ASCO GU 2025: Discussant: Advancements in Urothelial Cancer Perioperative Therapy

(UroToday.com) The 2025 GU ASCO annual meeting featured a urothelial carcinoma session and a discussant presentation by Dr. Scot Niglio discussing two abstracts: “Safety and efficacy of neoadjuvant immunotherapy with durvalumab in combination with neoadjuvant chemotherapy (gemcitabine/cisplatin or carboplatin) in patients with operable high-risk upper tract urothelial carcinoma” by Dr. Nadine Houede, and “Neoadjuvant treatment with disitamab vedotin plus perioperative toripalimab in patients with muscle-invasive bladder cancer with HER2 expression: Updated efficacy and safety results from the phase II RC48-C017 trial” by Dr. Xinan Sheng.

For localized upper tract urothelial carcinoma, there are important considerations for deciding whether a patient should receive neoadjuvant or adjuvant therapy:

There are have been two neoadjuvant upper tract urothelial carcinoma phase II studies. The first study was ECOG 81841, which accrued 30 high grade upper tract urothelial carcinoma patients that were treated with 4 cycles of neoadjuvant accelerated MVAC.¹ This resulted in a 14% pathological complete response rate and 61% <=ypT1 rate. The second study was a single center study at Memorial Sloan Kettering Cancer Center of 57 high grade upper tract urothelial carcinoma patients that were treated with 4 cycles of neoadjuvant gemcitabine + split dose cisplatin.² This regimen resulted in a 19% pathological complete response rate, and 63% pathologic response rate (defined as < ypT2N0). Dr. Niglio notes that there are currently three adjuvant checkpoint inhibitor phase III trials (IMvigor 010³, CheckMate 274⁴, and AMBASSADOR⁵) in urothelial carcinoma: 

 However, in these trials, accrual for upper tract patients was small, and efficacy outcomes were variable:

Dr. Niglio then discussed the iNDUCT (GETUG V 08) trial, which was a phase 2 clinical trial conducted in 10 French centers. Eligible patients had non metastatic, high-grade disease on ureteroscopic tumor biopsy or on urine cytology and infiltrative aspect of renal pelvis/ureteral wall on CT imaging. Subjects received a combination of: durvalumab/gemcitabine/cisplatin (cohort 1) or carboplatin (cohort 2) every 3 weeks for a total of 4 cycles based on glomerular filtration rate, prior to radical nephroureterectomy:

 The primary objective was to assess the pathological complete response (ypT0) rate of each combination. Importantly, in this trial, kidney function was preserved with treatment, given that baseline and cycle 4 kidney function was similar in the setting of cisplatin. This is also notable since up to 85% of patients will have stage 3+ chronic kidney disease after a radical nephroureterectomy. Dr. Niglio notes that pathological complete response rates and pathological response rates in iNDUCT among those treated with carboplatin were somewhat lower when compared to the other two aforementioned phase 2 trials that utilized a cisplatin-based regimen:

Dr. Niglio made the following concluding remarks with regards to the iNDUCT trial:

• This was a well designed trial in a difficult to accrue study population worthy of further investigation with cisplatin
• The small numbers make interpretation difficult
• There is concern that carboplatin will not reach immunogenic synergy seen with cisplatin

Dr. Niglio then discussed the phase II RC48-C017 trial by noting that perioperative therapy for T2-T4aN0M0 muscle invasive bladder cancer is either:

• Dose dense MVAC with growth factor support for 3-6 cycles, or
• Gemcitabine and cisplatin for 4 cycles, or
• Gemcitabine, cisplatin, and durvalumab for 4 cycles followed by 8 cycles post operative durvalumab (pending regulatory approval)

It is important to note that 60-80% of urothelial carcinoma demonstrates HER2 expression. Disitamab vedotin is a fully humanized HER2-directed monoclonal antibody with a microtubule disrupting MMAE. Toripalimab is a humanized monoclonal antibody targeting PD-1. The following figure highlights disitamab vedotin in metastatic urothelial carcinoma trials to date: 

In RC48-C017, key eligibility criteria included previously untreated muscle invasive bladder cancer (cT2-4aN0-1M0) with HER2 expression (IHC ≥1+ by local test), and eligible for curative-intent radical cystectomy and pelvic lymph node dissection. Patients received disitamab vedotin (2 mg/kg) + toripalimab (3 mg/kg) every 2 weeks for 6 cycles in the neoadjuvant phase. After radical cystectomy and pelvic lymph node dissection, patients received adjuvant toripalimab (3 mg/kg every 2 weeks) for up to 20 cycles:

The primary endpoint was pathological complete response (ypT0N0) rate assessed by the investigators, and secondary endpoints included pathological response rate (≤ypT1N0M0), overall survival, and safety. Pathological complete response (ypT0) in RC48-C017 was impressive at 63.6%, which compares very favorably to other neoadjuvant trials:

The pathological complete response rate by HER2 expression is also notable. The complete response rate for the HER2 IHC 3+ subgroup (84.6%) was numerically higher than those for IHC 1+ and IHC 2+ subgroups:

In RC48-C017, the 1-year event-free survival rate was 92.5% (95% CI: 72.8%-98.1%) and the 18 month rate was 85.9% (95% CI 60.5%-95.5%). By comparison, in NIAGARA, the 1-year event free survival rate was 76.0% and the 24-month rate was 67.8%:

Dr. Niglio concluded his discussion of the RC48-C017 trial with the following take-home points:

• HER2 is a promising biomarker in the perioperative setting for HER2 targeted therapy
• The pathological complete response rates as high as 84.6% in HER2 3+ suggest a biomarker driven approach as a potential bladder preservation approach
• The safety profile was tolerable and did not delay surgery 

Presented by: Scot A. Niglio, MD, Perlmutter Cancer Center, NYU Langone Health, 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 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025. 

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. 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.
4. 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.
5. Apolo AB, Ballman KV, Sonpavde G, et al. Adjuvant pembrolizumab versus observation in muscle-invasive urothelial carcinoma. N Engl J Med. 2025 Jan 2;392(1):45-55.