Inhaled KB707 Plus Pembrolizumab in Lung Cancer

Dale Shepard, MD, PhD:

Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist and co-director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Wen Ma, enterprise vice chair for research and director of the Novel Cancer Therapeutic Center here at Cleveland Clinic. He was previously a guest on this podcast to talk about clinical trial results with inhaled KB707 for treatment of lung cancer. That episode is still available for you to listen to. Today he’s here to discuss data presented at ASCO 2026 with addition of pembrolizumab to KB707 for patients with lung cancer. So welcome back.

Wen Wee Ma, MBBS:

Thank you, Dale. Thank you for having me back.

Dale Shepard, MD, PhD:

Absolutely. So, remind us, I gave your title, but remind us what you do here at Cleveland Clinic.

Wen Wee Ma, MBBS:

Yes. So, I'm a GI medical oncologist and also a phase 1 investigator. So, my area of research is really in early phase clinical trial. What it means is looking at new treatment that are just entering into clinical testing. So that's an opportunity to actually work with many interesting treatments such as this one.

Dale Shepard, MD, PhD:

So, people can go back and take a listen to the episode, but let's give them a little bit of a headstart. Remind us what we talked about last time in terms of using this drug KB707, again, early phase study, still has letters and numbers. What is the drug and what did that initial study show? Give me a big picture.

Wen Wee Ma, MBBS:

Yeah, yeah. So, yeah, thanks for this opportunity again. So KB707 is a modified herpes simplex virus that is designed to deliver genes that produce interleukin, specifically interleukin-2 and interleukin-12, which are a kind of a inflammatory chemical. And if we give it by IV or subcutaneous, it can produce what we now known as cytokine release syndrome where the patients can get fever, chills. So, it's very difficult to develop IL-2 and IL-12 as a systemic treatment. So, in this particular KB707 and this particular clinical study that we talked about last year is using the virus to insert the gene that manufacture IL-2 and IL-12 by inhalation, by breathing in, so side stepping the side effects that patients may develop from an IV infusion. So, it has that advantage of avoiding the systemic side effects from IL-2 and IL-12.

Dale Shepard, MD, PhD:

And again, just as people listening in, a bunch of different backgrounds, how do we think that happens? Because we know that we get oxygen into our blood from breathing in. So if we breathe in a virus, how do we keep that from getting into the bloodstream?

Wen Wee Ma, MBBS:

Yes. So that's fantastic question. So, as we know the virus actually, so virus can replicate. So, one thing that the researcher did was to modify the virus so that it doesn't replicate in the body. So, it's non-replicative. So, you avoid the safety issues about then this herpes virus then start to affect a bigger part of the body or other people. So, from that point of view, because of the way that the researchers has done to the virus, we avoided infectious risk.

Dale Shepard, MD, PhD:

Data looked promising with the drug itself as an inhalation. What was the next step?

Wen Wee Ma, MBBS:

Yes. So last year we talked about the data from a monotherapy single agent given by itself, and we saw interesting results in patients with lung cancer that the cancer in the lung shrink. So, because we breathe this in, it goes to the lung, so you affect the lung cancer. So, this year we presented a data of the next step, which is combining it with pembrolizumab. So pembrolizumab, as we know, is immune checkpoint inhibitor, which is standard of care now for treatment of lung cancer. So, looking to combine with pembrolizumab this time.

Dale Shepard, MD, PhD:

And so, these are patients that had had pembrolizumab, tumor had grown on pembrolizumab. Now we're giving the pembrolizumab again, but with this drug.

Wen Wee Ma, MBBS:

Correct. So, as we know, pembrolizumab and other immune checkpoint inhibitors are standard of care now. So, a lot of lung cancer patients have that. But for those of us, we have been monitoring these lung cancer patients. They do invariably progress. So, they have progressive disease. So, this particular study look at patients who has had those immune checkpoint inhibitor treatment and it has progression or for many different reason need to switch the treatment. So, this patient would then stop whatever kind of immune checkpoint inhibitor they had before. If they happen to be on pembrolizumab, they can go on this. So, they will then go on this study and they will get pembrolizumab together with the inhaled 707.

Dale Shepard, MD, PhD:

Do you get concerns from patients to say, "Well, my tumor just grew on this and you want to give it to me again?"

Wen Wee Ma, MBBS:

Yeah. So that's a very fantastic question. So, the mechanism is very novel and in cancer therapy, most of our cancer therapy are given for medical oncology. A lot of this treatment is given by IV or oral. So, when we talk to patients about that, "You're going to breathe this treatment in and we are looking to affect those in the lung that we see on CT scan," I think a lot of... Actually almost all the patients are very interested to join this, especially once the mechanism is explained to them of what we're trying to do with this treatment.

Dale Shepard, MD, PhD:

So, I guess two parts. First would be how well did it work? How well did it shrink tumors?

Wen Wee Ma, MBBS:

Yeah. So, bear in mind this group of patients who already had immunotherapy before. So, we had 16 patients who had enough treatment for us to do a CT scan to look how it works. So we saw a response rate of about 31%, which to me, in a situation where patients is progressing on immune checkpoint, then we add something on top of that, I think 30% is a really good signal. Also, symptomatically, patient has also reported feeling better as well in terms of breathing. So that's pretty optimistic about the results.

Dale Shepard, MD, PhD:

I guess if we're thinking about something's being inhaled, it gets incorporated into the tumor, generates IL-1 or IL-12, is there, of course, a limited number of patients at this point, is it too early to know, do patients with a smaller tumor burden, smaller tumors respond better than people with larger tumors?

Wen Wee Ma, MBBS:

Yeah. I think our number is a little bit too small to really look into that. In the study itself, we do not limit the cancer burden in the lung going to it as long as they fit the illegible criteria. We do have some patients, perhaps they're on oxygen. They continue to be on oxygen because that's the cancer they have. But we just don't have enough data to say, "Well, if the patient has less disease, would they respond differently from higher disease burden?"

Dale Shepard, MD, PhD:

There wasn't a criteria say, it couldn't be over a certain size or anything like that. What about off? How about tumors that are outside of the lungs?

Wen Wee Ma, MBBS:

We have not seen dramatic changes in terms of cancer outside of lung. Also partly because in this group of patients, we are primarily focused on patients with predominant lung disease. We did in these studies also measure the inflammatory marker changes in the blood as well. So, for this patient who inhaled 707, systemically we can actually detect these inflammatory changes. So, what we want to do next step is really, as we move this forward, to really look at A, like what you suggested, whether the disease burden in the lung make a difference, and also to really go into understanding how this affect the systemic disease as well.

Dale Shepard, MD, PhD:

How about toxicity? Was this by addition of the pembrolizumab? Was there much change in toxicity?

Wen Wee Ma, MBBS:

Yeah. So interestingly, there's not too different from what we saw in the data we presented last year with the monotherapy. There's no additional significant side effects from adding pembrolizumab to that.

Dale Shepard, MD, PhD:

Just back to about how this is even given because I agree. I talked to patients about this study and they were kind of excited about a new way to get a treatment, but from a logistic standpoint, just remind people how we're actually doing the study because if we're giving somebody something that's being inhaled, we don't want everyone else in the room to inhale it. So how exactly is this being given?

Wen Wee Ma, MBBS:

Yes, absolutely. That's a very interesting question because when I first got involved in this study, those are question that I have, but as it turned out, because of the way the virus is modified, it's non-replicative. And also, Cleveland Clinic, we have biosafety review committee as well. So, the committee reviewed and the conclusion was that the risk for people around the patient during the administration is really not that high. So, the way that it's given is actually the way to think about it is almost like asthma, having a nebulizer delivering the asthma medication. And this situation, the setup is pretty similar where it's a nebulizer delivering 707 and patients on the study, they literally breathe that in using that nebulizer.

Dale Shepard, MD, PhD:

Apparently, I would guess with a 30% response rate, then that looks promising enough that further studies moving forward, has it sort of met the criteria to move forward to further development?

Wen Wee Ma, MBBS:

There's definitely a lot of interest to continue the 707 and pembrolizumab. So, the few is very crowded with immune checkpoint or other immunotherapy, but fair to say that we do need more of different kind of immunotherapies. So, I think 707 has really fit into that in terms of modifying the tumor immune microenvironment. So definitely from the study and the sponsor point of view, there's a lot of interest to continue to develop this. The question is really which setting are we going to bring into, for example, neoadjuvant or are we going to adjuvant? So those are the interesting question that I think everyone is trying to figure out the next step. But in the meantime, the study is still ongoing, exploring other combination as well.

Dale Shepard, MD, PhD:

Are there particular subsets of lung cancer that are being included or excluded?

Wen Wee Ma, MBBS:

At the moment, we are at a milestone for pembro and 707. So, we're retooling and hopefully more to come in terms of where to go. And we are engaging our lung cancer colleague, for example, Dr. Adjei, to really try to figure out what's the next step. So, we're in partnership with the Cleveland Clinic, we're in partnership with the company to try to figure out the next step, how to bring this to lung cancer patients. So, there are also another cohort that's enrolling, which is using docetaxel with 707, which is currently active and it is open for enrollment for those patients who are appropriate for this. So yes, this 707 continues to be in development. So, we're looking for opportunity to really bring this to the patients.

Dale Shepard, MD, PhD:

I guess as a drug delivery system, certainly it's unique as you're sort of getting new phase 1 trials coming across your desk. Are there other compounds that are starting to utilize this as a delivery as well?

Wen Wee Ma, MBBS:

I would say this, at the moment, is one of a kind. So, we're actively looking at other treatment that can be administered by inhalation. So, I would say yeah, this is one of a kind at the moment.

Dale Shepard, MD, PhD:

Certainly, seems like a pretty promising combination, and I guess we'll look forward to hearing the final results and about other things coming up in the future.

Wen Wee Ma, MBBS:

We are looking forward and hopefully Dale will invite us back to talk about it the next step.

Dale Shepard, MD, PhD:

Absolutely. Always welcome.

Wen Wee Ma, MBBS:

Okay.

Dale Shepard, MD, PhD:

Thanks for being with us.

Wen Wee Ma, MBBS:

Thank you, Dale.

Dale Shepard, MD, PhD:

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