Arun S. Singh, MD, provides the history of sarcoma management and reviews the latest updates in treatment of targeted therapy.
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Good afternoon. My name is Man Veer Bengu. I'm a medical oncologist that scripts M. D. Anderson Cancer Center, and it's my privilege and pleasure to introduce our afternoon program. Dr. Arun Singh is a medical oncologist at UCLA, with a particular clinical and research focus and the management of patients with sarcoma. His topic this afternoon is targeted approaches in sarcoma, and it's our pleasure to have him join us. If you have questions, please use the ask a question chat function. During his presentation, he will be addressing questions during our panel session at the end. Thank you. I am a rinsing from the sarcoma service. The title of my talk today is evolution of sarcoma management and the Arab targeted therapy. These are my conflicts of interest. Sarcomas are rare and heterogeneous group of neo plasm that can occur anywhere in the body. Uh, they are tumors of your muscle fat bone, fibrous connective tissue, et cetera. They are. Incidents increases as people age, but it's one of those cancers in which the younger age groups are disproportionately affected. There's about 15 or 16,000 new cases a year in the United States with soft tissue sarcoma is much more common than bone sarcomas. Uh, these diseases are handled by multidisciplinary groups and the n C. C N guidelines for both bone and soft tissue sarcomas do recommend multidisciplinary approaches to handling these diseases. For instance, that involves orthopedic surgeons, surgical oncologist, medical oncologist, radiation oncologists, pathologists and radiologists who have expertise and taking care of patients with sarcomas. This is our U. C. L. A sarcoma program, uh, with people from several of these specialties and we sit together every week and, uh, determine how to take care of each patient that were taken care of. Um uh, sarcomas, um are a rich, um, and evolving field. Uh, at this time, uh, there are several different mutations that are seen in each sarcoma subtype. In fact, about 30% of sarcoma associated with trans locations and there is a series of point mutations that are seen in these diseases. In fact, some of some sarcomas are even being characterized based on the specific type of mutation that they have. So we're moving towards, rather than a histology specific determination of these diseases to more of a molecular determination of sarcomas. And, um, you know, it gets further complicated. Um, you know, um, for instance, uh, some of the trans locations, the binding partners of the trans locations and the specific cell types in which the trans locations occur really are important in determining the clinical phenotype that we see. For instance, E W s is, um, has a multitude of binding partners, and the different binding partners engender almost different diseases and also different responses to chemotherapy. And as we can see here, I guess rather complicated, because in each different subtype of sarcoma as you can have different binding partners also, so really, the disease continues. These diseases continue to get split split up further today, we're really focusing on systemic therapy for sarcomas, and the focus of my talk is really going to be on the metastatic or locally advanced sarcomas and this lesson old slide from Sloan Kettering. And it actually shows that for it doesn't matter where your disease starts if you have metastatic disease. By and large, all patients end up dying and do poorly. There's only exceptional cases that don't die from metastatic sarcomas. And unfortunately, this curve hasn't changed very much from 2000 and three or so when the slide was made and, as in many different cancers, advanced sarcoma as you see a diminishing benefit with each subsequent line of therapy today, while there there are several different approaches targeted approaches that are being evaluated and bone and soft tissue sarcomas. I'm really going to focus on some of the FDA approved therapies that have come out in the last few years. The disease I'm going to focus on are just Tino Synovial, giant cell tumor, epithelial sarcoma and track. Or you're in sarcoma, giant cell tumor of the bone lipo sarcoma. And finally, I'll touch a little bit on some general sarcomas. Um, today we're gonna start with just which has been one of the poster Children for targeted drug development. As you know, in the late nineties, kit immune system, chemical staining helped to identify just and two separate from other types of sarcoma such as Leo Maya sarcoma and other sarcomas of the GI tract, which are rather unusual. Um uh, Subsequently, uh, labs in Finland and Japan identified mutations within kit which ended up being the Uncle Logic. Drivers of this, this disease or series of diseases rather and at Dana Farber, a team understood that a magnet which was being evaluated for CML also had activity against Kit. And this this case report in the New England Journal from 2000 and one was the first demonstration that imatinib the small molecule could have a profound activity in gastrointestinal stromal tumor. And from panel eight to see you see a patient with mark liver metastases showing a significant clinical improvement within a few months. Uh, today we know a lot more about the gist mutation all landscape, and these mutations have been separated into primary and secondary mutations. Um, and the current clinical problem is really the t. K I resistance of secondary mutations. We know eggs on 11 is the most common mutation in kit, and eggs on nine is the second most common. But we also know this disease. There are some, uh, some variant instead are under the wild type category that have mutations be raft grass and F one substance. The hydrogen is complex as well. Um, and, uh, this slide, uh, basically shows that in reality, the mutation type that each individual patient possesses very instructive for not just the behavior of the disease, but also as uh, an impact on what dose of the math that we use. We know that for example, nine mutations we should use 800 mg of Gleevec rather than 400 mg over time. We've seen that TK I benefit declines with each subsequent drug. And the other two drugs that were approved up until this last year were, uh, punitive and Rajaratnam and, uh, all all the current agents that are listed on the N C. C N compendium. They all do the same thing. They inhibit they work interests, elderly to inhibit the mutated tire, seen kindnesses more recently, Uh, decipher, uh, develop this drug called Repression and previously known as D. C. C. 2618 It has a different mechanism of action than the other tyrosine kindnesses, and that it is actually what is called a switch pocket inhibitor. I don't know. I don't have time to go over the exact detail of how this works, But, uh, in the preclinical models and the panel panel on the right, um, we see that, uh, Dublin you can constructs were introduced into Bath three and Chinese hamster ovary cells and of the different types of kindness and inhibitors that were used reproductive, which is the left panels, actually was more efficacious and imatinib Sunita nib regular Affin, ib and, uh, blue to 85. This led the Cypriot to run trials in the 2nd and 4th line for advanced just and other diseases as well. And then victor study, Um uh, repetitive. Which is the other name for DCC 2618 was compared to placebo. So this is 1/4 line placebo trial. Um, it was randomized, and you were allowed crossover. And and, uh, the median PFS for the repetitive group was a little bit more than six months compared to one month with placebo. And this might be one of the last placebo trials we ever do see in just, um, this, uh This led to FDA approval in January about 2020. And if we look study further, we see that the different kit mutations eggs on 11 9 kids 17 or 13 that you see that repetitive has a much better activity than placebo. And that's not surprising. Would be more informative to see repetitive compared to turn line ready, Arraf nib or student in IB, but nevertheless, uh, these clinical data do support some of the pre clinical evidence that was seen for this particular drug. Um, the next study I'm going to talk about is the navigator study. This is actually a phase one trial of overprotective, otherwise known as Blue to 85 P d g f r D 8 42 v mutants, just And, uh, the water fall plot says it all. Almost every single patient had marked improvement of, um, of their just and only one patient had some tumor growth, and this received FDA approval of in January 2020 as well. Um, and we see that the benefit, uh, the overall response rate sorry was 84% but we see that the 12 month duration response was, uh, 70 76.3%. And the 12 month PFS was 81 was 81% which is remarkable for for a new drug. And really, I I think, uh, wanted a real breakthroughs for this disease. And sometimes, um, this drug is also valued in Fort Line just, and we see that it actually has activity that, uh, you know, uh, 60% of patients have, um, a reduction in about 25% of patients or maybe 20% or so actually get a resist response. However, unfortunately, this drug did fail compared to regular RAF and a 3rd, 3rd or fourth line treatment. Um, so I'm gonna leave just now and move on to Tino Synovial giant cell tumor. This was previously called pigmented villain. Ah, Justine Uveitis. These are rare us of the joints and tendons sheets, and there are only a few 100 cases a year in the United States, and it's often in younger people. It is felt to be a clone, only a plastic process in which there's too much CSF. One colony stimulating factor one is over expressed and in fact, a translocation between chromosomes one and two bringing CSF one, uh, in contact with collagen. Six a three is seen in more than half of cases. It's felt the path of physiology, for this has felt that this over expression of CSF one ends up leading to the recruitment of a variety of inflammatory cell types such as macrophages, giant cells and osteoclasts, and the large majority of the makeup of a Kosovo giant cell tumor. A really decent inflammatory cells and the, uh, uncle genic compartments, actually, rather small. So, uh, this led to a structure guided, uh, design of this drug called Qnexa Darknet frump lexicon. And, uh, it's, uh it's a CSF one receptor blocker. And this was put into early phase clinical trials for a variety of malignancies, But, um, but they saw some startling responses in Tina Snow build giant cell tumor. This is actually one of my patients. She was a nurse. And in February 2013, this is her right knee. Um, and this was basically a diagnosis of, uh, the diffuse type of Tino Synovial giant cell tumor. Not the modular, uh uh, version, which is mostly in the small joints and extremities. And she was using a cane to ambulance it. She was not eating very well. And her only option for surgery was an amputation. And she went into phase one trial, and within four months, this is what happened to her knee. She stopped using narcotics. She was back at work, she gained weight. And this is what her MRI showed. Actually, after two months, Uh, the outlined, uh, part is actually the, uh, neo plastic or malignant component per se, but again does mostly inflammatory type cells just within two months and marked reduction. And in four months, you know, she had a drastic, uh, improvement in in the amount of disease in her knee and a new metric or a new metric for oncology tumor volume score was used in this case, uh, to evaluate the, uh, the effect of the drug pecs, a dart and it and on a pet on her pet scans, you saw a marked reduction in the SUV as well. Just after two weeks of pecs, a dart which was previously known as P L X 3397 Almost all the patients on the, uh on the on the, uh the phase one trial had the disease response. And, uh, these were durable disease responses as well. This led to the Phase three and Live and Trial, which is a global double blind randomized placebo controlled Phase three trial of pecs, a darknet compared to placebo in advanced Tina Snow Belle giant cell tumor crossover was allowed and the primary endpoint was overall response. At six months via resist 1.1 the tumor volume score that I just talked about was an exploratory, um endpoint and is just being published now and this power to detect a 25% difference in response. And the pixie group that response to it is 40%. And, as expected, the placebo group, the response rate was zero. And there was some liver toxicity. Um uh, with this drug trial was initially halted and, uh, eventually the trial was reopened and the drug was approved by the FDA in August of 2019. And I think it's still the only CSF one receptor blocker that's FDA approved. Um, and patients on these drugs are expected to, uh, be very closely monitored by a platform set up between Daiichi and the FDA. So I'm going to move cancers now to epithelial. I'd sarcoma and a new drug was approved for this Called to Zometa Stat, otherwise known as Task Barrick and Epithelial oId Sarcoma is a disease as a terrible disease that happens mostly in younger patients. And it's this disease is characteristic, uh, by a loss of I and I won, and I and I one and e ch two r have opposing roles in chromosome remodeling complexes. And when I and I one is lost. That shifts the balance towards easy H two. And the idea is a testament to stat can help to restore homeostasis for chroma tin remodeling. And this is, uh, this drug was valued in a phase two study, an international phase two study with several sarcoma groups. And, you know, about half the patients showed a reduction in, um, in their two dimensions, which is unusual for this disease. You know, it's a disease that handled mostly by surgery and radiation. And there's a limited role for systemic therapy and this disease we still use, um uh, chemotherapy. But the benefit is not profound. And this is a remarkable demonstration of a trend. A really good translational model. Um, the PFS was a little right around six months and was better for treatment. Naive patients, and, uh, the median overall survival was, uh, 80 82.4 weeks with and again was better in treatment, naive patients. I'm gonna switch gears now to talk about the untracked fusions which have revolutionized a few malignancies. These fusions were first found in 1998 by Dr Sorenson and as a bitch uh, they describe E. T. V six and track three fusion in a patient and infantile fibrous sarcoma. Today we know more about the 95% of patients with infantile, fibrous sarcoma have and track fusions. We've gone on to learn that there are several binding partners to the end to, uh, contracts 12 and three, very similar to what happens with the E w s, uh, fusion proteins. Uh, these fusions and gender Ligon independent track activation. Um, and however, this does not seem to happen with the non fusions. Yeah, the track fusions are seen in both adult and pediatric malignancies. And then the sarcomas, particularly infantile fiber sarcoma, is fairly common. Otherwise, we see it in just we see it in life with sarcoma, undifferentiated, polymorphic sarcoma and some other sarcomas. We do see it in from time to time as well. The first track fusion patient treated with Larry Trek name was a patient, an undifferentiated polymorphic sarcoma, widespread lung metastases, and then the dose of 100 mg twice daily. The patient had a remarkable response, as you can follow the panel from left to right here, and, uh, this helped to fuel clinical trials that came later on on the first trials was in kids with both infantile fiber sarcoma and soft tissue sarcoma. And we see that all the patients in the pediatric Scout phase one study had a response, and the non track fusion patients did not respond as well. And these responses were durable and, uh, in a larger study, regardless of tumor type, as long as you had attract fusion. Most patients 8 81% in this study at this time point responded to attract inhibitor. But since we're focusing in star comas in the response rate in sarcomas was actually higher is 93%. Whether it's pediatric or adult, patients responded to an intractable are attracting it. And these responses were very durable, as we can see here, another drug contracting. It also has activity and a variety of, uh, malignancies, regardless of the translocation. And here, the ones in black, about nine sarcoma patients responded rather well to interact in it as well. Um, and most of these were patients would rather advanced disease. Um uh, some of the focus is starting to shift towards doing this in a new agreement. Fashion. This is a patient that our, um, our board with infantile fiber sarcoma with an E. T. V six and track three Fusion. And on the panel on the left, I hope you can see my curse. Or you see a large amount of disease in the forearm compartment. And after a few months of, uh, this child had failed other treatments. And after a few months of treatment, five months, um uh, with Lara tricked and they've had a remarkable response here at the point where this patient had a pathologic r zero reception pathologic complete response within our zero sections. Uh, and there's a study with lots of 195 to address some of the resistant mutations. Primarily, uh, G 5 95 are that are occurring. Uh, in these, uh, patients, we switch now to giant cell tumor bone. These are lyrics skeletal, uh, lesions that are felt to be due to an imbalance between osteoclasts and osteoblasts activity. Um, and there it felt that there's too much rank ligand available in the micro environment for these diseases, and that helps to lead to the development of osteoclasts like giant cells. Hence giants the term giant cell tumor bone. These diseases were traditionally treated with curettage and cement, but in some difficult to treat areas such as the pelvis. And, uh, when you have this disease close to the joint, uh, you can have a lot of morbidity, and engine developed the rank ligand denosumab, which is also approved for osteoporosis. Um, and this was tested in giant cell tumor bone. This is a face to open label study. And really, the key to this is if you look in panel de you see the, um uh, with patients with giant cell tumors of bone, you get re formation of normal bone after some treatment with denosumab. Probably more telling is this patient with giant cell tumor here of, uh, the ulna, Um, and you can see marked, uh, destruction. But after six doses of denosumab, this is my patient actually had marks sclerosing sclerosis of this area and made surgery a lot easier. Um, and, uh, finally, as we wrap up now, I'm going to talk about, uh, all the all the things we've been talking about have been really mutation specific drug selection. But now, in sarcoma, we also talk about histology tailored therapy, and over the last few years, a few drugs have come online that really do address particular sarcoma. Histology is, for instance, Trebek didn has shown benefit in both lymphoma, sarcoma and lipo sarcoma, with an improvement in PFS over the carbon seen from 1.5 to 4.2 months. It has also been shown that it can be beneficial in patients with translocation associated sarcomas, but this is not in the FDA label. Vote treatment is has activity against a wide variety of sarcomas except at a Pacific Sir comas, and this was approved in 2000 and 12 and has a median PFS. After failing frontline chemotherapy of about 4.5 months, Caribbean got FDA approval for lipo sarcoma, but not Leo Maya sarcoma, because in the trial it was compared to the carbon seen as well. And there's the lipo sarcoma subgroup that was driving all of the benefit for this disease at the last thing I want to say, you know, the sarcoma field is, you know, a model for trans translational research. There's a rich variety of, uh, mutations that that are seen in these diseases that we're trying to unlock with you and your targeted therapies. Immunotherapy, etcetera. Um, these are just some of the drugs and the, uh, mutations that they target. And but, you know, in, uh, in rare sarcoma is there's It's very hard to run adequately powered clinical trials to get these agents approved for diseases for which there is 203 100 cases a year in the United States. So we do use a lot of off label drugs, and even some of the drugs listed here are off label for these individual indications, even though there is known clinical benefit and this list both of the mutations as well as the agents is expanding. And this this slide is even rather outdated by at this point, thank you.
