Radiation Oncology-Biology Integration Network (ROBIN)

Podcast Transcript

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 Shepherd, a medical oncologist here at Cleveland Clinic, overseeing our Taussig Phase I and Sarcoma programs.

Today I'm happy to be joined by Dr. Tim Chan, Chair of the Cleveland Clinic Center for Immunotherapy and Precision Immuno-Oncology. Dr. Chan was previously a guest on this podcast to discuss cancer genomic testing, and to discuss immunotherapy and precision immuno-oncology. He's here today to discuss the Radiation Oncology-Biology Integration Network. So welcome back, Tim.

Timothy Chan, MD: Thanks so much, Dale. Thanks so much for having me. It's always a pleasure.

Dale Shepard, MD, PhD: Absolutely. Just give us a really broad view, what exactly you do here at the Cleveland Clinic, as a backdrop.

Timothy Chan, MD: Sure. Yeah. I'm the chair of the Center for Immunotherapy and Precision Immuno-Oncology, I'm a physician scientist. And here I'm responsible for setting up translational efforts that span the bench to early phase clinical trials with the cancer center, to boost the number of innovative treatments going into patients, and making sure that we have the capability and the resources to be able to learn as much as we can from our patients on these trials. And lastly, to develop new, more effective combinations and targets for therapies for cancer.

Dale Shepard, MD, PhD: Excellent. Today we're going to be talking about the Radiation Oncology-Biology Integration Network, and this is referred to as ROBIN. Give us a little idea, what exactly is this?

Timothy Chan, MD: Yeah, and I'm happy to, Dale. ROBIN is a new network of centers that is set up now by the NIH. And what the NIH usually does is it utilizes this U54 mechanism, sometimes other efforts are using spores for instance, but these types of multi-site networks are used by federal funding agencies like the NIH to put together a set of centers in institutions in different parts of the country that can push forward an area of need. And that's what ROBIN is, it's the newest of the NIH centers. It's funded under the U54 mechanism, so we were funded by U54. As a comparison for instance, when COVID hit NIH did the same thing. There's a U54 for COVID research as well.

Now for ROBIN, the concentration is on multi-modality therapies. Now what does that mean? It means that most of the cancers these days are treated, as you know, Dale, by many different types of therapies. You have surgery, you have radiation, you have systemic therapies, which you're very active in. And it's the combination of these therapies that can result in cures, especially in the setting of what's called locally advanced settings.

And so even though this has been standard of care and it's an ongoing program of improving standards of care as we go into the future, it's used a lot but not very much is understood. The last generation of science and trials done with chemotherapy, radiation and also chemotherapy and targeted therapies together with or without radiation, was done in the setting of these large trials run by things like the RTOG, these big consortium groups. And science has really not been the forte. Sometimes the samples are obtained, sometimes people look into this. But most of the time they read out and then that's it. There's no more learning.

Fast forward to now, where we know that biology is very, very important in terms of determining what subset of patients respond well. NIH and the federal government have gotten smarter. They've set up the ROBIN network to really systematically give us the resources and the network to be able to answer the question in the setting of multi-modality therapies, why certain therapies work. And to do this by collecting samples and really basically, quote, sciencing the heck out of it and allowing us to understand what drives efficacy.

Dale Shepard, MD, PhD: And when we talk about this network of institutions, give us an idea of who's going to be involved.

Timothy Chan, MD: Last year there was an RFA that went out and over 50 groups applied, and our team here won out actually as one of the three centers that were funded. Our center consists of Cleveland Clinic in Emory University, Emory School of Medicine. We are the lead institution and they're the partnering institution. The other two institutions are the University of Maryland in Jefferson, and then the triad of University of Chicago, Cornell, and Memorial Sloan Kettering.

They kicked it off with these three, and there's another two that are being funded this year to expand the total network to five.

Dale Shepard, MD, PhD: Excellent. Let's talk a little bit about the practical aspects here, because I like the thought that we're trying to learn more about patients and using samples we collect in a meaningful way. Because certainly, a frustration in early clinical trials is we collect data, like you say, and we collect a lot of biopsies, and we're not really sometimes sure what happens with that. So how are we going to collect samples and turn that into useful information to treat patients?

Timothy Chan, MD: Oh, that's a great question. So inherent within each one of these centers are molecular characterization trials, that is the centerpiece of all of these. Each center has a molecular characterization trial, which I can talk about in a little bit.

But the purpose of these trials is testing a new promising therapeutic, and comparing this to what the standard of care does and how the new therapeutic expands. And the design is to be very data dense. That is, we throw the full gamut of genetic analysis, like genome sequencing as well as circulating tumor DNAs, metabolic analysis, imaging analysis, so functional and CT and MRI imaging, all on the same data sets. So we can put together atlases of defining what's important and not that drives response and resistance.

Dale Shepard, MD, PhD: And so, do we have any proposed targets at this point that we think are going to be more important than others, or is it still too early to know?

Timothy Chan, MD: Well, we do have two trials that were funded as part of the Cleveland Clinic ROBIN Center, and the two are basically one in bladder cancer and one in head and neck cancer. The one in bladder cancer, the PIs are Shilpa Gupta and Omar Mian, both in the Taussig Cancer Center. And the trial basically is to look at bladder preservation for patients with locally advanced bladder cancer, and they're treated with radiation and an antibody drug conjugate called sacituzumab. And sacituzumab has recently been approved for metastatic breast cancer and it's on its way of being utilized in bladder cancer as well.

This is a drug that has an antibody, it's an immunotherapy, that targets something called TRIO-2, which is a target, and it has a chemotherapy attached to it, irinotecan. And the idea is that sacituzumab can bring the chemotherapy, and also potential immune modulation aspects because the antibody is also an immunotherapy, to the bladder cancer and then treat that with standard-of-care radiation as well. And we're hopeful that more people will be able to keep their bladders in bladder preservation therapy with this new combination therapy. At least in the clinic right now it looks like chemotherapy and sacituzumab together can be quite synergistic, so we have great hopes for this.

The second trial is something we are doing in combination with Emory University and the trial leaders here are Nabil Saba, who is a medical oncologist at Emory, and our own Shlomo Koyfman, who's a radiation oncologist here. They're both head and neck experts. And that trial is to look at recurrent head and neck cancer, and what happens when you add nivolumab in the adjuvant setting or afterwards to treatment for recurrent head and neck cancer. That trial actually is already completed. So, some of these trials are already well underway and it's met its primary endpoint, meaning that it is effective.

And as part of ROBIN, we'll be looking at what nivolumab does to make it better, to make the tumor environment better. And as part of that we'll be collecting standard-of-care patients and then comparing that data to samples from patients treated with nivolumab, we'll be able to understand exactly what nivolumab is doing. And nivolumab is one of the immune checkpoint blockade agents, I might just say, that has been revolutionizing the treatment of a lot of solid cancers.

Dale Shepard, MD, PhD: And so, when we look at these interactions of the antibody drug conjugates, the immunotherapies, is the thought that if we collect enough information and we learn enough about patients, that we might know which patients are better for which of the two therapies, that we can change the amount of radiation delivered? What is the ultimate goal?

Timothy Chan, MD: I think you summed it up, the question, extremely well. I think that what our goals are basically are several fold. A, we are testing novel combinations, and these are Phase I's and Phase II's so they're early phase. But we want to find a signal to see potentially if there's some efficacy and if they're safe. And then if it meets these endpoints then we want obviously, in the best-case scenario, to move this forward to a later phase trial to really quantitate that benefit.

Secondly, we want to use the science to understand who is going to benefit. There might be some people who will benefit from radiation and chemotherapy or radiation alone or ADC alone, and we want to identify patients that eventually we can provide some information upfront before treatment starts of how well patients may do. This has been slower these days. Predictive biomarkers have become more and more used in the clinic now, of course, especially with these pan-cancer or cross-cancer approvals. But I think a lot of work needs to be done.

And thirdly, perhaps most importantly is, as we know, cancer therapies now work in some people and not others. How are we going to improve upon what to do? Well, it's to really understand what causes resistance, both upfront, upfront, and also after therapy when this comes back, acquired resistance. Why do we want to understand that? Because understanding the targets that are responsible there will generate the ideas and design of the next generation trials. That's the only way we're going to push forward for new therapies that may improve our current standard of care.

Dale Shepard, MD, PhD: And I guess, if we learn enough about the patient tumor and those treatment, those treatments that might be effective, are we going to get to a situation where, right now, we're talking about a bladder cancer trial and we're talking about a head and neck trial. And as we have genomic therapies that are more tumor type agnostic, is it maybe going to be a situation where we're treating tumor characteristics instead of geography?

Timothy Chan, MD: Absolutely. And, Dale, I think that's has already started. I mean, some of my earlier work was showing that mismatch repair and tumor mutation burden can tell you about whether a patient or a tumor will respond, independent of whether the disease site is in question. So MSI, for instance, and TMB, are approved across different cancer sites. The goal, of course, there's many of these now, including NTRK and other things that are on the horizon, like FGF receptor inhibitors and RET fusion inhibitors.

So absolutely, I do think that moving forward we are going to have a library of different indications that we're going to have to check. Now do I think that this is going to be able to be used alone? In some cases, yes, in a lot of cases, no. I think it's still an integrative decision we have to make. An example is, basically BRAF inhibitors works great in melanoma, works great in some types of lymphomas, but doesn't work in colon cancer. So, there are going to be individual exceptions to these pan-cancer approvals that we're talking about. And we're just going to have to better understand them.

Every tumor is different. Every tumor is different that different people have. But also, the immune systems may be different in different tumors, so that immunotherapies may work in one setting, but hey, the mechanisms for immunosuppression may be different, so the drugs may be different. And so, our goal is to figure out why. But I will say that for the most part it is promising. We're sort of in the exciting age of these pan-cancer approvals right now, which I think is really a step forward.

Dale Shepard, MD, PhD: And I guess along that line, are there particular tumor types that you think are going to be more difficult to tackle with this approach?

Timothy Chan, MD: I do. Well, one of the cancers that I treat at my own clinic is brain cancer gliomas. And that's been resistant to almost everything under the sun, unfortunately. I would love to see nothing better than to be able to boost the number of patients that I can help long-term, and so those are going to be pretty difficult.

And also, you remember, for patients that we treat with certain types of tumors that do respond, well, sometimes resistance can happen. And that is not uncommon, like in melanoma and renal cell carcinoma. And then there are other ones that are just resistant upfront, like sarcomas, like ones that you treat, that can be very recalcitrant towards the current generation of immunotherapies.

So again, we have a lot of work to do. I got to tell you that for most cancers, we are not curing more, not nearly 50 percent of our patients, of advanced patients. So even despite the fact that response rates are much, much higher and outcomes are much better, there's still a lot more to do before we can actually say that we're curing those patients.

Dale Shepard, MD, PhD: When you talk about things like resistance and things that certainly metastatic disease, there's more heterogeneity. And are you focusing more on neoadjuvant or adjuvant settings upfront, are you tackling metastatic as well?

Timothy Chan, MD: Yeah, that's a great question. The bladder cancer trial is a definitive trial, so it's somewhat neoadjuvant. It's not really, but it's treatment for the goal of cure. Of course, if it fails, these patients will then be converted to cystectomy and it becomes really your neoadjuvant therapy. For the head and neck cancer, in the recurrent setting, in its adjuvant nivolumab. So, we have a little bit of both.

But I will say that the important thing is, we are very excited to work with the clinicians in Taussig Cancer Center, largely because with the arrival of Alexa Jay there's a wholesale expansion of novel therapeutics now. And we're excited to set up some of these translational efforts and pipelines so that we can broaden this across all the Phase I trials. And because, if there's anything about Phase I besides pharmacokinetics and pharmacodynamics, it's really just a learn mechanism. That's what's clearly important now. And so hopefully we can use this as a launching pad for all the exciting trials that you and others are undoubtedly going to run as we move forward this year.

Dale Shepard, MD, PhD: Yeah, and sounds like great opportunities. What do you think will be the biggest barrier to success?

Timothy Chan, MD: The biggest barriers to success? Well, I think when setting up a new center and network, there's always growing pains. There's not been anything really like this for combination therapies before. So, we are dealing with some of it, such as data deposition and data sharing. This is going to be sponsored by the NCIs, to make sure that the data is deposited.

Also, in the past, you'll remember that different networks tend to attract people of the same types of investigation. Here, by nature, if you're having a multi-modality team you need people from different disciplines. Now the ROBIN network has built in support for something called cross-training. And there's a cross-training core that's part of every single center that's funded, with the specific hope that you get people together to learn about best practices across different disciplines. So, for instance here, Omar Mian, as the head of this, will be an opportunity for surgeons, medical oncologists, radiation oncologists, pathologists, and medical physicists actually, to come together to go over best practices and present new research as part of the cross-training program.

So that I think was very prescient of NIH to think about this and build this into the RFA. It is one of the big challenges, speaking across lines of disciplines, but we're hoping that the cross-training core can help address that challenge.

Dale Shepard, MD, PhD: That's fantastic. What do you see are the biggest gaps that remain?

Timothy Chan, MD: Well, I think one of the major gaps right now, and again, there's many gaps that we need to learn about, but one of the major gaps is basically what happens during therapy. A lot of times, what happens is an amazing amount of biology that can happen when we treat somebody with either radiation or chemotherapy or targeted therapies, and taking advantage of all that information. It's very, very difficult right now on clinical trials to do on-treatment sampling.

And so that's something that we are really trying to focus in on. There are on-treatment biopsies as well as circulating tumor DNA collected throughout the course of therapy for these molecular characterization trials. And the goal there is to tackle that problem that you talked about, is the understanding what the dynamic changes are. Very frequently it has become clear that resistance, innate resistance, upfront resistance to a drug, happens very quickly. You will know that if a patient upfront is resistant or not, even after the first cycle of a therapy. This is something that we worked on before. You don't have to wait three months, four months for a CT scan to show you something. And often, as in the case with immunotherapy for solid tumors like lung cancer, CT and imaging response isn't even really reflective of what will happen down the road.

So, figuring this out I think will be a step forward. It is a major problem. It's a huge problem for diseases like brain cancers where you can't get any tissue, even if you wanted to. Very difficult to do on treatment biopsies in the brain, pretty much not done. So, lot of opportunity in the setting, and certainly a challenge.

Dale Shepard, MD, PhD: Well, really important questions, and it looks like you have a mechanism to come up with some important answers, so thanks for being with us.

Timothy Chan, MD: Well, thanks, thanks. And of course, Dale, thank you so much for everything you're doing with Phase I. I think pushing the envelope here at Cleveland Clinic and Taussig is what we like to do for patients. This is how we move the needle towards better and better outcomes. So, I'm really delighted to get together and chat about these efforts with you today.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

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