Rare Disease Day 2024: A Live Panel Discussion With Dr. Rahul Banerjee, Matthew Hadfield, Joseph Kalis, and Nagashree Seetharamu

On Rare Disease Day on February 29, members of the Oncology Data Advisor Editorial Board and Fellows Forum hosted a live panel discussion focused on the rare diseases that they treat, including tireless efforts underway to develop novel treatment strategies, enhance quality of life, and improve outcomes for patients. 

Oncology Data Advisor: Hi, everyone, and thank you so much for joining us today for Rare Disease Day. We have a really exciting discussion planned for today about the rare diseases that our panelists treat and some insights into how to improve treatment options for them. We’re really looking forward to the discussion. With that, I will turn it over to Dr. Rahul Banerjee, our Editor in Chief, to get started with some introductions.

Rahul Banerjee, MD, FACP: Wonderful. Thank you, Keira, for that kind introduction, and thank you all for listening. I think it’s by accident that it happens to be a Leap Day today, but today’s February 29, and we’re here to celebrate Rare Disease Day. Rare diseases are much rarer than leap years are, but I think it’s an important point that this will be both oncology and hematology that we’ll talking about today, andI’m glad that we’ll have the chance to do it.

I’ll have us each introduce ourselves, and I can go first. My name is Rahul Banerjee. I’m an Assistant Professor of Medicine at the Fred Hutchinson Cancer Center and at the University of Washington in Seattle, Washington. I specialize in multiple myeloma, which I wouldn’t necessarily call a rare disorder, but there are many paraneoplastic conditions or preneoplastic conditions that can cause symptoms in this space of plasma cell disorders—for example, amyloid light chain (AL) amyloidosis; polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome; and Waldenstrom macroglobulinemia, and we’ll talk about those as they come. I’m excited to be here. Matt, Dr. Hadfield, it can go to you next.

Matthew Hadfield, DO: Absolutely, thanks. I’m so excited to be doing this. Again, happy Leap Day to everyone. I’m Matt Hadfield, I’m a third-year Medical Oncology Fellow at Brown University in the Legorreta Cancer Center in Providence, Rhode Island. I will be staying on there, focusing in melanoma and cutaneous malignancies as well as early drug development and phase 1 clinical trials. Similar to what Dr. Banerjee said, melanoma is not a rare disease necessarily, but it is on the more uncommon spectrum. One of the topics I’m hoping to talk about a little bit today is uveal melanoma, which is quite rare and has had some very interesting advancements in terms of FDA approvals in the last couple of years. So, I’m very excited to be having this conversation.

Dr. Banerjee: Wonderful, thank you, Matt. Dr. Kalis?

Joseph Kalis, PharmD, BCOP: Yes, hello, everyone. Thanks for having me here today. I’m Joe Kalis, I’m an Oncology Specialist Pharmacist with the University of Colorado (UC) Health System here in Colorado Springs, Colorado. In the practice that I’m part of, we see all patients, so nothing particularly rare about that, but we’ve had more recent cases lately of paroxysmal nocturnal hemoglobinuria (PNH) and then some other rare conditions, so I’ll be focusing on those today.

Dr. Banerjee: Wonderful, very nice to have you. Our fourth panelist just joined, so Dr. Seetharamu, can I have you introduce yourself?

Nagashree Seetharamu, MD: Hi, everyone, I’m Nagashree Seetharamu. I am a Thoracic and Head and Neck Oncologist. Within this space, I see a lot of rare tumors, particularly salivary gland, some rare thyroid cancers, thymic tumors, parathyroid cancers, and NUT midline carcinomas. These are all extremely rare tumors. I’ve had the privilege to work with these patients, and I’m excited that we’re having a discussion about this today.

Dr. Banerjee: Absolutely, likewise. So, we’ll get into it. Again, we’ll make this not just about cancer, because rare diseases obviously are not just with cancer. Many of us treat both hematologic malignancies and nonmalignant hematologic conditions in oncology or some permutation thereof. We will actually pivot first, and let’s talk about classical nonmalignant hematology. Dr. Kalis, Joe, if I may, I’ll start with you. You mentioned, for example, PNH in your introductory remarks. What are some examples of that and other rare diseases you see? And in the last 10 years, how have we made progress with new drugs, and where haven’t we?

Dr. Kalis: Certainly. Just by way of background, paroxysmal nocturnal hemoglobinuria—I won’t say that five times fast—is a rare, acquired disorder. It happens because of genetic mutations after someone’s born, whereas germline would happen when they are born. Really, what characterizes PNH is a loss of some cell surface proteins for signaling that block the complement pathway, allowing the body to recognize itself as itself. When these proteins are missing, we can end up with either chronic or paroxysmal hemolysis, which carries with it an increased risk of clotting, organ dysfunction, and in some severe cases, dysplastic bone marrow, where patients just aren’t forming the cells that they need for their normal daily lives.

Since it is a rare disease, I thought it’d be helpful to share some statistics to keep it in perspective. We’re looking at anywhere between 1 to 10 cases per million people, and there’s some thought now that this could even be underestimated because it’s a challenging condition to diagnose. Sometimes, it could even be a diagnosis of exclusion. But as you mentioned, Rahul, over the past 10 years, there have been some treatment advances. I think back to when I was starting my career 10 to 12 years ago. We had eculizumab, a complement-inhibiting medication. It carried with it some risks of infection, because we can’t add that surface protein back to a patient’s cells, trying to block the part of the immune system that’s causing some of the concern and the conditions.

What I want to focus on today is the next generation, if you will, of the complement inhibitors. A more recently approved drug is ravulizumab, or Ultomiris® for those of you out there who are familiar with brand names. As a pharmacist, I think generically, and my wife is also a pharmacist, so we joke about that and have some interesting dinner table conversations. Ravulizumab is somewhat unique in that it’s got a more favorable schedule for patients. They’re not having to come in as often. Eculizumab could be given every two weeks indefinitely. With ravulizumab, it’s still functioning just as a complement inhibitor, and we can’t change the patient’s genetics and cells, but we can block or blunt that part of the immune system that’s leading to these symptoms.

One thing I would encourage folks to keep in mind is that ravulizumab does come with some risks of infection, so we need to be able to prophylax patients. Neisseria meningitis is a concern. Some vaccinations are often required both before and then even after or during treatment. So, PNH is a condition and ravulizumab is a drug that I really wanted to focus on today for Rare Disease Day. It’s something that’s come up recently in my practice. Have any of my fellow board members here seen patients recently with PNH or used ravulizumab?

Dr. Banerjee: I’ve used eculizumab off-label for any number of comediated pathways in the myeloma space. Carfilzomib, for example, can sometimes cause thrombotic microangiopathies. I think it’s funny that you’re calling it next generation, which I agree with. We have a class that works for these patients, and it’s going up a step. Maybe we can all go around. If any of you have expertise or have seen patients like this, feel free to chime in.

I think one thing I’ll ask you about, Joe, is that you had mentioned the infectious risk, and I remember that. I feel like many physicians know this drug purely because on boards, if you see the word eculizumab, the answer is automatically meningococcal, no questions asked. Obviously, in real life, things are more complicated than that. These are real patients living with this who have many, many side effects. For a rare disease like this, as rare as you said, what evidence is there? How do you figure out what prophylaxis schedule, how often to give them the meningococcal vaccines, antibiotics, and intravenous immune globulin (IVIG)? We don’t have great data, so how do you go into the unknown with supportive care for this paradigm?

Dr. Kalis: Absolutely. There are recommendations out now that, if you’re able to, to wait at least two weeks before starting ravulizumab to vaccinate patients with the available meningococcal bacteria vaccine—looking at least at the serogroups, ACWY, and then also meningococcal B. The flip side here is that if the risk of delaying therapy to give the vaccination outweighs the benefits, then you of course could give ravulizumab first. But that’s what I would really focus on. As you said, if you see eculizumab or ravulizumab, you think meningococcal right after that, but then you’re really focusing just on the immunization aspects. Ideally, those are given two weeks before starting therapy if possible; if not, then as soon as possible after a patient begins.

Dr. Banerjee: This makes sense. Innately, ravulizumab shouldn’t impair someone’s ability to mount their response to vaccines, right? So, it should work when you do it. That’s helpful.

Dr. Kalis: Right. It’s just blunting the complement-mediated pathways more, but not necessarily affecting B-cell or antibody function.

Dr. Hadfield: Joe, one of the interesting things that I’ve seen, at least in other novel therapeutics in this type of space—there’s a name that escapes me, but a new drug for thrombotic thrombocytopenic purpura (TTP)—is that given the rarity that we use these drugs, the cost is remarkably high and sometimes can be very, very challenging for patients. I’ve been in situations, again speaking in TTP, but a similar situation where you try and get access through the company or through insurance. Have you seen that with this drug? Do you have any insight or advice on how to grease wheels faster if you find yourself in such a situation?

Dr. Kalis: Certainly—I think you might be referring to caplacizumab for TTP. That really hits the nail on the head. I mean, many of the drugs we use have high cost anyway, and then you get into a rare disease space where there aren’t that many patients. Then you end up with subsequently higher cost for the drugs. At my institution, we’ve got a really robust financial assistance team who’s out there if we identify that maybe there’s an insurance gap or there’s no insurance or no coverage at all to help secure a free drug from the companies.

The challenge that comes along with that is sometimes the documentation that’s required for the company programs and then often the turnaround. Even if you’ve done everything you can, everything’s been turned in, and it’s often that I want to start the drug yesterday, we’re still waiting multiple business days to try and get it for somebody. I haven’t found any home-run type of strategies for that. One thing, again, being in pharmacy, that I’ve found somewhat helpful is to keep contact information for some of the medical science liaisons or even reps for those products. In cases where we have that urgent need, I’ve often found that somebody on the inside at the pharma company can grease the skids, so to speak, to speed things along.

Dr. Hadfield: Absolutely.

Dr. Banerjee: Excellent point and agreed on all fronts. I think in the interest of time, unless Joe, you want to speak some more about caplacizumab, or should we move on to the next topic?

Dr. Kalis: I think briefly just for caplacizumab, since TTP is an acquired condition, what I would emphasize here is that similar to how ravulizumab is blocking complement, caplacizumab is blocking the function of von Willebrand factor so that the platelets can’t really adhere to each other. With TTP, we’re more concerned about some of the microthrombotic angiopathy and other things that are happening. To Dr. Hadfield’s point, again, it’s an expensive drug—something that if we need to use it, we need it quickly.

Dr. Banerjee: Right. The tricky part that both you alluded to is that I’m sure caplacizumab would pay for itself eventually, because these patients aren’t requiring plasma exchange often, maybe shorter hospitalizations, and it’s just hard to do a cost-effectiveness analysis here. A lot of them obviously have industry partners just writing the cost-effectiveness analysis where people say, “This is a biased study.” Obviously, for payers, it’s hard to convince the payer that actually, these newer medications are making your patient feel better and saving you money, but it’s hard to prove.

Dr. Kalis: Exactly, we’ve got effective medications, cutting-edge type of therapies that I think can save time and then take the place of perhaps multiple courses of what we would’ve used otherwise.

Dr. Banerjee: Agreed. Maybe the last thing I’ll say regarding caplacizumab before we pivot to Matt and Nagashree for our next part for the malignancy side is that for listeners who are interested, Oncology Data Advisor does have a free continuing medical education (CME) activity on current standards and new directions in the treatment of acquired TTP with Dr. Cataland as the presenter. He’s from the Ohio State University. You can get a lot more information about caplacizumab here.

The one thing I’ll say about eculizumab, just as an example, is that even though it is approved for this super rare disease, the drug is extremely helpful in other scenario. For example, while multiple myeloma is not rare—I treat it, and I wouldn’t call it rare, maybe not as common as other cancers, but common—I have used eculizumab off-label for different pathways, the same pathway but a different issue, like carfilzomib-mediated thrombotic microangiopathies (TMAs) as we discussed. That’s a good example where yes, you may say for these rare diseases that the market share is so small for them, but I think when we have them, that innovation pays off for our other patients as well.

Maybe we can pivot now to the malignancy setting, Matt and Nagashree, if you’re willing. Matt, would you like to present a rare disease from your arena? You can choose. I think you had mentioned you wanted to talk about uveal melanoma, and I think that’d be fascinating.Nagashree, maybe we can go to you next and talk about an example. Basically, what we’re discussing is what changed in the last 10 years with these rare conditions and what needs to change in terms of pharmacology, better medications, better diagnostics, supportive care, and so forth. Matt, I’ll turn it over to you.

Dr. Hadfield: Absolutely. Uveal melanoma is something I felt particularly compelled to talk about. I just saw a patient with a choroidal melanoma in clinic just a couple of weeks ago who unfortunately has progressed through multiple lines of immunotherapy and is now looking for a trial. We do have that anecdotal evidence of seeing these patients, but it is quite rare, only about five cases per million people per year. Really up until the last two years, there haven’t been any advancements in the field of uveal melanoma. Typically, we use chemotherapy, and response rates and survival mirror cutaneous melanoma, and that hasn’t been very promising in the past. Immunotherapy has been somewhat effective for uveal melanoma, but not nearly on the same scale and scope of what we’ve seen with cutaneous melanoma.

Then two years ago, we did have our first FDA-approved drug for uveal melanoma, tebentafusp. This is interesting for a few different reasons. It’s a GP100 peptide, human leukocyte antigen (HLA)–directed CD3 T-cell engager, and it targets a specific population of patients with HLA A21 genotype, which occurs in about 30% of patients from European descent and about 10% patients from African descent. The trial that led to the FDA approval looked at tebentafusp versus investigator’s choice of ipilimumab, nivolumab, or dacarbazine. Progression-free survival was shown to be improved by five or six months, which seems modest, but in a field where there’s been nothing prior to this, it was actually a very, very big advancement. I think the thing that I find most interesting about this specifically—and Rahul, you may have been seeing this with similar things in myeloma like daclizumab—these T-cell–engaging drugs are very interesting. I think we’re starting to see new ways to engage the immune system that we haven’t seen in the past, which is really fascinating.

Another interesting advancement recently is SD-101 being developed by TriSalus. The Chief Medical Officer (CMO), Steven Katz, is actually here at Brown University in the Legorreta Cancer Center. They recently presented at the Society for the Immunotherapy of Cancer (SITC) their preliminary data showing really, really great progression-free survival of 86% at one year. They use a novel delivery mechanism of pressure-enabled delivery directly into hepatic lesions. A lot of great correlative studies are showing decreased T-regulatory cells and decreased myeloid-derived stem cells. So, there are interesting things for sure in a population where we really need to have more treatment options. I’m pretty excited about the future, but we’ve made some progress recently as well.

Dr. Kalis: Matt, I’m glad you mentioned tebentafusp. Even as the self-proclaimed drug nerd of the group, the mechanism of how it works is fascinating to me. I describe it to my residents as just a bridge between the T cells and the cancer cells, physically linking them and stimulating the immune system that way. I’m sure Rahul has treated patients with talquetamab, teclistamab and other bispecifics in myeloma. The one piece I’d bring up for our audience is that whether it’s myeloma or uveal melanoma, we are still watching out for the risks of cytokine release syndrome and other toxicities. It’s been an interesting development for me that you see bispecific T-cell–engaging antibodies employed across multiple disease states, but the toxicity profiles of them have been fairly consistent so far, at least in my review and experience.

Dr. Hadfield: I’m really glad you raised that point, and Rahul, I’m not sure if you’re seeing this a lot, but as we’ve started to get more teclistamab on the inpatient service, we’ve had admissions for ramp-up dosing. The logistics that go into this really make it a very big question of when we start to use more and more of these therapies, we’re starting to use more investigational therapies that require inpatient monitoring. How are we going to manage this in more of a rural setting, a community setting, or even just outside large academic medical centers? I think it’s a pretty fair question as we start to have more and more of these therapies.

Dr. Banerjee: Completely agreed, especially with these novel toxicities. It’s one thing if the toxicity was bleeding, like with caplacizumab. Any oncologist or hematologist can handle that toxicity. This is a little bit of a unique situation. One thing I don’t think I’d realized is the HLA restriction. I actually had not realized that at all until you bought it up. Matt, I’ll put you on the spot, but is there a reason that it wouldn’t work in other HLA subtypes? Is that a genomic when the patient has HLA or what the tumor cells are presenting? Two, the follow-up to that, with these advanced therapeutics comes advanced diagnostics, how typically is that being sent for patients with uveal melanoma? Obviously, it’s rare, but is this testing also being sent?

Dr. Hadfield: We certainly send it for anyone with uveal melanoma, and I think it is encouraged that everyone should at time of diagnosis. It is a genetic HLA subtype. It has to do with the peptide expression and the binding of the drug, which is unfortunate, because if you think about uveal melanoma being pretty rare, only about a third of patients actually have that HLA subtype. We really are getting into a small subset of patients for whom this therapy is available for, but I do think it’s a good therapy that is good for the patients that it’s available for and has been used quite frequently now for the last couple of years.

Dr. Banerjee: Agreed, that’s good to see. Should we pivot now? We’re coming up against a half hour mark here. Nagashree, maybe I’ll call on you next then. Moving from uveal melanoma, what are some of the rare cancers that you see in your realm? What progress do you think has been made, what progress that hasn’t been made, and so forth?

Dr. Seetharamu: I’m going to be talking about cancers that really are so rare that they are still setting up global registries. NUT midline carcinoma, parathyroid carcinoma, and tumors of that nature are really rare. The progress is that people have started recognizing these as entities, and we’ve started collecting information and registries. The lack of progress is that they’re so rare that you don’t really have good data. These are often young individuals who have these cancers. One of the unifying factors for many of these tumors is a genomic unifier. Let’s say there is an actionable mutation that we can target, irrespective of the type of tumor. Then we have tumors that have mutations and translocations, but at this time, they’re not targetable.

It’s a situation where the only progress we’ve made is that we now know what they are, but we don’t know how to treat them. The insurance companies are at a standstill because there’s nothing approved in this space. We are left to work with the individual patients, and we try a lot of strategies that we use in other types of tumors, immunotherapy and immune checkpoint inhibitors being an example. In this case, a lot of times we end up writing extensive letters of support with very limited data that we can gather from individual case reports. So far, I’ve been extremely lucky. The pharma has been extremely collaborative, and we’ve been able to get expensive medications to these patients to great therapeutic benefit.

Those are the really rare diseases, but coming to diseases that are a little more common, I’m talking about salivary gland tumors. Within that, we have so many subtypes. When you look at the data, it’s all clubbed together. There’s not much available. Each individual is an individual by themselves, and we don’t have that type of granular data. Now, we have started classifying them based on centric-fusion translocation, for example, or classifying them based on androgen receptor overexpression or human epidermal growth factor receptor 2 (HER2). We have some genomic classifiers. That’s probably the biggest advance that we have. We have some more treatments to offer to these patients. But for the most part, I would say that we are more at a standstill and dealing with patients on an individual basis.

Dr. Banerjee: This is very illuminating for me, because I remember when the HER2 connections with these salivary gland tumors came out, we were like, “This is really cool.” In reality, it’s much more complicated than that. Maybe in reverse, I’ll ask about that. If you are able to identify a targetable mutation for which something from the melanoma space for BRAF or something from breast or esophageal space like HER2 applies, has it been easy for you to be able to treat these patients off-label with a targeted therapy? Or has it been kicking and screaming with the insurance company every time?

Dr. Seetharamu: It’s a challenge, and it’s hit or miss. I have a patient right now who I was able to get to directed therapies for an HER2-overexpressed salary gland tumor. But come January, her insurance changed, and the new insurance refuses to continue the medication that has been benefiting the patient. So, I am forced to terminate something that was working for the patient. That’s a very hard discussion. Multiple letters of support have been submitted. Now we have to wait and see if there’s progression. It’s a hard discussion.

On the other hand, similarly, I have a patient with a rare head and neck tumor with PIK3CA who progressed on multiple agents, and I was able to get alpelisib. The patient had a great response. It’s been over a year now with a great response. It was off-label use of the medication, and the manufacturer agreed provide it. In January, they changed their policies for who they were going to approve this for, and the patient no longer qualifies. The medication was stopped. Now it’s more of a social situation, because qualification was based on the fact that the combined income did not qualify for whatever threshold they had. The patient and their spouse were even thinking of breaking up for the purposes of continuing the medication. Socially and emotionally, it’s a very difficult thing. Thankfully, like I said, we’ve been able to work around the bench and have been able to get our patients what they need for the most part.

Dr. Kalis: As targeted therapies have grown, we’ve got new targets that are identified. I’ve found it interesting to see, okay, what’s a driver mutation like the PIK3CA you mentioned versus carriers? Well, we’ve got something targetable, but are we targeting the right thing? I think that’s definitely an area where more research is needed, especially as we’re seeing these mutations pop up in what are currently non–FDA-approved or off-label situations.

Dr. Seetharamu: Absolutely, absolutely. There are some basket trials, if you will, that are looking at this, but even within that, we do know that depending on the primary site, the targetability of a mutation is different—meaning you may not be able to get the same response if it’s lung cancer versus if it’s colon cancer. Putting all of them in the same basket sometimes gives you confusing results, and I don’t know how you can utilize that in a global space.

Dr. Hadfield: I’m so glad you made that point, because one thing that I’ve been thinking for the last 5 or 10 minutes is that I could see tissue-agnostic basket trials being beneficial for rare tumors. If you did get an FDA approval and it’s lumped in, then it’s easy to get the drug approved. But it really does raise the question, and I’ve seen this with a couple of basket trials where you may have two patients with a certain type of tumor and then 10 or 13 of another type, and then you wonder if the end point that was met was actually just those two being brought up by the rest or if there was actually a benefit there. It’s very hard to tease out, and that’s one of the problems that’s not being talked about enough with basket trials.

Dr. Banerjee: This is an excellent segue, because I think we were going to talk in the last 10 to 15 minutes about how we can improve care for a patient with rare diseases, including both hematologic malignant and nonmalignant. Let’s maybe start with clinical trials. That’s a good example. I think basket trials are important in some ways, but you’re right. There’s all the heterogeneity you’re now missing behind the scenes. That can be a problem. We’ll come back and talk about the insurance issues separately, but is there advice that all of you would have or good practices you have seen with basket trial or any trials for rare diseases that make some more feasible or more useful than others?

Dr. Kalis: I can’t think of any particular trial designs or things right offhand, but the point I would make is that at diagnosis when we’re identifying and working up some of these patients with rare conditions, it’s really just underscoring the importance of the genetic testing and whatever tests you’re running. I think we need to keep that broad swath of tests and complements out there to make sure of that. I think of NTRK fusions—maybe we weren’t looking for them in the past, but now we are because we’ve got an agent for it. I would encourage clinicians in the audience to keep a broad mind when it comes to some of that testing.

Dr. Hadfield: That’s such a good point. I was thinking a similar thought. There have been multiple papers that have come out. There was one in the Journal of Clinical Oncology just a couple of years ago showing that outside large academic medical centers, the amount of whole exome sequencing or targeted mutation panels—particularly in lung cancer, which is very pertinent—is really, really below where it should be, less than 50%. We need to be constantly raising awareness that there are targeted therapies out there. To Nagashree’s point, someone with a PIK3CA mutation might do really, really well with capivasertib. You may be opening up an option, or it may be something where it doesn’t work as well as it did in the trial, but at least you’re opening up options that otherwise wouldn’t have happened. So, it’s a really great point to make.

Dr. Banerjee: When you have done that, for example, Nagashree, did you have to do an investigational new drug (IND) application? Because it’s approved, you just got insurance or you had the separate program that covered it, right?

Dr. Seetharamu: In this case, it was an off-label, but I have had to go through the Expanded Access Program (EAP) or single-patient IND process, which is obviously much more cumbersome and time-consuming. Often our patients don’t have that time. So, I think that if there’s any progress that can be made in quick order, it should be changes in policies so that we are able to get these medications. There should be committees that approve this, rather than treating it as when you do a single-patient IND. It’s like opening a clinical trial, and I don’t know that it’s necessary. Most of the time, it’s mostly cut and paste that I’m doing from approved indications or whatever it is. It should be a much quicker process. There can be a panel of reviewers because you don’t want to misuse the process, but at the same time, it can be made much easier, I think.

Dr. Banerjee: Agreed. What you’re saying is the IND is a lot of work for one patient. A basket trial is a lot of work to get off the ground. Ideally, there would be something in between that can allow patients to get these drugs, but in a way that somehow someone can keep tabs and say, “Oh, look, in the real-world setting, this is happening, this is happening, and so forth.”

Pivoting slightly to that point, you had mentioned it’s rare tumors you need global registries for. POEMS syndrome is an example of a plasma cell disorder where we’re working on creating a national POEMS registry to get a better sense of what’s happening in the real world. We have a good transplant registry, the Center for International Blood and Marrow Transplant Research (CIBMTR). For patients with POEMS who get transplanted, we know exactly what’s happening. For everybody else, we know nothing of what’s happening. Any experience that any of you have had with making these real-world collaboratives or real-world data collection initiatives for these rare conditions either in the US or globally? What works about them, how do you get them started, and so forth?

Dr. Kalis: Here in the US, I’ve collaborated with some of the physicians in my group and residents. We’ve written case reports, which is one way to get things out there, but then you can get further into the weeds of, “Well, the journal you submit to, is it carried on PubMed or others? How available is that report going to be?” I’m almost thinking now if there was a way, like you talk about national registries or global registries—and this could just be my own ignorance, maybe there is something out there. If there were a forum or registry where if we do have these rare cases and rare diseases and we’re treating patients off-label with agents, it could be like having a repository where clinicians could go and search to see, “Okay, I’ve got a rare head and neck salivary gland tumor, but it tested PIK3CA positive.” Has anybody else done this in a place where clinicians could go to find that type of information?

Dr. Hadfield: That’s a brilliant idea. I think you just found a side hustle. What I was thinking is one of the silver linings of the COVID-19 pandemic was the COVID-19 & Cancer Consortium. Jeremy Warner’s here at Brown, and he really helped spearhead that. I think when you get enough interest and people feel passionately enough, these things can come together pretty fast. It is certainly possible. I think you’ve got to find the right people that are willing to engage and do the work, because honestly, no registry ever happens unless people at all these centers put the work in and actually get data. It’s hard to find those teams of people, but we have seen examples where it’s worked.

Dr. Banerjee: Agreed. The publication angle is interesting, because you need that incentive for people. Even for our real-world Myeloma CAR T Consortium, it’s a lot of work for data coordinators to put all these data points in, or it ends up being put on the fellow the day before the ASH or the ASCO deadline to “Go, go, go, put all these charts in.” I think there needs to be a better way of doing that, because I agree with you. I think with a lot of these rare disease, if one center is doing something and it’s working for those patients, nobody else finds out about unless you happen to bring it up on social media or at a talk. That’s not a very efficient way of doing this.

Dr. Hadfield: Right. To your point, we all want to do things that are good and make patient care better, but there has to be some type of tangible outcomes like publications or presentations or something that you’re a part of, because otherwise it just falls down the priority list too far and it just doesn’t get done. I mean, we’re all so busy and we all have patient responsibilities, but that has to be a part of it. I think with any of those endeavors, the engine really has to be an academic one. People have to really want to pull their results and publish them and get that out there.

Dr. Banerjee: Agreed. Sometimes those case reports or case series or small cohorts are important not just to say how things are done, but so that when a new condition comes along, the FDA has looked favorably upon using a real-world control arm—meaning that the control arm is historical, but it’s how they would’ve done otherwise. Obviously, it’s not great. Obviously, I prefer for every drug ever to have a randomized, controlled phase 3 trial, but that’s not going to happen with a rare disease. Even a phase 3 trial is unlikely to happen with a rare disease. I think getting those real-world data is supremely important. Well, go ahead, Matt. Were you about to say something?

Maybe the last question I’ll ask just to close it out would be to hear from each of you—for patients with rare diseases, any advice for them? In each of your respective realms that we talked about, what would you tell them about how to navigate rare diseases, not as a clinician, but as a patient? Maybe I’ll go last, because otherwise, I can keep talking forever. Any brave volunteers? What advice you would tell patients on Rare Disease Day?

Dr. Seetharamu: I think it helps to hear the patient’s voice. We have seen advocacy groups—for, let’s say, KRAS, and we have KRAS Kickers. We have a group called EGFR Resisters. I know that there is a group for rare diseases, but at the same time, because it’s so rare and so diverse, I think it makes it difficult. So, I think the patient’s voice is important. Social media can be definitely used as a platform to express or reach out to individuals who might have experience in treating a particular condition that’s so rare. I encourage my patients to use the social media platform to reach out to experts or people who might have had some experience with their specific type of disease.

Also, we spoke about earlier about case reports. I think it’s extremely important to understand the value of case reports. In rare diseases, it is of extreme importance, because one case may be worth so many others when you compare it to other more common conditions. So, I would say to collaborate with other clinicians to write a case report. Putting in a personal piece that many journals now allow might be helpful as well. It might help patients who are in similar situation across the globe.

Dr. Banerjee: That was excellently stated. I have very little to add. I agree with you, Nagashree, on all fronts. Thoughts from the other panelists?

Dr. Hadfield: No, I completely agree. That was very, very well said. I think in my experience, the one thing I would say is that I don’t think any patient ever wants to hear that the cancer or the horrible condition they have, like TTP or PNH, is really rare. It’s almost like saying you won the wrong lottery. I think we just always have to be mindful with the language we use with patients, because those types of comments can really make people feel not so good about their condition that they’re already not feeling so good about. I’ve seen that happen before and I think it’s important to highlight that.

Dr. Kalis: I’ll take a slightly different track before we have any questions from the audience. Working directly with patients as I do, I do a lot of patient education and counseling on therapies. I’ve heard patients joke about it like, “Oh, yeah, I always wanted to be the 1%. This just isn’t the 1% that I thought I’d be part of.” But I would put in a bit of a plug for some of our patients continuing to function as their own advocates, like the social media aspect and trying to find some of those support groups.

I think too, on a clinical side, keep an open mind to some of those questions or concerns or ideas that patients bring in. Maybe there’s some validity to it and it’s something we haven’t considered. I would just encourage patients who have rare diseases to keep on your own research and continue to advocate for yourself. At least in my own experience with many of these conditions, I think about an interaction I had. Full disclosure, I’m a type I diabetic. I’ve been since I was 10. I saw a new endocrinologist a couple years ago. On our first visit, he said, “Okay, you’ve had this disease for 30+ years. I’ve only been treating it for 10 years. Let’s work together to find what’s best for you.” I think that approach is really what’s needed in rare diseases.

Dr. Banerjee: Thank you, Joe, for sharing that. Completely agreed. The last thing I’ll say is, obviously while rare diseases individually are rare, I think there are some estimates that like 200 to 250 million people worldwide are living with what’s considered a rare disease. The numbers clearly add up, and we need strategies like this that involve patient advocacy, patients reaching for themselves, patients working with physicians to make this happen, and pharmacists and the whole team. At this point, I think we’ll wrap up here in terms of scheduled remarks. Any chance that anyone on the live stream has had any questions so far?

Oncology Data Advisor: We don’t have any questions yet, but this recording will stay up on YouTube after it’s over, so if anybody has any questions, feel free to type them into the chat and we can always answer them offline after the fact.

Dr. Banerjee: Perfect, absolutely. We are happy to help. Obviously, we are not the experts in every single rare disease and might not be able to answer, but we’ll find people who can. I think that’s the other part of this—that the network of physicians needs to be intact to consult if you don’t know what to do. If you haven’t seen many patients with a certain disease, you don’t get penalized for phoning a friend, right? This is exactly what we need, because we need that expertise. The expertise forms by having seen even five more patients than your colleague has. With something like POEMS syndrome or uveal melanoma, that’s a lot.

To wrap up here, again, we encourage people if you have questions, you could reach out to us through the YouTube video or through the Oncology Data Advisor portal. Thank you all for taking the time to join us for Rare Disease Day. Today is February 29th, 2024, a leap year. Again, rare diseases are rarer than a leap year is, but they’re super important. I certainly learned a lot from my co-panelists, so thank you all for your time.

Oncology Data Advisor: Yes, thank all of you so much. It was wonderful to hear your perspectives on this, and thank you to the audience for tuning in. Hope everybody has a great rest of the day.

Dr. Hadfield: Great. Thank you, guys.

Dr. Seetharamu: Thank you.

About the Speakers

Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington. He also holds a faculty appointment at the Fred Hutchinson Cancer Center in Seattle, Washington. Dr. Banerjee previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR-T therapy. His research interests are in toxicity management, digital health, and the patient experience.

Matthew Hadfield, DO, is a Hematology/Oncology Fellow at Brown University/Legoretta Cancer Center in Providence, Rhode Island. Prior to fellowship, he completed his Internal Medicine Residency at the University of Connecticut in 2021. Dr. Hadfield’s research focuses on melanoma and early-phase clinical trials. To date, he has published numerous peer-reviewed articles and studies, and he has presented his research at multiple national and international meetings. His main areas of interest include early-phase drug development, novel immunotherapeutic combinations to overcome therapeutic resistance, and predictive biomarkers for immunotherapy toxicities.

Joseph Kalis, PharmD, BCOP, is an Ambulatory Oncology Clinical Pharmacy Specialist at the University of Colorado Health. In this position, he educates patients about their chemotherapy and immunotherapy treatments, reviews treatment plans and dose adjustments, and assists with supportive care. Dr. Kalis’ professional interests include multiple myeloma and hematologic malignancies. He enjoys teaching learners from all walks of life. Dr. Kalis has spoken extensively for continuing education programs, along with various peer-reviewed papers on oncology and pharmacy.

Nagashree Seetharamu, MD, is a Professor in the Department of Medicine, Division of Hematology and Oncology, at the Barbara and Donald Zucker School of Medicine at Hofstra/Northwell Health. In addition to being a nationally and internationally renowned thoracic and head and neck oncologist, with a busy clinical practice, she is a very active academician. She has conducted several research projects in the fields of lung cancer prevention, early detection, predicative and prognostic biomarkers, as well as novel therapeutics in thoracic and head and neck oncology. In addition, Dr. Seetharamu is passionate about mentoring the new generation of oncologists and plays an active role in the fellowship program at Northwell Health. She also serves as a mentor for trainees in other institutions through the ASCO mentorship program.

For More Information

Patel SP, Carvajal R, Montazeri K, et al (2023). Clinical activity of SD-101 with immune checkpoint inhibition (ICI) in metastatic uveal melanoma liver metastasis (MUM-LM) from the PERIO-01 phase 1 trial. J Immunother Cancer (SITC Annual Meeting Abstracts), 11(suppl_2). Abstract 1534. DOI:10.1136/jitc-2023-SITC2023.1534

Nathan P, Hassel JC, Rutkowski P, et al (2021). Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med, 385:1196-1206. DOI:10.1056/NEJMoa2103485

The COVID-19 & Cancer Consortium (2024). Available at: https://ccc19.org/

KRAS Kickers (2024). Available at: https://www.kraskickers.org/

EGFR Resisters (2024). Available at: https://egfrcancer.org/

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 

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