When it comes to perioperative chemotherapy, there are several pros and cons with regards to neoadjuvant or adjuvant treatment:
The POUT trial is the first phase III RCT reported for adjuvant chemotherapy specifically for patients with UTUC [1]. For this trial, patients (maximum n=345) that had a WHO performance status 0-1, and were ≤90 days post nephroureterectomy were randomized (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance. The primary endpoint was disease-free survival (DFS), and patients had cross sectional imaging and cystoscopy every 6 months for the first 2 years, then annually to 5 years. There were 248 patients included in the trial, including 123 patients randomized to surveillance and 125 to chemotherapy at 57 UK centers. In October 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected to date met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Patients were a median 69 years of age (range 36-88), 30% had pT2 disease, 65% pT3, and 91% pN0. There were 47 (38.2%) DFS events in the surveillance cohort and 29 (23.2%) in the chemotherapy cohort; the unadjusted HR was 0.47 (95%CI 0.29-0.74) in favor of chemotherapy (log-rank p= 0.0009). Two year DFS was 51% for surveillance (95%CI 39-61) and 70% for chemotherapy (95%CI 58-79). Metastasis-free survival also favored chemotherapy, with a HR of 0.49 (95%CI 0.30-0.79, p=0.003).
Now that we have POUT, Dr. Bossé wonders, now what? POUT established the new standard of care for resected UTUC, but (i) what about preoperative downstaging? (ii) Is there a better tolerated and less toxic alternative? (iii) What about the unsatisfactory outcomes despite platinum-based chemotherapy (70% DFS at 2-years)? Large early-phase immune checkpoint inhibitor trials in first-line metastatic urothelial carcinoma suggest activity of checkpoint inhibitors in untreated patients. In KEYNOTE-052, pembrolizumab was associated with an ORR of 22% among UTUC patients [2], whereas in IMvigor 210, atezolizumab was associated with an ORR of 39% [3].
There are several exciting immune checkpoint inhibitor trials ongoing, including but not limited to:
- IMvigor 010: adjuvant atezolizumab in high-risk resected MIBC and UTUC. Inclusion criteria include those with ypT2-4a or ypN+, pT3-4a or pN+ and ineligible for adjuvant cisplatin. The primary endpoint is DFS and completion is expected in the spring of 2020.
- AMBASSADOR: adjuvant pembrolizumab in high-risk resected MIBC and UTUC. Inclusion criteria include those with ypT2-4a or ypN+, pT3-4a or pN+ and ineligible for adjuvant cisplatin. The primary endpoint is DFS and OS; completion is expected in early 2019.
- It is paramount to continue enrolling patients on trials to improve outcomes
- Adjuvant immunotherapy phase III trials including UTUC patients will inform us whether non-platinum containing perioperative systemic therapy can be used in this population of patients, but will need to be repeated in larger trials with UTUC stratification
- Combination therapy (immunotherapy + chemotherapy) and targeted therapy will likely be the next steps in adjuvant/neoadjuvant if proven efficacious in the metastatic setting
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia
References:
1. Birtle A, Johnson M, Kockelbergh R, et al. Results of POUT: A phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). EAU 2018 abstr 1017.
2. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18(11):1483-1492.
3. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet 2017;389(10064):67-76.