Rashid Sayyid: Hello, everyone, and thank you for joining us today for this UroToday journal club recording. I'm Rashid Sayyid, Robotic Urologic Oncology fellow at the University of Southern California in LA. And I'm glad to be joined today by Zach Klaassen, Associate Professor and program director at Wellstar MCG Health in Augusta, Georgia.

And today, we'll be discussing the recently published Phase III CREST trial that looked at the combination of sasanlimab plus BCG in BCG-naive, high-risk, non-muscle invasive bladder cancer. This paper was recently published in Nature Medicine with Doctor Neal Shore as the first author and Doctor Gary Steinberg as the last or senior author.

The majority of the focus to date has been in the BCG-unresponsive non-muscle invasive space. And given the high-risk nature of this disease, obviously, all of these efforts have been in to prevent the ultimate standard of care, which remains radical cystectomy for these patients. And these efforts have been, for the most part, pretty fruitful.

And over the last decade, we've seen three agents approved by the FDA in this space – pembrolizumab, the KEYNOTE-057 trial. In 2022, we saw nadofaragene firadenovec approved. And then more recently in 2024, we saw N-803 or Anktiva plus BCG. This combination approved in 2024 based on the results of the QUILT-3.032 trial.

But what about the BCG-naive high-risk space? And so the standard of care has and has been for a while actually, TURBT followed by adjuvant intravesical BCG induction given once weekly for six weeks, followed by three years of maintenance. But despite this schedule, the risk or the rate of disease recurrence or progression within two years remains high at 40%.

And really, this really underscores the importance of novel agents and combinations in order to avoid radical cystectomy with the systemic therapies that come with that for advanced disease, namely EV (enfortumab vedotin) plus pembro, and Gem-Cis and maintain quality of life as well by avoiding these treatments.

And it's important to highlight that in the locally advanced metastatic setting, that multi-agent systemic therapy – meaning EV plus pembro or gemcitabine plus cisplatin – remains standard of care. So two systemic therapy drugs given at the same time.

And so one of the rationales, as we'll see later, for giving one agent is you give a patient one agent, although systemic therapy in the noninvasive setting. But you potentially, can avoid giving them two agents and the increased toxicity that comes with that down the line. So this is something to think about as we consider incorporating systemic therapy into the treatment paradigm of the BCG-naive high-risk patients.

And so what is sasanlimab? It's an anti-PD-1 monoclonal antibody that's typically administered subcu, but can also be administered IV in select cases. It's been studied in a couple of different cohorts. We had a Phase I trial published in 2019 that looked at the safety and efficacy of this drug in 40 patients with locally advanced or metastatic solid tumors, with an objective response rate of 18%. These are heavily pretreated patients and with a favorable safety profile with 7% grade 3 or worse treatment-related events with the subcu formulation.

More recently, in 2023, we saw this drug tested in a phase Ib/II trial in a cohort of patients that included both non-small cell lung cancer and then urothelial carcinoma, who had disease progression or intolerance to systemic therapy. And again, we saw a similar signal here with an objective response rate of about 18%, median progression-free survival modest at three months, and median overall survival of just under one year. But again, a heavily pretreated cohort of patients. Clearly, there's an early signal of some efficacy and importantly, a favorable safety profile.

And so why would we look at sasanlimab and BCG in the first place? What is the rationale for combining these two agents? We've known for a while that BCG exposure increases your PD-L1 expression. And we know that PD-L1 expression or increased expression is a contributing factor to the immune escape mechanism in bladder cancer cells.

And when we look at the data from the Phase Ib/II trial published in 2023 by Cho et al., those patients that had tumors with a higher PD-L1 expression, 25% or higher, had an improved objective response rate, progression-free, and overall survival with sasanlimab. So this is similar to what we would see with BCG. And so we would expect that patients who receive BCG with sasanlimab potentially a synergistic effect would be in effect here.

And so the study objective of this Phase III trial was to compare the efficacy and safety of sasanlimab given subcutaneously with BCG induction and maintenance to BCG induction maintenance alone. And here we see the study design. Very important to understand that this Phase III trial included those who are BCG-naive or high-risk non-muscle invasive bladder cancer, meaning either T1 disease, high-grade TA and/or CIS. And none of these patients had received a prior immune checkpoint inhibitor in different disease states.

Eligible patients were randomized into one of three arms. The main comparison for the purposes of this trial were arms A and C. So arm A is the group of patients that received everything. So sasanlimab up to 25 cycles subcu with the BCG induction for six doses plus maintenance. I just want to note here that it's two years of maintenance, not three.

And then arm C below here is BCG induction plus maintenance, which is the standard of care arm. And then we have an arm B here, which is middle of the ground treatment arm, where patients receive sasanlimab but only BCG induction. So no maintenance component. And that's how it differs from arm A, which received maintenance for up to two years. But for the highest focus here is arm A versus arm C.

The study objectives were to compare arm A, so everything, to BCG induction plus maintenance or arm C, in terms of prolonging the investigator-assessed event-free survival.

And so what was an event in this study? It was either high-grade recurrence, disease progression, CIS persistence, or death. Any of these four events was considered an event for the purposes of this trial.

In terms of secondary objectives, it was to compare event-free survival for arm B, meaning sasanlimab plus BCG induction only, compared to the BCG induction plus maintenance arm C. Also, overall survival, arms A and B, so this is synonym of arms versus C, which is the no sasanlimab arm. Looked at complete response in CIS patients, and importantly, the duration of complete response as we'll see later on. Looked at the safety adverse events as well as the quality-of-life outcomes in these patients.

And so with this introduction, let's move on to the results and discussion where Zach will go over this and frame these results for our patients, and how it falls in terms of our treatment sequencing for these high-risk patients.

Zachary Klaassen: Excellent introduction as always, Rashid. Really setting the stage for the CREST trial and the hypothesis of combining sasanlimab plus BCG.

And so this is the table 1 from this trial looking at the three arms - sasanlimab plus BCG induction and maintenance here arm A. Arm B, sasanlimab plus BCG induction in the middle. And then to the far right, the standard of care, BCG induction plus maintenance.

And when we look at these here, we see that the median age was 67. Roughly 80% of these were male. Roughly 2/3 of patients were white, all with excellent performance status.

In terms of the presence of CIS at the time of enrollment, roughly 1/4 of patients, and we see a very geographic heterogeneous population across the globe in the middle of the table here.

Majority of these patients were pure urothelial carcinoma. The worst T stage. Roughly 11% to 14% CIS, about 1/4 to 1/3 TA, and roughly 1/2 or just over 1/2 were T1 patients. So truly a high-risk group when we look at the number of T1 patients, the number of CIS patients.

So this is the primary outcome for the study. This is event-free survival comparing arm A versus arm C. Arm A is in blue and arm C is in gray. We see a statistically significant improvement in event-free survival favoring sasanlimab plus BCG induction and maintenance. Hazard ratio of 0.68. 95% confidence interval, 0.49 to 0.94. And we can see here at 36 months, 82.1% of patients were event-free in the combination arm, compared to 74.8% in the standard-of-care BCG induction plus maintenance arm.

When we look at the subgroup analysis for arm A versus arm C, generally, we see that all of these point estimates are to the left, which favors sasanlimab plus BCG induction and maintenance. I'll point out a couple of key subgroups here. We see with CIS patients, a benefit for combination hazard ratio of 0.53; for those with T1 disease, again, a benefit for plus BCG with a point estimate of 0.63. So generally the majority of these all favoring the combination, specifically highlighting the CIS and the T1 patients.

This is one of the secondary endpoints. This is event-free survival looking at arm B versus arm C, as Rashid mentioned. Arm B was sasanlimab plus just induction BCG versus standard-of-care BCG induction and maintenance. Here we do not see a benefit for the sasanlimab arm, a hazard ratio of 1.16. And clearly the confidence interval is crossing one. So no benefit for just BCG induction plus sasanlimab.

This is the event-free survival in the intention-to-treat population, again, stratified by arm A, B, and C. I've highlighted some of these boxes because this is really what's the components of event-free survival. So progressive disease was one of them. Very similar between the two where we really see a difference, and where the majority of these events are probably driven from was recurrence of high-grade disease.

So 7.4% in arm A, compared to 17.3% in arm B, and 15.1% in arm C. Persistence of CIS very low across all 3, and death also quite uncommon during the follow-up. And no appreciable differences between these three arms. So really, the event-free survival – the take-home message from this slide – is that it was primarily driven by recurrence of high-grade disease, which clearly was lower in the sasanlimab plus BCG induction and maintenance.

Overall survival. This is arm A versus arm C on the left, no difference. Hazard ratio of 1.13. On the right is B versus arm C. Again, no difference in overall survival, 1.07 hazard ratio.

As Rashid mentioned, the probability of remaining in complete response for CIS patients who achieved a complete response looking at arm A versus arm C. So if patients had a complete response at three months, at the time point of three years, they had a 91.7% probability of remaining in complete response in the sasanlimab plus BCG induction and maintenance arm, compared to only 67.7% in the standard-of-care BCG induction and maintenance arm. So again, those patients that do achieve that quick complete response at three months do have what seems to be a very durable complete response, particularly at three years.

Importantly, for this trial is treatment-related adverse events during the on-treatment period. Again, arm A versus arm B versus arm C. Just comparing these across the board, we see that patients with any event grade 3 plus 29.1% in arm A, the highest, down to 21.8% for arm B and 6.3% in arm C.

Looking at some of these events of note, 6% grade 3 plus lipase increase in arm A versus 1.4% in arm B. Very little hypothyroidism, only 0.6% in arm A for grade 3 plus events. Fatigue also very well tolerated. Very few grade 3 plus fatigue adverse events. Slightly higher any-grade adverse events for arm A compared to arm B and C. And finally hyperthyroidism, limited grade 3 or any-grade for arm A and arm B.

What's important from a context standpoint also is the immune-related adverse events. So this is, again, looking a little more specific at those thyroid disorders, 17.7% any grade for arm A compared to 20.4% any grade in arm B, and 1.4% in arm C. Rash around 13% for both arm A and arm B. Hepatitis, handful of grade 3, but also roughly 4% any-grade pancreatitis. Very similar 4% any-grade, as well as coming down to pneumonitis and colitis. So certainly not high numbers, but there was a proportion of patients that did have some of these immune-related adverse events in arm A and B, which primarily related to sasanlimab.

So by way of discussion, the key finding from the CREST trial was that the risk of an event-free survival event was 32% lower in the sasanlimab plus BCG induction plus maintenance arm compared to BCG induction and maintenance. And so when we look at the sasanlimab plus BCG induction, this arm B did not result in prolongation of event-free survival compared to standard-of-care BCG induction plus maintenance.

And so what this really underscores is the need for BCG maintenance, not only a standard of care for BCG currently, but also in combination with sasanlimab. As expected, there was a higher frequency of any-grade treatment-related adverse events, as well as grade 3+ and immune-related adverse events in the sasanlimab plus BCG arms.

This suggests that there are no relevant safety differences between shorter or longer exposure to BCG, but really, the benefit and risk of adding sasanlimab to BCG in clinical practice will certainly rely heavily on shared decision-making.

So there's likely several outstanding questions from the CREST trial. And one of them is certainly the comfort level of the urologist to giving subcu sasanlimab. Certainly, this is going to be easier to give than an IV, which we've seen in pembrolizumab in the high-risk BCG-unresponsive cohort.

And so whether this is given by urologists or whether there's partnership with medical oncologists in this high-risk BCG-naive cohort will remain to be seen, and likely, will be practice dependent as well.

There's also the impact of the ongoing BCG shortage, particularly in the United States, where there still are areas of very limited BCG availability. Hopefully, that will improve with recombinant BCG as well as increasing efforts to make BCG more available. So certainly, there may be other outstanding questions. These are certainly two that we thought were relevant to putting CREST into context in clinical practice.

So take-home messages from the CREST trial. The significant reduction in the risk of recurrence of high-grade disease, persistence of CIS, disease progression, or death led to durable disease control in patients receiving sasanlimab plus BCG and two years of maintenance. The safety profile of the combination was manageable.

And thus sasanlimab plus BCG induction and maintenance has the potential to redefine the treatment paradigm and clinical decision-making for patients with aggressive CIS or T1 BCG-naive non-muscle invasive bladder cancer. We thank you very much for attending this UroToday Journal Club on the CREST trial. Thank you so much for your attention.