Richard Cathomas: I'm happy to be here. Thank you for the invitation. So what we did is actually we treated these patients with chemoimmunotherapy. We did a predecessor study using cisplatin/gemcitabine/durvalumab, very similar to NIAGARA. We started that a little bit earlier and that was published a few years ago. And so based on that, we thought, well, how could we expand on the response? And we had some experience with recombinant BCG in the non-muscle-invasive bladder cancer setting, which is kindly genetically modified BCG supposedly to have better immunogenicity and less systemic side effects. And so we were hypothesizing that if we include an intravesical part, we would boost at least the local response. Well, we were somewhat hoping that maybe we could see some systemic boost as well.
So what we did is we started off with the checkpoint inhibitor, which was actually atezolizumab in this trial. And so on day one of the treatment, the neoadjuvant treatment, they received atezolizumab and intravesical rBCG. And the rBCG was given in total three times once per week. And then from cycle two onwards, the chemotherapy part started cisplatin/gemcitabine together with the atezo and that continued for four cycles.
Then we did the re-staging and then patients underwent radical cystectomy and extended pelvic lymph node dissection. That was the setup. The adjuvant part was atezolizumab again for 13 cycles, but only patients who still had muscle-invasive residual disease received atezo. And we amended the trial actually after a few patients when the results from the adjuvant trials came out and we thought, well, why should we give adjuvant treatment if a patient has pCR-
Elizabeth Plimack: Right. Absolutely.
Richard Cathomas: ... or pathological downstaging? So we were free to do that and we are happy. Actually, I think that was really a very good decision. So this trial has two interesting components. One is the intravesical rBCG and two, it's really the adjuvant part that is omitted in all patients with pathological downstaging.
Elizabeth Plimack: Right. That's great because as you know, the current paradigm is a sandwich approach with neoadjuvant, then cystectomy, then the same thing. Adjuvant for the most part with EVP, we do get great results, but all of us wonder how much of that adjuvant portion you need and in which patients. So the fact that you defined it by pathology makes a lot of sense. Let me ask you a question about this sort of dual approach giving the intravesical therapy and then the platinum-based therapy and then the cystectomy. We've thought a lot obviously about this in this bladder preservation setting. You had pretty good path-CR rates as a result. How do you think this might be a setup for a future trial using that dual approach, but maybe with bladder sparing?
Richard Cathomas: Absolutely. I think this is really the next step. So first of all, the trial was conceived in 2019. So we used what was at the time we thought would be the standard of care. So chemoimmunotherapy, which by 2019 was not yet the standard, but still based on our previous trial. These days, obviously you need ADC IO as a backbone, so EVP. And then if we then add in the recombinant BCG intravesically to this backbone, eventually we might get even higher pCR rates.
And hen the next step really is to have a very thorough clinical re-staging so that we can say this is in clinical complete response, and then patients could go on to keep their bladder without radiotherapy, without the surgery. Big question there is, do we need to give some consolidation systemic treatment or is it just enough with say four cycles and what do we do the ones that have non-muscle invasive residual, could we maybe just escalate the intravesical treatment? And that is our idea. So for the next study, this is going to be the next step, definitely. We need to go down the road of patients that can keep their bladder really untreated.
Elizabeth Plimack: Absolutely. Remind our audience what your path-CR rate was with the intravesical BCG plus cisplatin-based chemo IO.
Richard Cathomas: Yeah. So our pCR rate was 68%, which is really quite nice and we were-
Elizabeth Plimack: Maybe the highest ever.
Richard Cathomas: It was actually the highest ever in an unselected patient population. That's right. And it's really exciting, especially since what we saw we had a preplanned comparison with our predecessor studies. So these trials were really running back to back in the same centers.
Elizabeth Plimack: And your predecessor study, what was the pCR rate?
Richard Cathomas: It was SAKK 06/17. This was cis/gemcitabine/durvalumab, perioperative more or less NIAGARA style. And there we had a pCR rate of 32%, which is rather low and NIAGARA was slightly higher. But even so, I think we did propensity score weighted analysis between the two studies and so this still holds up. So we have in the propensity score weighted comparison, 32% in the O6/17 using cis/gem/durva and 67% in the O6/19 trial using cis/gem/atezo plus the three intravesical instillations. And it's on the expense of we increase the pCR and we decrease really the patients who have muscle-invasive disease, whereas the patient with non-muscle invasive disease, they're more or less the same, which is really interesting and to me really points towards a systemic effect of what we're doing with this intravesical BCG rather than to improve local control.
Elizabeth Plimack: Fascinating. Fascinating.
Richard Cathomas: It is. Yeah.
Elizabeth Plimack: Yeah, I mean, the science is really interesting. Along those lines, so BCG we talk about as an immunotherapy and if you're looking for a systemic response, that's sort of the theory behind it. What do you think about some of the newer intravesical therapies that we have and whether those might play a role in a bladder sparing approach in combination with systemic therapy?
Richard Cathomas: I think that they are another additional very interesting aspect, especially if we have patients that remain with non-muscle invasive residual disease. This is really a great time to salvage them locally with intravesical treatment rather than to have patients undergoing cystectomy when maybe they don't even need it. So I think this is really exciting. So many different compounds that come in and non-muscle invasive disease, it's a local disease. We should treat it locally. And so this is all coming up. And for us, the next obvious step really is when you use BCG probably to use the IL-15 superagonist in addition, maybe even in the induction phase, even there increase the response or at least for some consolidation, you see patients who have inside-tube disease to start with, they're probably not off the hook with just four cycles EVP plus some BCG. You probably need to treat them a little bit longer as we do in a muscle-invasive disease as well. So it's quite many unanswered questions, but a lot of opportunities.
Elizabeth Plimack: A lot of opportunities and thank you for taking one of them by doing this study and presenting this to us. This is a homegrown study that was ahead of its time in 2019 and gives us a lot of really good food for thought going forward as we move to bladder sparing. Thank you.
Richard Cathomas: Thank you very much.