Sasanlimab Plus BCG Could Alter Treatment Paradigm in BCG-Naive, High-Risk NMIBC

Neal Shore, MD, FACS

Data from the phase 3 CREST trial (NCT04165317) could drive a shift in the clinical management of Bacillus Calmette-Guérin (BCG)–naive, high-risk non–muscle-invasive bladder cancer, where BCG alone has been the long-established standard of care, according to Neal Shore, MD, FACS.

Topline findings from CREST announced by Pfizer earlier in January 2024 showed that the combination of the anti–PD-1 monoclonal antibody sasanlimab (PF-06801591) and induction BCG, with or without maintenance BCG, generated a statistically significant and clinically meaningful improvement in event-free survival (EFS) vs BCG induction and maintenance alone in patients with BCG-naive, high-risk NMIBC.

Safety results were consistent with prior data for sasanlimab and the known profile of BCG.

“These data are important because [they could help] augment shared decision-making, giving patients [with high-risk NMIBC] and physicians choice and preference in optimizing care,” Shore said.

Before full topline data from CREST are presented and published, Shore sat down for an interview with OncLive^® to discuss the implications of the findings. He highlighted the rationale for adding an anti–PD-1 agent to BCG in the treatment of patients with BCG-naive, high-risk NMIBC, and detailed how sasanlimab plus BCG could alter the treatment paradigm in high-risk NMIBC if the CREST findings support regulatory approval.

Shore is the primary investigator of the CREST trial and medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

OncLive: What differentiates the anti–PD-1 monoclonal antibody sasanlimab from other immune checkpoint inhibitors?

Shore: The most important aspect is that sasanlimab is administered subcutaneously. Historically, PD-1 blockers had been administrated intravenously. [CREST] was the first phase 3 trial in bladder cancer [to evaluate this type of subcutaneous treatment], with sasanlimab administered once every 4 weeks in a subcutaneous delivery system.

The obvious advantage to [subcutaneous administration] is a more rapid throughput in the clinic. Whether you’re in urology or medical oncology, you do not need to deliver therapy intravenously [IV], and it can be administered [faster]. There's not as much technical skill involved in subcutaneous administration vs IV access and administration. That provides nice efficiency for clinics and patients.

What was the rationale for adding sasanlimab to standard-of-care BCG for patients with BCG-naive, high-risk NMIBC?

We knew from earlier work with other checkpoint inhibitors that PD-1 blockers have been beneficial in BCG-unresponsive CIS, and we have compelling data for other PD-1 blockers being successful in patients with frontline, metastatic urothelial cancer. [CREST] looked to combine the old, standard use of BCG [in the BCG-naive setting in combination with sasanlimab], using BCG as induction only or as induction and maintenance.

[CREST] was a 3-arm trial [that enrolled] patients with high-risk, BCG-naive NMIBC. They had either high-grade papillary disease, T1 lamina propria invasion, or carcinoma in situ [CIS]—the more traditional definition of high-risk NMIBC. The 3-arm study [enrolled] over 1000 patients globally. Patients in arm A received traditional induction and maintenance BCG in conjunction with 2 years of sasanlimab [given] once every 4 weeks. [Patients in] arm B received sasanlimab for the 2-year period; however, those patients received only induction BCG with no maintenance. In arm C, patients did not receive sasanlimab; they received induction and maintenance BCG for 2 years.

Topline data showed CREST met its primary end point with sasanlimab plus BCG improving EFS vs BCG alone. What are the potential implications of these findings?

The traditional challenge that we face with patients with high-risk NMIBC is that they could have recurrent disease and then are considered unresponsive to BCG. Many of these patients may also go on to progress to a more advanced histopathology. Therefore, by adding an immunotherapeutic—as a class, [these agents] have been known to have benefit in muscle-invasive disease, metastatic disease, and BCG-unresponsive CIS—the goal was to cut down on the likelihood of recurrence, progression, or death.

It's remarkably rewarding to see that this was a successful study. After we present [and publish] the full data set, [sasanlimab plus BCG] certainly has a potential for regulatory approval.

If sasanlimab plus BCG does earn approval from regulatory authorities, what would be the implications for the treatment paradigm for BCG-naive, high-risk NMIBC?

It [would be] important for patients and clinicians because it would expand our armamentarium for shared decision-making. [There could be] patients who would say, ‘I want more than just BCG,’ which clearly has a beneficial effect as induction and maintenance. Are there going to be specific types of patients and histopathology [where we would] want to combine traditional BCG with a PD-1 blocker?

Could there be a potential role for sasanlimab in combination with BCG outside of the population of patients with high-risk NMIBC?

I think there will clearly be a role for PD-1 blockers in intermediate-risk disease. There are several ongoing early-phase trials right now combining PD-1 blockers with other novel mechanisms of action for patients with intermediate-risk disease.

In addition, there are opportunities to combine PD-1 blockers with neoadjuvant strategies and bladder-sparing strategies, in addition to BCG-unresponsive combinations. It's an exciting time for researchers and health care providers who care patients with bladder cancer, and that's throughout the entire continuum, [including] NMIBC, bladder-sparing opportunities, neoadjuvant [therapy] prior to radical cystectomy, perioperative therapeutics around cystectomy, and then all the wonderful work we've already seen with frontline and metastatic disease.

Reference

Pfizer’s sasanlimab in combination with BCG improves event-free survival in patients with BCG-naïve, high-risk non-muscle invasive bladder cancer. News release. Pfizer. January 10, 2025. Accessed January 13, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-sasanlimab-combination-bcg-improves-event-free