Sasanlimab Plus BCG Emerges as a Potential Option for High-Risk NMIBC Despite Predictive Challenges

With encouraging efficacy signals observed with immune checkpoint inhibitors in earlier lines of treatment for BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC), the novel PD-1 inhibitor sasanlimab may be an attractive option for select patients who experience local or metastatic disease relapse, according to Thomas Powles, MD, MBBS, MRCP.

Data from a subgroup analysis of the phase 3 CREST study (NCT04165317) presented during the 2025 ASCO Annual Meeting showed that sasanlimab plus BCG (n = 352) produced superior event-free survival (EFS) rates vs BCG alone (n = 351; HR, 0.68; 95% CI, 0.49-0.94).1 Notably, EFS benefit with the combination vs BCG monotherapy was observed across key subgroups, including patients with CIS with or without Ta/T1 disease (HR, 0.53; 95% CI, 0.29-0.98), T1 disease with or without CIS (HR, 0.63; 95% CI, 0.41-0.96), and those with high-grade Ta disease with or without CIS (HR, 0.88; 95% CI, 0.46-1.70).

Powles added that more precise methods of identifying patients who are best suited for the combination are needed.

“[Sasanlimab plus BCG] does appear to be working across the board,” Powles, a professor of genitourinary oncology and director of Barts Cancer Centre at St Bartholomew’s Hospital, Queen Mary University of London in England, shared with OncLive®. “We [found some] enrichment in select subgroups, but it's not complete. We do need to identify biomarkers of associated response; sadly, PD-L1 doesn't seem to be that. No does [the presence of] CIS seem to be the whole answer to that question.”

In the interview, Powles described what sets sasanlimab apart from other checkpoint inhibitors in NMIBC, shared key findings from the subgroup analysis of EFS by disease stage, outlined ongoing efforts to maximize immune checkpoint inhibitor efficacy through increasing use in earlier stages, and shared avenues for future research to pinpoint the agent’s ideal application.

OncLive: What is the mechanism of action of sasanlimab? How might its use in combination with BCG enhance efficacy in high-risk, BCG-naive NMIBC?

Powles: Sasanlimab is a subcutaneous PD-1 inhibitor. PD-1 inhibitors are well known throughout cancer. They are associated with long-term, durable remissions. They work by removing some of the cancer-related brakes, which results in long-term efficacy in subsets of patients.

There are issues about who these [patient subsets] might be and there’s work looking at different biomarkers [to elucidate this]. BCG is a treatment that's been around since the 1930s. It's a immune activator that goes into the bladder and is associated with immune infiltration. This combination of removing the brakes [with sasanlimab] and hitting the accelerator [with BCG] could be additive or synergistic, and therefore it's a very reasonable research question.

How was the CREST study designed, and what primary efficacy data were previously reported from this study?

CREST is a big randomized, phase 3 study. It includes patients with BCG-naive, high-risk, NMIBC. The intervention is a sasanlimab and the control arm is BCG alone. The study was positive for EFS, with an HR of 0.68 in the intention-to-treat population.

How did sasanlimab plus BCG compare with BCG alone in terms of 3-year EFS rates for patients with CIS and those with T1 tumors?

We looked at some of the subsets, particularly the CIS subset. We also looked at the role of PD-L1 as a biomarker in this disease. We essentially showed some enrichment in the HR from 0.68 [in the ITT population] to 0.53 in the CIS population. We showed quite nice Kaplan Meier curves that go apart and stay apart in that subgroup. [However], if we look at this more in detail, the confidence intervals in the ITT population were somewhat overlapping with [that of the CIS population]. HRs for other subsets, like T1 and TA, or high-grade [disease], were also within those confidence intervals. Therefore, it's possible to say that although there might be some enrichment [in select subgroups], [sasanlimab plus BCG] seems to be working in a broader population as well.

Of course, any subset analysis has the risk of false positive results. [To account for this,] we tried to link [outcomes] with the PD-L1 biomarker. If these were linked with that biomarker, we might say it provides a strong rationale for that [combination] working. In actuality, we showed that PD-L1 expression was lower in the CIS population. We then tried to see if it was predictive of response to sasanlimab in the ITT population, and the CIS T1 or the grade 3 TA population. We didn't show biomarker enrichment, particularly in that CIS population.

Overall, it's fair to say that sasanlimab plus BCG works to prevent events in BCG-naive NMIBC, which is great. The drug is associated with a 10% to 15% chance of long-term adverse effects, and there's a risk-benefit ratio to be had there.

What additional data will be necessary to fully establish the clinical utility of sasanlimab plus BCG in this setting?

The immune checkpoint inhibition journey has been a 10- to 12-year journey since the first atezolizumab and pembrolizumab data came out in heavily pretreated patients very late in the disease. The drugs are not great at getting fabulous control, and many patients progressed. We showed that immune checkpoint inhibition sometimes struggled in aggressive disease, which had spread to many sites.

As we have moved earlier into muscle-invasive disease, and now non–muscle-invasive disease, we are seeing some quite clear EFS signals. This underlines that the biology of earlier disease, from an efficacy perspective, is probably more attractive. One of the dangers of MIBC and NMIBC is that many patients can be cured by surgery alone, and so there may be a degree of overtreatment. We need to think carefully about that balance.

It is also fair to say that there are urothelial cancer patients who do come into harm’s way, even in non–muscle-invasive disease, with either local relapse or metastatic relapse. Preventing that is important, and this will be an attractive option for some of those patients. I would like to identify those patients better, and we are going to try to do that.

What might these findings suggest regarding the potential role of sasanlimab in these high-risk populations, and how might they inform future clinical trial creation?

The takeaway is that sasanlimab has activity in urothelial cancer. We've tested it in NMIBC in combination with BCG, where it showed a reduction in the risk of EFS, and we've tried to identify subgroups which have much better outcomes. We've shown a degree of enrichment, but it's not complete. There's activity in other patients as well, but we have not been able to link it with a PD-1 or a biomarker overall.

There's more work to do in this space. There are other studies, like the phase 3 POTOMAC study evaluating duvalumab [Imfinzi] plus [BCG induction and maintenance therapy]. We don't know the [full data] yet, but it [was reported to be] positive [for improved disease-free survival with the combination in high-risk NMIBC vs BCG alone], which reinforces the results [in CREST].2

References

1. Powles T, Shore N, Galsky M, et al. Sasanlimab in combination with bacillus Calmette-Guérin (BCG) in BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC): Event-free survival (EFS) subgroup analyses based on disease stage from the CREST study. J Clin Oncol. 2025;43(suppl 17):4517. doi:10.1200/JCO.2025.43.16_suppl.4517
2. Imfinzi regimen demonstrated statistically significant and clinically meaningful improvement in disease-free survival for high-risk non-muscle-invasive bladder cancer in POTOMAC phase III trial. News release. AstraZeneca. May 9, 2025. Accessed August 18, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/imfinzi-improved-dfs-in-early-bladder-cancer.html