therapy includes further studies based on subset analyses, as well as biomarker based selection. This may include ERCC2, TMB, PD1/PDL1 status, utilization of ctDNA, and targeted therapy (FGFR3 alterations are present in 40-74% of upper tract urothelial carcinoma). As such, PROOF 302 is testing adjuvant infigratinib versus placebo for invasive urothelial carcinoma with susceptible FGFR3 alterations:
Dr. Porten concluded her presentation by discussing adjuvant therapy after nephroureterectomy for high-risk upper tract urothelial carcinoma with the following concluding statements:
- Patients at high risk of recurrence after definitive surgical treatment for upper tract urothelial carcinoma should be referred for consideration of adjuvant therapy, including patients with (i) high grade pT2-pT4 and/or pN+ disease, and (ii) if neoadjuvant chemotherapy was given, ypT3-4a and/or ypN+ disease
- There is level 1 evidence for adjuvant chemotherapy (gemcitabine + platinum)
- There is FDA approval for adjuvant treatment for high-risk urothelial carcinoma (upper tract urothelial carcinoma and muscle invasive bladder cancer)
- Future studies of targeted therapy (FGFR inhibition) have a strong basis in biology and are ongoing
Presented by: Sima Porten, MD, MPH, University of California – San Francisco, San Francisco, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022.
- Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020.
- Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): A multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):525-537.
- Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114.