Andrea Necchi, MD, on promising SunRISe-4 data of TAR-200 in MIBC

In this interview, Andrea Necchi, MD, highlights the background and key findings from the phase 2 SunRISe-4 trial (NCT04919512), which is assessing the safety and efficacy of neoadjuvant treatment with TAR-200 plus cetrelimab and cetrelimab monotherapy in patients with muscle-invasive bladder cancer (MIBC) who are scheduled for radical cystectomy and who are ineligible for or refuse neoadjuvant chemotherapy.

Andrea Necchi, MD

Initial data from the trial were recently presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain. Overall, results showed that TAR-200 plus cetrelimab was associated with strong pathologic complete response and pathologic overall response rates.

Necchi is an associate professor of oncology at the Vita-Salute San Raffaele University and the director of GU medical oncology at San Raffaele Hospital in Milan, Italy.

This transcription was AI generated and edited by human editors for clarity.

Could you describe the background/rationale for this study?

SunRISe-4 is a platform study as part of the SunRISe studies. In particular, SunRISe-4 aims to target the population of patients with MIBC who are ineligible for or refuse to receive cisplatin-based chemotherapy. The standard of care for patients with MIBC is radical cystectomy with or without neoadjuvant chemotherapy. We know very well what the limitations are of the use of neoadjuvant chemotherapy. Up to 50% of the patients with MIBC are ineligible for neoadjuvant chemo, primarily due to poor renal function, comorbidities, or poor performance status. There is a consistent proportion of patients reported in the literature who refuse to get neoadjuvant chemotherapy, primarily due to the concerns related to toxicity. Furthermore, [of the] 50% of the patient population who experience a recurrence, usually within 2 years of radical cystectomy, the 5-year survival estimate is small. So, there is clearly an unmet medical need.

We do have data that link pathological complete response to neoadjuvant chemotherapy to lower risk of having disease relapse and lower risk of dying from the disease [in patients with MIBC]. Pathologic complete response [pCR] rates from various therapies like radical cystectomy upfront or neoadjuvant chemotherapy or neoadjuvant checkpoint inhibitors have been reported already in the literature, being 10% to 15% for cystectomy alone, around 30% with the neoadjuvant chemo, and then reported to be between 30% and 40% with various trials of checkpoint inhibitors. Overall, there is an opportunity to investigate the new drugs and to test the neoadjuvant [therapies] and invest in new studies in this disease. SunRISe-4 is the study that is investing in this patient population.

What is the design of the study?

SunRISe-4 is a randomized study that aimed to test 2 different approaches: the neoadjuvant combination of TAR-200 and cetrelimab [and cetrelimab alone]. TAR-200 is an intravesical delivery system that is aimed to provide a sustained, continuous release of gemcitabine into the bladder. It is a therapy with an easy outpatient procedure that usually take 2 to 3 minutes. Phase 1 studies have already provided [data on the initial] activity and safety of TAR-200 in patients with MIBC. Cetrelimab is a one of the many checkpoint inhibitors targeting PD-1, which is also based in being investigated in the early disease stage, like a non–muscle-invasive disease within the SunRISe platform; in particular, SunRISe-1.

SunRISe-4 is enrolling patients with cT2-cT4 N0M0 MIBC with pure, predominant urothelial carcinoma histology ineligible for or refusing chemotherapy, randomized to receive the combination of TAR-200 and cetrelimab or cetrelimab monotherapy. The study is aimed to provide evidence of the efficacy and safety of the 2 components toward the primary outcome. There are 2 important stratifications factoring into randomization, which are the completeness of the TURBT prior to study neoadjuvant therapy and the clinical tumor stage. The study, importantly, is not aimed to compare the efficacy of the combination vs the monotherapy. It's aimed to provide a descriptive analysis of their efficacy and safety data and to investigate on the contribution of the 2 components toward the towards the primary end point. Patients receive 4 cycles in either arm of TAR-200 and cetrelimab or cetrelimab monotherapy every 3 weeks up to radical cystectomy, followed by 2 years of follow-up.

The primary end point of SunRISe-4 is pCR rate, with a stringent definition of pCR, meaning absence of any residual viable cancer on the tissue specimen at the time of radical cystectomy. Secondary end points included relapse-free survival and safety. There are, of course, exploratory end points, represented by pathological downstaging to non–muscle-invasive disease, other survival end points, [including] overall survival biomarkers, and quality-of-life parameters. The study is aimed to accrue a total of 160 patients.

What were the key findings that were presented at ESMO this year?

At ESMO 2024, we have provided data from the interim analysis 2, which was a predefined analysis on the first 80 evaluable patients [who underwent] radical cystectomy. The findings that we have provided are related to the first 122 patients––80 patients in cohort 1, the combination therapy, and 42 in cohort 2, the monotherapy with cetrelimab. Of this population, 53 were evaluable in cohort 1, the combination therapy, and 31 in the cetrelimab monotherapy [cohort]. We are reporting data from these 2 populations in particular, with efficacy-evaluable data.

The baseline characteristics were well balanced between arms. Around 40% of the patients were ineligible to cisplatin in cohort 1 vs 36.6% [in cohort 2]. Twenty percent of the patients [in the combination arm] vs 14% of patients [in the monotherapy arm] presented with residual disease at the time of treatment initiation. Clinical T2 stage was primarily the stage of patients presenting in the study, [with] 78% in cohort 1 vs 85% [in cohort 2]. There was a proportion of 20% and 26% in both arms of patients with a variant histology within the urothelial cancer in the bladder. There were a few patients with a history of previous non–muscle-invasive disease and previous intravesical installations.

The primary end point data in the efficacy-evaluable patient population of clinical T2-T4 patient population provided a pCR rate of 42% in the combination therapy arm with a pathological downstaging to non–muscle-invasive disease of 60%. The pCR rate with cetrelimab monotherapy was 23% vs 36% pathological downstaging.

In particular, when we look at the breakdown of the data according to the 2 stratification factors, the completeness of the TURBT and the clinical tumor stage, we saw that with the combination therapy in cohort 1, the pCR rate in the population of cT2 patients rose to 48%, with 68% of patients downstaging to non–muscle-invasive disease. In cT3-cT4, the pCR rate with the combination therapy was 23%. The data for the combination therapy of TAR-200 and cetrelimab seemed to be consistent regardless of the completeness of the TURBT. We should acknowledge the fact that the preliminary group of patients presenting with an incomplete TURBT was small. We need to validate this information in a higher number [of patients].

For the cetrelimab monotherapy arm, we had 23% of the patient population with the cT2 stage achieving pCR. The results were consistent regardless of the clinical tumor stage for immune therapy. There were no pCR and no downstaging with cetrelimab in patients presenting with incomplete TURBT. The pCR for patients presenting with the complete TURBT was 26%, so in the range of the data reported the all-comers.

The very important data to me are related to the association between TAR-200 exposure and pathological response. We realized that in the patients initially enrolled at the beginning of the trial, when we were at the beginning of the learning curve for urologists using TAR-200 and managing patients with TAR-200 therapy in their outpatient clinic, [those patients] were only able to get 1 or 2 doses [of TAR-200] and had interrupted treatment due to toxicity, physician decision, patient decision, compliance, or different decisions. [They still] benefited [from therapy], with a pCR of 27%. The PCR rate increased to 30% in the population of patients who got 3 doses of TAR-200. [It] increased to 50% in the majority of patients who were able to complete the full course of 4 cycles of TAR-200 plus cetrelimab, with a pathological downstaging in this population reaching 70% cut-off, so very high proportion. [This is a] very important proportion of pathological responses in the majority of patients who were able to get the full course of treatment.

Toxicity and the safety data are consistent with previous studies and the studies already reported in non–muscle invasive disease within SunRISe-1. The grade 3/4 treatment-related adverse events were in the range of 11.4% with the combination therapy and less than 5% with cetrelimab monotherapy. The immune-related adverse events were less than 10% in both arms. The median time to radical cystectomy was in the range of 12 to 13 weeks. This in the range of what is recommended in the guidelines.

Overall, these efficacy and safety data [are] the first data [reported that] support the use of a combination of intravesical therapy and systemic checkpoint inhibitors in patients with MIBC.

What are the next steps for the trial, or with TAR-200 in general?

The study is accruing very fast. As with all the SunRISe studies, the accrual rate is tremendously quick. The study is slated to complete the full accrual of the patient population by the end of this year, meaning that we will likely have more complete data, or almost final data from the SunRISe-4 study in 2025.

The TAR-200 development in general is being pursued in other SunRISe studies, as I mentioned, SunRISe-1 -2 -3, -4, and -5. [These studies] include patients with non-muscle invasive disease in SunRISe-1, -3, and -5, and patients with the MIBC in SunRISe-2 and -4. TAR-200 is being developed with various strategies, aimed to provide an improvement in the standard of care therapy from various perspectives. [For example], from the bladder-sparing perspective in SunRISe-2, from the neoadjuvant therapy perspective in SunRISe-4, in BCG-unresponsive disease in SunRISe-1, and in the BCG-naïve [setting] in the other studies. Overall, TAR-200 is being tested with the aim of changing the therapeutic paradigm of patients with an early bladder cancer diagnosis, including non–muscle-invasive disease and muscle-invasive disease.

Is there anything else you’d like to add?

TAR-200 and cetrelimab is [also being studied in] SunRISe-1 [in patients with BCG-unresponsive NMIBC]. We have reported the last update from the entire cohorts of patients included in SunRISe-1, with data on the clinical complete response from the 3 arms: combination therapy with TAR-200 plus cetrelimab, TAR-200 monotherapy, and cetrelimab monotherapy. [Data have] confirmed the efficacy, activity, and safety of TAR-200 monotherapy in this population. It is slated to become a potential new player in the field based on the clinical complete response, which was higher than 80%. This is the highest reported thus far in this population. So, [TAR-200 is] a potential change in the way we treat patients, and an additional player in the therapeutic armamentarium of patients with BCG-unresponsive disease.