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Sam Chang: Hi, my name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center in Nashville, Tennessee, and we are quite fortunate to have Dr. Patrick Soon-Shiong here. We are going to have a discussion on N-803, looking at its impact, hopefully in the future, for those patients with BCG unresponsive disease. ImmunityBio has put together kind of a summary of a New England Journal paper that came out looking at the effectiveness of BCG.

In looking at it, Patrick, there are certain areas that I think are important when one would consider the aspects that would be important for an agent to treat BCG unresponsive disease. This packet kind of outlines some of those things that would be important for an ideal profile. What would some of those include?

Patrick Soon-Shiong: Well, first of all, thank you for having me, Sam.

Sam Chang: Absolutely.

Patrick Soon-Shiong: Thank you for your work. I think this is such an exciting time for non-muscle invasive bladder cancers. Yes, we did put together a booklet as an educational tool. The question of, what's an ideal profile? What would be the holy grail of a product, especially in the world of immunotherapy? Clearly, a high complete remission rate or complete response rate. But I think one of the most important things, the durability of that response, and if you get together a durable response beyond 24 months, that would be remarkable, but together with a durable remission in both CIS and papillary disease. And then, finally, obviously the whole point with this is a cystectomy avoidance rate, so a high cystectomy avoidance rate. If one can combine all those profiles in a molecule that is safer in terms of no serious immune adverse events and given locally by the urologist who understands how to manage BCG and have no difference in his methodologies, all those elements become, I think, the components of an ideal profile of what we should generate.

Sam Chang: Those points that you raised, I think, are really important. As we've looked at giving this agent, that combination of all those things, so giving the agent, is it easy, is it familiar for the urologist? It is. It's something that they're familiar with. It's different from a systemic therapy or it's different from a new technology that, perhaps, people are not familiar with. This is an agent given into the bladder. And then for urologists, just as you said, that combination of efficacy with tolerability, and then being able to have that long term, I think, clearly, is something that we all strive for, any kind of therapeutic intervention.

And so, as we put the study together and recently published it, you've outlined some quotations here from some of the editorials, and they're complimentary summaries, they're very nice in that. To me, some of the things that are most striking for me personally is, peers and mentors that I have great respect have noted that this may be a treatment that clearly separates it from other therapies, and clearly compared to those that are available now are clearly different.

Dr. Herr says that to have something clinically meaningful at 12 and 18 months and this combination of efficacy and minimal toxicity, he states that the author should be congratulated. For Dr. Herr to say that is quite telling because he has a very high bar. I don't know if you know that, Patrick, But Dr. Herr is a stickler for sure.

Patrick Soon-Shiong: No, I don't.

Sam Chang: And then the colleagues at European Urology, this is led by Peter Black, who I respect significantly, states that the trial really sets a new benchmark for those patients with the 3 to 6 month complete response rate, but then that 12 month, the durability that you talk about. I think quite telling when you look at the results of this, this combination of BCG plus the N-803, the effectiveness, that complete response rate of more than 70%, I think, is quite telling. As you have been involved in so many different trials, different agents, different drug components, tell me what struck you most with the results when we looked at CIS patients that were BCG unresponsive.

Patrick Soon-Shiong: I think this was not just an evolution, but when we actually did the first phase I trial in both CIS and papillary, and in the naive setting, 9 out of 9 had a complete remission, but it went on for 24 months. The sustainability of that complete remission or evidence of disease-free in the case of papillary. To me, that was remarkable and was telling that, in fact, we wanted something with regard to this N-803 that is doing something different when you add it with BCG. It's not published yet, but we are now following up those patients that were in two centers, and there's some, at least anecdotal until we get the data, that these patients still have complete remission 7 years later.

Sam Chang: Amazing.

Patrick Soon-Shiong: Yes, to me, and obviously we will wait until we get that data, it says the durability of this response must be that we are doing something in the human body.

Sam Chang: Exactly. In terms of baking into their system, an idea or the ability to recognize those tumor cells, and before they develop, then being able to actually initiate an immune response that has been altered because of the therapy that they've received. In looking at that data, because I became aware of that data as we were doing our trial that, yes, this is well tolerated, and then to be able to see that those patients that have had a response, we're not saying everybody will have this durable response, but that the vast majority of those early patients that had CRs or disease rates were able to continue, I think, was quite telling. Tell me what you think about the side effect profile of this medication. It seems to be well tolerated, yes?

Patrick Soon-Shiong: Absolutely. But let me, before we even go into that, the side effects, one of the, I think, hallmarks was, which is maybe different even from the current therapies, if you have a CR in the first six induction phases, and this is a reflection, I believe, on the status of your immune system at that point, your natural killer cells, but what's remarkable is that the agency, as well as the trial, is designed such that that's not the last shot. Because if you then don't see a CR, you're able to give another six doses. Which is the re-induction.

Sam Chang: Exactly.

Patrick Soon-Shiong: And then we do see, in some of those patients, a CR. And in all cases the side effects are not of equivalent of BCG alone. So, in fact, there's no statistics around it, but when I speak to people like yourself in the clinic, they said, "Wow, this even appears to be even less than BCG." What's what Dr. Kamat was asking me, and I said, "Well, I think there's a basis for that because what the N-803 does, it actually creates a tamping down effect of the inflammatory response of BCG itself." So the good news is that there's no systemic immune-related adverse events. The adverse events are equivalent to that of BCG alone, and there's no systemic absorption of this molecule because it's given locally.

Sam Chang: The safety component, I think, is really important. That it takes into account like you were saying, the measurable amount of this agent in the serum is basically nil. That really for tells why there's really very little systemic kind of side effects. You add this combination, this combination seems to decrease that inflammatory response. And to be honest, these are patients that have been heavily pretreated before, they tolerate some intravesical therapy. So when individuals say, "I don't know about this, how can they have less side effects?" I said, there are individuals early on that cannot tolerate intravesical therapy, cannot tolerate BCG, cannot get to even a BCG unresponsive. They have significant side effects. Those patients aren't in this trial. These are patients who've had intravesical therapy, are able to tolerate intravesical therapy, and now this combination may, in fact, be less inflammatory. It actually makes sense to me that there's going to be actually less side effects.

To me, I think also telling, back to the idea of the efficacy, there's been some concern raised regarding, well, what do you do with this repeat re-induction, this repeat treatment? Other studies have not had that, otherwise it's at 3 months and that's that. My response is, well, what do we do with our intravesical therapies upfront? BCG, chemotherapy, almost every single indication, unless there's progression, gets a repeat attempt, induction, and chemotherapy. So different mechanisms of action, because there's clearly a percentage of patients that respond.

And so, when I talk with exciting new medications that are out there, but not yet available, their thought is, "Well, our responses could be better if we're able to give a repeat reinduction." I said, "Well, unfortunately, you didn't. Yes, they could be better. But this trial design was actually, in fact, unique and important, because there's very much real-world of what physicians would do in those patients who are unfit for cystectomy, not able to have a radical cystectomy or choose not to. What do we normally do? We normally, if there's no progression, attempt another treatment. And a significant number of patients responded, just like they would do with BCG, just like they would do with chemotherapy. And so, when people suggest that there are perhaps some issues, I, in fact, think they're strengths. This is real-world.

Patrick Soon-Shiong: Well, I think, and this is why it was so important for me to do that session with Dr. Kamat about the mechanism of action, I don't know of any of these other molecules that are already out there that, even if they did repeat, had an ability to induce memory.

Sam Chang: Right.

Patrick Soon-Shiong: So that was the big difference. And when we did this, it was purposeful to say, and if you turn to this page 11 here where we talked about the trifecta, the combination of the killer T-cell and the natural killer cell are cross-talking to each other to drive the memory and the efficacy. That's the mechanism of action of this molecule, and there is no other molecule, actually, to my knowledge, that is approved out there on the market doing that.

And so I think the opportunity, and you could go to page 16, and if you look at these red dots, the red dots is the timing of those complete remissions. And you see they vary amongst patients depending on their natural killer status at that time. You may have some patients who don't have a strong natural killer status based on their age or shingles or immunosuppressed.

Sam Chang: Sure, sure. Some other things are going on. Absolutely. Right.

Patrick Soon-Shiong: By actually having a cumulative effect of the proliferation of the natural killer cell, which this thing does, the T-cell, in generating memory, we are clearly seeing ongoing complete remissions. Obviously surgeons like yourself work hard to avoid cystectomy, and as you know, these patients do everything they can, including going to gemcitabine, going to other chemotherapy therapies, et cetera.

Sam Chang: Sure, absolutely.

Patrick Soon-Shiong: And then when you add to the fact that there's very little toxicity and you're seeing this kind of effect, we designed the study in that way, and I'm so glad we did because it falls within the mechanism of action here of driving.

Sam Chang: Sure, absolutely. And being able to give that, it clearly justifies that repeat induction course for those individuals, because it does allow the evolution of the inflammatory immune response to actually then be able to recruit, change the natural killer cells, change. And so, as a result, I think by that mechanism of action, that helps to explain the long-term response as well.

Patrick Soon-Shiong: We've learned, even in solid tumors, that it takes a time for an immune therapy to work, if you recall the word concept of pseudoprogression when people had immunotherapy and they think something blew up, but it wasn't the tumor, it was really just inflammatory of the T-cells occurring. So it requires time. That's one of the things why this is a pure immunotherapy component, where BCG itself is also an immunotherapy component now actually synergizing with that.

Sam Chang: Absolutely.

Patrick Soon-Shiong: So this is why this induction, re-induction, phase actually is an important component of the therapy.

Sam Chang: Right, and that combination really allows those patients to get the most likely benefit of being able to turn on the system that way and to gain memory. If you look at the future here, Patrick, all right, with this medication, clearly the ability to avoid cystectomy is quite high in the vast majority of the patients that receive this medication. From a standpoint of a patient choosing this option, what do you tell that individual in terms of, "Hey, this is what this medication could do and this is what it could do for you in the future." What do you think we should be telling patients?

Patrick Soon-Shiong: Well, I think you have to go with the data, and that's really important. And that's why I'm so pleased that the prestigious, tough peer-reviewed journal, like the New England Journal of Medicine, took us on, and obviously whatever the FDA is going to put out there. But the data, what speaks is the 95% confidence interval, and that's now statistics, that a 24 months there's a 90% chance of you avoiding a cystectomy. So I think if you had a response, you can be assured. So the good news, you can say, and that's what the data says, if you're going to get a response, there's a high chance, beyond 50% close, 60%, 70% chance of getting a response. And then when you do get a response, you can rest assured, at least from a 95% confidence interval, now, nothing's 100%, that at 24 months you still have your bladder.

Sam Chang: You still have your bladder.

Patrick Soon-Shiong: And more importantly, at 24 months, you still actually have a complete remission. Because the other data point that's important is the median duration of the duration is 26 months. That means that some patients are beyond 26 months.

Sam Chang: Even further. Exactly.

Patrick Soon-Shiong: And that high end of the confidence rate is yet to be reached. So, that's why we are following these patients now, not only 3 years, 4 years, 5 years. I think the comfort I take is, look at the data, speak to the data so that you have real comfort as you are sharing with your patient, it's data-based, data-driven.

Sam Chang: Right. Well, Patrick, thank you so much for spending some time with us. We really appreciate, not only the efforts with this agent, but all the different medications, vaccines, interventions that you've helped spearhead have really, really altered the landscape of medicine. So I personally, and I think all of us are indebted to you, so thanks so much.

Patrick Soon-Shiong: Well, thank you, Sam. I'm a surgeon, a fellow surgeon. I think the earlier we get the disease in cancer, whether it be bladder cancer, kidney cancer, prostate cancer, the earlier we get the disease, the faster we can actually find a way to treat it. What's exciting, as I shared with you, we just launched this week, we are the first now molecules with this Anktiva plus adeno in Lynch syndrome, where we are actually going to try and prevent the onset of the cancer. While that's a trial, so there's no physical data on that, but the fact that the NIH has now chosen our molecules to start this national trial speaks to the fact that we are on the verge now, truly, looking at urologic cancer as early as possible, which means it has to come from the surgeons.

Sam Chang: Yes.

Patrick Soon-Shiong: So my goal is to make this a surgical disease that US surgeons can treat.

Sam Chang: Unbelievable. Thanks again, Patrick.

Patrick Soon-Shiong: All right. Thank you, Sam.