Perioperative therapy with sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) could provide a safe, effective alternative to radical cystectomy for patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC) who refuse the procedure and lack any other standard-of-care options, according to Andrea Necchi, MD.
Findings from the phase 2 SURE-02 trial (NCT05535218) presented during the 2025 ASCO Annual Meeting showed that the clinical complete response (cCR) rate with neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by response-adapted bladder sparing and adjuvant pembrolizumab (n = 16), was 44.4% (95% CI: 27.9-61.9).1 Notably, all of these patients underwent repeated transurethral resection of a bladder tumor (re-TURBT); 55.6% achieved ypT ≤1N0-x following radical cystectomy or bladder preservation.
Previously reported results from the phase 2 SURE-01 trial (NCT05226117), which evaluated neoadjuvant sacituzumab govitecan, also showed a pathological complete response (pCR) rate of 36.4% (95% CI, 14.9%-64.8%) among patients who subsequently underwent radical cystectomy (n = 11).2
“Patients have driven the way and are leading the direction for newer perioperative therapy,” Necchi stated. “Therefore, [based on SURE-02], bladder preservation with flexibility depending on patient preference and response to treatment, is simply the way to go.”
In an interview with OncLive®, Necchi elaborated on the rationale for SURE-02, early clinical and molecular data from the study, and discusses how this study is emblematic of the way that patient preference and response to treatment are driving treatment choices in MIBC.
Necchi is an associate professor at Vita-Salute Raffaele University and the head of genitourinary medical oncology at IRCCS San Raffaele Hospital and Scientific Institute in Milan, Italy.
OncLive: What was the rationale for conducting SURE-02?
Necchi: The SURE-02 study was built upon prior studies in MIBC: the [phase 2] PURE study [NCT02736266], which [evaluated] the activity of pembrolizumab monotherapy, and the SURE-02 study, [which investigated the] activity of sacituzumab govitecan. [Both studies] provided the background for [these therapies as neoadjuvant] single agents in this patient population. The natural evolution for our trial was to combine these 2 drugs together.
What should be known about the trial design, objectives, and patient population? How was the study protocol amended from its original protocol?
The SURE-02 study was actually designed at the beginning as a classical perioperative study, including a neoadjuvant combination therapy with sacituzumab govitecan, followed by cystectomy and then followed by maintenance or adjuvant pembrolizumab. Soon after we started with the treatment and the study [began], we realized that there were a lot of protocol deviations. [This was] due to the fact that the vast majority of patients, particularly when achieving a deep response to neoadjuvant therapy, questioned the need to undergo a radical cystectomy.
Based on this and on patient preference that emerged during the study, we amended the [protocol to] allow [for] a multidisciplinary discussion after neoadjuvant [treatment]. This allowed for a re-TURBT and the maintenance of pembrolizumab, thus providing the possibility to keep the bladder intact during treatment, depending on the response and patient preference. We shifted our focus a little bit from the primary end point of pCR to cCR, defined as negative imaging and negative biopsy assessed with TURBT.
What preliminary efficacy results were reported from this study?
The study provided very interesting signals regarding the observed cCR rate. Although it has concluded its enrollment of 49 patients, we are still waiting for the results of the primary end point for the last 13 patients. Therefore, the data are still a bit preliminary and are likely to change a little. Nevertheless, the interim findings showed that the cCR rate was 44.1%, which is quite promising. In particular, all those patients who were able to keep their bladder and underwent re-TURBT were actually metastasis-free at the last follow-up. There were only 2 intravesical relapses. Therefore, the metastasis-free survival rate in complete responders was 100%. In parallel, we have generated a lot of initial signals of biomarkers that are potentially associated with both therapeutic components, such as sacituzumab govitecan and pembrolizumab.
What do initial biomarker data suggest about the regimen’s efficacy in select patient subgroups?
What we presented at the 2025 ASCO Annual Meeting was that, in particular, [patients with] luminal subtype tumors were more likely to respond to treatment. Luminal subtypes are classically associated with immunotherapy resistance or poor responses, [indicating that] sacituzumab govitecan could be contributing in this regard. In fact, we saw that higher levels of TROP-2 expression were associated with a flat event-free survival curve. We also observed ARID1A mutations. Furthermore, TROP-2 expression in complete responders is enriched in the luminal subtype.
The story [of these data are] pretty consistent [with] the classical biomarker associated with immunotherapy: higher tumor mutational burden portended higher responses and higher clinical responses. These are also the initial data, the first data ever presented, on a biomarker associated with a TROP-2[–directed] antibody-drug conjugate [ADC].
What next steps are planned for investigating the validity and optimal use of this bladder preservation strategy?
There are many steps that should be completed. First, validation of the cCR [rate] is needed, as we have to accumulate information on its validity as an interim end point, and as a surrogate for survival in the perioperative setting, particularly in patients who keep the bladder intact. Second, we need more data regarding outcomes, and we possibly need to increase the rate of cCRs to over 50% to [indicate that our approach is] reliable strategy for bladder preservation. This highlights the need for the selection of patients [using] biomarkers.
SURE-02 was an older, general study. Perhaps in the future, we will be able to look at the luminal subtype as a potential way of selecting patients who are more likely to respond to a TROP-2 ADC, with or without immunotherapy.
How are these findings emblematic of the increasing emphasis placed on patient preference and response to treatment when navigating treatment choices in MIBC?
It is easy to realize from our study that avoiding cystectomy as much as possible is simply the way to go. How can we pursue this goal? With what kind of therapy? Therapies that are more likely to be successful in this context need to be developed. ADC [and immuno-oncology] combinations are pretty well-suited [to this task]. The possibility of avoiding chemotherapy and radiation is a good thing. However, we still need to optimize the regimen, the maintenance therapy, the duration of therapy, or the de-escalation of therapy for those who have responded well. This possibly includes using biomarkers like circulating tumor DNA or other tools that may prevent further relapses.
In this regard, [we are seeing] a few cases of local intravesical relapses in patients preserving the bladder with systemic therapy. This means we will likely need an intravesical therapy as a consolidation therapy for complete responders. Drugs like TAR-200 may be well-suited to be used in this kind of strategy as a consolidation therapy together with systemic therapy.
References
- Necchi A, Jong J, Raggi D, et al. First results of SURE-02: A phase 2 study of neoadjuvant sacituzumab govitecan (SG) plus pembrolizumab (Pembro), followed by response-adapted bladder sparing and adjuvant pembro, in patients with muscle-invasive bladder cancer (MIBC). J Clin Oncol. 2025;43(suppl 16):45. doi:10.1200/JCO.2025.43.16_suppl.45
- Cigliola A, Moschini M, Tateo V, et al. Perioperative sacituzumab govitecan (SG) alone or in combination with pembrolizumab (pembro) for patients with muscle-invasive urothelial bladder cancer (MIBC): SURE-01/02 interim results. J Clin Oncol. 2024;42(suppl 17):LBA4517. doi:10.1200/JCO.2024.42.17_suppl.LBA4517