SUO 2023: Systemic Therapy: Choosing Among Neoadjuvant/adjuvant Approaches for Upper Tract Urothelial Carcinoma

(UroToday.com) The 2023 SUO annual meeting included a session on urothelial cancer, featuring a presentation by Dr. Jean Hoffman-Censits discussing choosing among neoadjuvant or adjuvant approaches for systemic therapy. Dr. Hoffman-Censits started by summarizing the two prospective neoadjuvant cisplatin trials.

Published in 2020, Margulis et al. performed a phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high grade upper tract urothelial carcinoma (ECOG-ACRIN 8141).¹ There were 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) arm from 2015 to 2017, as well as six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Among 29 eligible patients in the MVAC arm, 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0 and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9-28.8) of patients. The ECOG-ACRIN 8141 trial demonstrated feasibility of a prospective multicenter trial of cisplatin-based neoadjuvant chemotherapy in upper tract urothelial carcinoma.

Published earlier in 2023, Coleman et al. assessed neoadjuvant chemotherapy in 57 patients, with a 63% pathologic response, 19% complete response rate, as well as improved progression free (5-year 72%) and overall survival (5-year 79%):²
An important consideration is that renal function in platinum eligible patients remains stable during neoadjuvant chemotherapy and declines after radical nephroureterectomy. In the EA8141 study, following nephroureterectomy, 69% of patients had a creatinine clearance < 60 mL/min and a median decrease of 40.8% from baseline. In the MD Anderson Cancer Center retrospective assessment, following nephroureterectomy, the mean decrease in GFR baseline to 1-3 months post radical nephroureterectomy was 19.0 mL/min/1.73 m², with a mean GFR of 40.8 mL/min/1.73 m².

Both the AUA guidelines and EAU guidelines have language providing guidance in the neoadjuvant setting. From the AUA guidelines, “Clinicians should offer cisplatin-based neoadjuvant chemotherapy to patients undergoing radical nephroureterectomy or ureterectomy with high risk upper tract urothelial carcinoma, particularly in those patients whose post-operative eGFR is expected to be <60 mL/min/1.73 m² or those with other medical comorbidities that would preclude platinum-based chemotherapy in the post-operative setting (Strong Recommendation; Evidence Level: Grade B).” The EAU guidelines state that “the primary advantage of neoadjuvant chemotherapy is the ability to give cisplatin based regimens when patients still have maximal renal function. A meta-analysis (n = 800) revealed that neoadjuvant chemotherapy was associated with a pathological partial response rate of 43% and a downstaging rate of 33%, and overall survival and cancer specific survival benefits in comparison to radical nephroureterectomy alone. However, it is important to note that the available evidence is not conclusive, given the significant bias and heterogeneity.”

Dr. Hoffman-Censits then discussed the POUT trial, first presented at GU ASCO in 2018 and subsequently published in The Lancet in 2020, followed by an updated analysis presented at GU ASCO 2021.³ This was a phase III, parallel group, open-label, randomized controlled trial done at 71 NHS hospitals in the UK. Eligible patients who had received a radical nephroureterectomy for UTUC were postoperatively staged with either muscle-invasive (pT2–pT4, pN_any) or lymph node-positive (pT_any, 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. Patients 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 and <50 mL/min) received carboplatin rather than cisplatin. The primary endpoint of this trial was disease free survival, and 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, including 129 patients randomized to surveillance and 132 to chemotherapy; 260 patients were included in the intention to treat analysis. There were 60 (47%) disease free survival 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 an 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. At the time of the 2021 GU ASCO 2021 update, there were 64/129 disease free survival events in the surveillance arm compared to 45/131 in the chemotherapy arm (HR 0.54, 95% CI 0.36-0.79). For metastasis free survival, there were 66/129 events in the surveillance arm and 45/131 in the chemotherapy arm (HR 0.55, 95% CI 0.37-0.82), thus both endpoints showing continued benefit for chemotherapy. With regards to overall survival, the trial was not powered for this endpoint and since POUT met its primary endpoint of disease free survival, the trial was closed early. However, GU ASCO 2021 was the first presentation of mature overall survival data, with 52/129 events in the surveillance arm compared to 41/131 in the chemotherapy arm (HR 0.77, 0.50-1.17):
Dr. Hoffman-Censits states that chemotherapy tolerance in prospective upper tract urothelial carcinoma trials is better in the neoadjuvant setting with the following cross-study comparison: 
Switching to the adjuvant setting, Dr. Hoffman-Censits notes that there are three complete adjuvant phase III checkpoint inhibitor studies in high risk urothelial carcinoma: AMBASSADOR, IMvigor010,⁴ and CheckMate 274.⁵ There are several key points to highlight. First, CheckMate 274 was a positive trial, IMvigor010 was negative, and AMBASSADOR has pending results, but based on a press release it met 1 of 2 primary endpoints (disease free survival, overall survival). Second, CheckMate 274 had a 20% cap for patients with upper tract urothelial carcinoma, IMvigor010 a 10% cap, however, AMBASSADOR has no cap for upper tract urothelial carcinoma patients:
The CheckMate 274 trial is a phase 3, randomized, double-blind, multicenter study of adjuvant nivolumab versus placebo in patients with high-risk muscle invasive urothelial carcinoma.⁵ The trial design for CheckMate 274 is as follows:
This was a positive trial, with a disease free survival benefit in both the intention to treat analysis and the PD-L1 > 1% analysis:
Of note, overall survival currently has insufficient events and thus no data for survival has been presented to date. CheckMate 274 also included patients with ureteral and renal pelvis tumors, however by subgroup analysis, there was no benefit to nivolumab:
The IMvigor010 trial randomized patients with muscle invasive urothelial carcinoma to adjuvant atezolizumab versus observation, with the following trial design:⁴
Unfortunately, this was a negative trial, with no DFS benefit in the intention to treat population (HR 0.89, 95% CI 0.74-1.08). However, the IMvigor010 trial showed us that circulating tumor DNA (ctDNA) is prognostic and predictive after adjuvant atezolizumab.⁶ Among 581 patients, ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm HR 6.3, 95% CI 4.45-8.92). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival HR 0.58, 95% CI 0.43-0.79, OS HR 0.59, 95% CI 0.41-0.86):
Dr. Hoffman-Censits emphasized that the ctDNA platform is now Medicare approved for bladder cancer in the adjuvant setting and for any patients on checkpoint inhibitor therapy.

Much like in the neoadjuvant setting, the guidelines have language to guide considerations for treatment of upper tract urothelial carcinoma in the adjuvant setting. The AUA guideline states that “Clinicians should offer platinum-based adjuvant chemotherapy to patients with advanced pathological stage (pT2-T4 pN0-N3 M0 or pTanyN1-3 M0) upper tract urothelial carcinoma after radical nephroureterectomy or ureterectomy who have not received neoadjuvant platinum-based therapy (Strong Recommendation, Evidence Level: Grade A).” The EAU guidelines state “A phase 3 multicenter prospective randomized clinical trial (n = 261) evaluating the benefit of four cycles of adjuvant gemcitabine-platinum combination chemotherapy initiated within 90 days after radical nephroureterectomy versus surveillance reported a significant improvement in disease-free survival in patients with pT2-4, Nany or lymph node positive (pTany, N1-3) M0 upper tract urothelial carcinoma.”

Dr. Hoffman-Censits concluded her presentation discussing choosing among neoadjuvant or adjuvant approaches for systemic therapy with the following take-home points:

• Systemic perioperative therapy in high grade upper tract urothelial carcinoma is standard of care
• High grade upper tract urothelial carcinoma should be considered for neoadjuvant cisplatin chemotherapy
  • Associated with lower final pathologic stage and survival outcomes
  • There are risks of over treatment, but it tends to not impact eGFR/surgical outcomes
  • Provides biologic data on treatment responses
  • An opportunity for adjuvant nivolumab for non-responding tumors
• Adjuvant platinum chemotherapy should be given for selected poor risk patients:
  • Improves disease free survival and overall survival (but not significant)
  • There is risk of under treatment, thus selection of patients with the highest cancer risk for treatment setting where chemotherapy is least likely to be completed
• Adjuvant nivolumab should be for selected poorest risk and those that are chemotherapy ineligible:
  • Improves disease free survival and overall survival is pending
  • The decision to treat with nivolumab is currently not ctDNA driven
  • It may impact activity of future lines of therapy
  • These results are based on intention to treat, but it is unclear in the subgroups and is underpowered due to the cap on the upper tract urothelial carcinoma subgroup

Presented by: Jean Hoffman-Censits, MD, Johns Hopkins Medicine, Baltimore, MD

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023.

References:

1. Margulis V, Puligandla M, Trabulsi EJ, et al. Phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high grade upper tract urothelial carcinoma. J Urol. 2020 Apr;203(4):690-698.
2. Coleman JA, Yip W, Wong NC, et al. Multicenter phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for patients with high-grade upper tract urothelial carcinoma. J Clin Oncol. 2023 Mar 10;41(8):1618-1625.
3. 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.
4. 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.
5. 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.
6. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021 Jl;595(7867):432-437.