(UroToday.com) The 2024 ESMO annual meeting included a session on urothelial carcinoma, featuring a discussant presentation by Dr. Maria De Santis discussing three abstracts including “TAR-200 +/- cetrelimab and cetrelimab alone in patients with BCG-unresponsive high-risk NMIBC: Updated results from SunRISe-1” by Dr. Michiel Van der Heijden, “Alliance A031501: AMBASSADOR Study of Adjuvant Pembrolizumab in Muscle-Invasive Urothelial Carcinoma vs Observation: Extended follow-up DFS results and metastatic disease recurrence distribution” by Dr. Andrea Apolo, and “ctDNA clearance with neoadjuvant durvalumab + tremelimumab + enfortumab vedotin for cisplatin-ineligible MIBC from the safety run-in cohort of the phase 3 VOLGA trial” by Dr. Alexandra Drakaki.
The treatment of BCG-unresponsive NMIBC has several goals, including preserving the bladder and avoiding recurrence and/or progression to muscle invasive or metastatic disease. There are several ways to achieve these goals, including:
- Optimizing the use of available agents: improving intravesical delivery
- Intensifying treatment combinations: assessing the risk/benefit ratio
- Introducing novel drugs
TAR-200 is one way to improve intravesical delivery, by way of a novel gemcitabine intravesical system designed for sustained, local delivery of chemotherapy in the bladder:
Gemcitabine bladder instillation itself is not a novel idea, as it has been used in liquid form in the bladder for years. Preclinical studies suggest there is high mucosal but low plasma absorption in the bladder, thus making it an excellent choice for intravesical use. A phase 3 randomized trial from 2010 assessed gemcitabine versus mitomycin in recurrence superficial bladder cancer, showing that gemcitabine had greater efficacy and better tolerability in papillary tumors:
SunRISe-1 (NCT04640623) is an ongoing randomized, phase 2b study evaluating the efficacy and safety of TAR-200 + cetrelimab (Cohort 1), TAR-200 alone (Cohort 2), or cetrelimab alone (Cohort 3) in patients with BCG unresponsive high-risk NMIBC ineligible for/refusing radical cystectomy. Eligible patients (≥18 years) had histologically confirmed carcinoma in situ (CIS) ± papillary disease (high-grade Ta, any T1) with last dose of adequate BCG ≤12 months of CIS diagnosis, and ECOG performance status 0-2. TAR-200 was dosed Q3W to week 24 then Q12W to week 96, while cetrelimab was dosed Q3W to week 78. The primary endpoint was complete response rate at any time, and secondary endpoints included duration of response, overall survival, safety, and tolerability. The SunRISe-1 trial design is highlighted below:
Centrally confirmed complete response rates in Cohort 1, Cohort 2, and Cohort 3 were 68%, 84%, and 46%, respectively. In Cohort 2, the estimated 12-month complete response rate was 57.4%, estimated 12-month duration of response rate was 65.7%, median follow-up in responders was 9.2 months (range: 3.7-36.6), and patients remaining in response was 81.6%.
Dr. De Santis notes that with TAR-200 monotherapy, more than 80% of patients had a complete response, and at a median follow-up of 9.2 months, a number of patients continue to have a response. TAR-200 was overall well tolerated (serious adverse events: 5.9%), in particular in comparison with the combination of TAR-200 and cetrelimab. The current treatment options for BCG unresponsive NMIBC continues to grow and are summarized in the following table.
Dr. De Santis summarized BCG unresponsive NMIBC with TAR-200 monotherapy with the following conclusions:
- A high complete response rate is the first critical step: the complete response rate with TAR-200 is impressive, but the durability of complete response and bladder preservation in the long-term are still to be confirmed with longer follow-up
- The device for delivery is important, but dependent on the drug used: intravesical gemcitabine is an active agent
Dr. De Santis then discussed the extended follow-up of the AMBASSADOR trial assessing pembrolizumab as adjuvant therapy after surgery for muscle invasive urothelial carcinoma. Based on this data from AMBASSADOR, there are now two options for adjuvant immune checkpoint inhibitors:
AMBASSADOR now has the longest disease free survival benefit compared to other options in this disease space, however, there is still a lack of overall survival data based on too few events to date:
Dr. De Santis notes that it is important to listen to the voice of the patient, particularly for adjuvant therapy options. In a survey of 207 patients with muscle invasive urothelial carcinoma regarding adjuvant treatment options, patients chose adjuvant treatment 91.2% of the time versus no treatment. The most important factor was prolonging overall survival, followed by reducing serious side effects. Of note, cancer-free survival was less important.
Dr. De Santis also emphasized that there is rationale for combining chemotherapy and immunotherapy (from IMVigor130) when considering a disease free survival benefit with or without prior neoadjuvant chemotherapy: (i) cisplatin versus carboplatin modulates immune-related transcriptional programs, (ii) tumor cells are primed by cisplatin versus carboplatin are sensitive to T-cell killing.
The following highlights the study landscape of perioperative therapy concepts in patients with muscle invasive bladder cancer stratified by cisplatin-fit and cisplatin-unfit:
Finally, Dr. De Santis discussed the ctDNA analysis from the VOLGA trial. She notes that in the EAU guidelines, there is a category 2b recommendation stating that “circulating tumor DNA holds promise as both a prognostic and predictive biomarker to guide the use of adjuvant IO for urothelial carcinoma in patients who are at a high risk of recurrence and positive for ctDNA treated with adjuvant atezolizumab demonstrating improved outcomes compared with observation.”
In the negative IMvigor010 trial assessing adjuvant atezolizumab, Powles et al. showed us that ctDNA is prognostic and predictive after adjuvant atezolizumab [2]. 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, overall survival HR 0.59, 95% CI 0.41-0.86):
This leads us to the VOLGA trial which accrued eligible patients who were ≥18 years old with cisplatin-ineligible MIBC (clinical stage T2-4aN0-N1M0/T1N1M0). Patients received 3 cycles of neoadjuvant therapy every 3 weeks: durvalumab (1500 mg; day 1 each cycle) + tremelimumab (75 mg; day 1 cycle 1, and day 8 cycle 2) + enfortumab vedotin (1.25 mg/kg; days 1 and 8 each cycle), followed by radical cystectomy, then 9 cycles of adjuvant durvalumab (every 4 weeks; day 1 each cycle) and tremelimumab (day 1, cycle 1 only). The trial design for VOLGA is as follows:
Dr. De Santis notes that methylation is indicative of tumor DNA and can be thought of as a cancer “fingerprint.” Additionally, a ctDNA methylation test has a high specificity, however sensitivity is less clear. Although the ctDNA data from VOLGA are limited, they are still inspiring. She notes the following:
- 7/10 patients had ctDNA clearance
- All 9 patients with pathologic complete response or downstaging were ctDNA negative pre-cystectomy. This leads to several hypotheses:
- #1: Is it safe enough for bladder preservation?
- #2: Can we safely omit adjuvant therapy?
- Two patients with pathologically unchanged tumors had ctDNA clearance pre-cystectomy. The hypothesis here is that ctDNA clearance may add important information to the pathological result and spare patients from treatment escalation
Dr. De Santis concluded this discussant presentation with the following summary statements:
- TAR-200 monotherapy shows a very high complete response rate, low toxicity, but duration of response still needs to be confirmed after longer follow-up
- Pembrolizumab significantly increased disease free survival in high risk muscle invasive urothelial carcinoma patients, but with rare life-changing side effects. Overall survival data are still pending
- ctDNA clearance is an important research biomarker, with methylation testing having high specificity that may help tailor treatment
Presented by: Maria De Santis, MD, PhD, Charite Universitatsmedizin, Berlin, Germany
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 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024.
References:
- Addeo R, Caraglia M, Bellini S, et al. Randomized phase III trial on gemcitabine versus mitomycin in recurrent superficial bladder cancer: Evaluation of efficacy and tolerance. J Clin Oncol. 2010 Feb 1;28(4):54-548.
- Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021 Jl;595(7867):432-437.