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Clinical

In season 3, episode 2 of Targeted Talks, Mark Agulnik, MD, section chief of Sarcoma Medical Oncology, Department of Medical Oncology & Therapeutics, and research professor, Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center (City of Hope), discusses molecular testing for patients with sarcoma, targeted therapies, and ongoing research.

Getting a picture of the molecular characteristics of a patient’s disease is a process that has evolved over time, according to Agulnik. The importance of this testing is to identify molecular drivers that could make patients eligible for clinical trial enrollment or if there are any FDA-approved drugs that can be administered to the patient.

In recent years, the number of targeted therapies and immunotherapies for the treatment of sarcoma has greatly increased. Agulnik notes that most patients are hoping for chemotherapy-free treatment options. Pazopanib and a 3-to-4-month improvement in progression-free survival over placebo, which was not robust enough for the patient group. Today, therapies like regorafenib (Stivarga), entrectinib (Rozlytrek), and larotrectinib (Vitrakvi) appear to achieve better outcomes, explains Agulnik. More therapies are being explored for the treatment of sarcomas like cabozantinib (Cabometyx) and immunotherapies.

Agulnik also touches on the current Clinical Practice Guidelines for the treatment of sarcoma and how practices, how practices are carried out at City of Hope, and what community oncologists should know about treating sarcoma in today’s landscape.

In season 3, episode 2 of Targeted Talks, Mark Agulnik, MD, discusses molecular testing for patients with sarcoma, treatment with targeted therapies, and ongoing research.

Advances and Pending Innovations in the Treatment of Sarcoma

In season 2, episode 10 of Targeted Talks, Sandra P. D'Angelo, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center speaks joins Katherine Poruk, MD, a surgical oncologist at Cancer Treatment Centers of America for a conversation about frontline treatment practices in the sarcoma space.

Using a case scenario of a patient with localized soft tissue sarcoma in the right thigh, Poruk first explains the best approach for surgical intervention. The key for treating a patient with these characteristics, according to Poruk, is to start with history, a physical, and imaging. Often, imaging can reveal a lot about the tumor. In other cases, a biopsy is needed before surgery.

In terms of systemic therapy, D'Angelo explains that for metastatic disease, chemotherapy is the mainstay of therapy. Deciding on which agents to use in a patient is usually based on the patient's comorbidities. The options are more plentiful in later-line settings.

Both physicians agree that histology is important for the treatment of patients with sarcoma. Further, pathologists, surgical oncologists, radiation oncologists, and medical oncologists must work together to treat patients with sarcoma.

In season 2, episode 10 of Targeted Talks, Sandra P. D'Angelo, MD, and Katherine Poruk, MD, discuss frontline treatment practices in the sarcoma space.

Treating Sarcoma With a Multidisciplinary Approach

In an interview with Targeted Oncology, Neeta Somaiah, MD, explained how targeted therapies have started to re-shape the treatment of sarcomas and the potential role of immunotherapy in the future.

Targeted Therapies Begin to Transform the Treatment of Sarcomas

Both pediatric brain cancers and sarcomas have an extremely dismal outcome in the relapse setting, according to Catherine Bollard, MD. A new Cancer Grand Challenge aims to address the issue with the development of new therapies.

Taking on the Challenge to Develop New Therapies for Pediatric Solid Tumors

A phase 1 trial showed efficacy of a novel T-cell therapy targeting MAGE-A4 in solid tumors, particularly synovial sarcoma. 

Afami-cel T-Cell Therapy Shows Early Efficacy in Synovial Sarcoma

In an interview with Targeted Oncology, Matthew A. Ingham, MD, explains the uniqueness of uterine sarcomas and how years of research around these tumors have led to advances in precision medicine for patients.

Bringing Targeted Agents from Clinical Trials to the Clinic for Patients With Uterine Sarcoma

Investigators in the IT-01 trial of INT230-6 as monotherapy or combined with ipilimumab showed safety and potential efficacy in patients with sarcoma. 

Intratumoral Injection Shows Antitumor Activity and Safety in Sarcoma

Neeta Somaiah, MD, an associate professor and deputy department chair in the department of sarcoma medical oncology, division of cancer medicine at The University of Texas MD Anderson Cancer Center, discusses new and upcoming targeted therapies for sarcomas at the Inaugural Miami Cancer Institute Precision Medicine Oncology Symposium.

Due to the variety of sarcomas, different targets are under investigation. According to Somaiah, liposarcomas and desmoid sarcomas are subtypes where targeted therapies have shown efficacy, including CDK4 inhibitors and MDM2 inhibitors. Gamma secretase inhibitors have been employed in Kaposi sarcoma. Additionally, 

 mutations have shown potential as targets in some soft tissue sarcomas and bone sarcomas.

Somaiah says that immunotherapy is an important area of investigation for her, though there is a challenge in finding the right subtype that will respond to immunotherapy. Combination immunotherapies are under investigation in patients with soft tissue and bone sarcoma, but the same combinations used in other cancers may not be effective in sarcomas. Currently the only sarcoma with an approved immunotherapy is alveolar soft part sarcoma, where pembrolizumab (Keytruda) alone or in combination with axitinib (Inlyta) are preferred regimens.

We have targets within the liposarcoma space, we have CDK4 inhibitors, MDM2 inhibitors that are of interest. In the desmoid space, there are newer gamma secretase inhibitors that are being looked at, similarly there are specific mutations in 

, etc, that are being targeted across certain soft tissue sarcomas and bone sarcomas.

I personally am very interested in advancing immunotherapy in the sarcoma space. The challenge there is finding the right subtypes that will respond and also finding the right type of immunotherapy combinations that will be helpful for these [patients with sarcoma] that are different than some of the carcinomas that we see. I think there are some combination trials that we'll be seeing in the future that we hope can bring the immunotherapy into the soft tissue and bone sarcoma spaces as well. Right now, [immunotherapy] is only approved for a small subtype called alveolar soft part sarcomas.

Videos

Neeta Somaiah, MD, discusses new and upcoming targeted therapies for sarcomas at the Inaugural Miami Cancer Institute Precision Medicine Oncology Symposium.

Targeted Therapies and Immunotherapy Play Greater Role in Sarcomas

Matthew Ingham, MD, an assistant professor of Medicine in the Division of Hematology and Oncology at New York Presbyterian Hospital/Columbia University Medical Center, highlights a recent clinical study in the sarcoma space and discusses what else is being evaluated for this patient population.

Uterine sarcoma is a a rare disease that has many different subtypes, but clinical trial and molecular profiling have helped researchers further understand their diagnosis and classification.

According to Ingham, there are ongoing trials evaluating new targets for uterine sarcomas related to PARP inhibitors. These studies will help further understand this type of sarcoma and develop new treatment strategies to improve patient outcomes.

We ran a study at Columbia that is a good example of this. The study involves a combination of a PARP inhibitor called olaparib [Lynparza] with a low dose of chemotherapy called temozolomide. In this study, which was mostly patients who had progression on chemotherapy, we found that the treatment offered some activity. The response rate was about 27%, and the median progression-free survival was about 7 months. There are limitations but it seems to compare a little bit favorably to some of the existing drugs that we have after chemotherapy, like trabectedin, or pazopanib. We hope that it is starting to establish proof of principle that these targeted approaches with PARP inhibitors and DNA-damaging agents may be a new class of drugs that could help these patients.

There are a number of other exciting clinical trials that are following this and being developed at centers across the country. Those are looking at other targets that are related to PARP inhibitors…and a protein called PLK1, [and other inhibitors] that are related but a little different. They are all DNA-damaging checkpoints that we hope will offer a new class of targeted therapies for these patients. We just have to better understand which target is going to be the best one.

Matthew Ingham, MD, highlights a recent clinical study in the sarcoma space and discusses what else is being evaluated for this patient population.

News

Clinical Trials Help Experts Understand Classification/Diagnosis of Sarcomas 

Matthew Ingham, MD, an assistant professor of Medicine in the Division of Hematology and Oncology at New York Presbyterian Hospital/Columbia University Medical Center, discusses some of the most recent clinical updates in the sarcoma space.

According to Ingham, uterine sarcoma is a rare disease that has many different subtypes. Because each of these subtypes differ from one another both biologically and clinically, it is important for experts to understand all of them. Each of these subtypes should be treated individually as they are all different and can be genomically complex.

Further, experts believe they have found a 

 like phenotype in uterine leiomyosarcoma. This has led to the development of multiple clinical trials that are evaluating a number of targeted drugs for this patient population.

 To focus on uterine sarcomas, it really is a challenging disease to treat when it's metastatic. We do have some chemotherapy options, so we use drugs like doxorubicin or gemcitabine plus docetaxel. Those have been the standard chemotherapy treatment for many years. They do certainly have some efficacy, but they have a fair amount of toxicity. Unfortunately, progression-free survival is relatively short. I think what we're trying to do with uterine sarcoma is to really understand the biology so that we can develop treatment approaches that are more targeted.

Probably the most exciting development in the field, which I think is really taking a collaborative effort from a lot of research groups working together, is that it does seem that as a subset of uterine leiomyosarcoma, they have a defect in their ability to repair their DNA. It's sort of what we call a practice like phenotype. So people have probably heard about 

 in ovarian cancer, breast cancer, and really what 

 mutations do is that they impart a vulnerability and sort of a deficiency in the cancers ability to repair certain types of DNA damage, and it makes them sensitive to certain targeted treatment approaches with DNA damaging agents. We think that we've found a 

 like phenotype in uterine leiomyosarcoma. That has prompted a number of clinical trials that are looking at targeted drugs to take advantage of that to hopefully offer patients a more targeted, less toxic, and more effective treatment option.

Matthew Ingham, MD, discusses some of the most recent clinical updates in the sarcoma space. 


Understanding the Biology of Uterine Sarcoma

Matthew Ingham, MD, an assistant professor of Medicine in the Division of Hematology and Oncology at New York Presbyterian Hospital/Columbia University Medical Center, discusses understanding the genomics of sarcomas and how molecular testing can be useful in this space.

Uterine sarcoma is a rare disease with many different subtypes that are different both biologically and clinically. According to Ingham, experts must understand and treat these subtypes individually as they are all different.

Since these tumors can be genomically complex, Ingham discusses how molecular testing can be beneficial in this setting as it aids in diagnosing and treating patients.


In sarcoma, I think we find that molecular testing really can help us in 2 ways. It can really help us from a diagnostic perspective. Some of the less common uterine sarcomas that I mentioned, like high-grade endometrial, stromal sarcoma, low- grade endometrial stromal sarcoma, do harbor some characteristic gene fusions that we would only pick up with molecular testing. Sometimes these diseases can be difficult to diagnose just based upon histology. I think the first use of molecular testing and sequencing is to help us make sure that we have the right diagnosis so we can offer the patient the best treatment.

Then the second aspect of it is that sometimes genomics and understanding the molecular basis of the tumor will also help us with treatment selection. There's a couple of subtypes of uterine sarcoma where we actually find really actionable alterations. For example, PEComas are characterized by loss of this gene called tuberous sclerosis 2, TSC2. It is important to make that diagnosis because they can be very sensitive to target a class of drugs called mTOR inhibitors. There was just a drug that was approved that's very efficacious, and probably much more so than chemotherapy. Sometimes, we'll also find 

 fusions, other highly actionable alterations, that can help us with targeted treatment.

 I think getting them more common uterine sarcoma, which is the uterine leiomyosarcoma, that's a subtype of sarcoma where we have some recurrent genomic alterations, oftentimes, we see 

 Rb deletions, those are the most common genomic events. Those are a little bit more challenging because we don't have a targeted drug that works directly against those alterations. What we're trying to do is understand the biological effects that some of those alterations have in uterine leiomyosarcoma if we can't target them directly. It seems that what they do is create a high level of replicative stress and related to that, we see that a lot of uterine leiomyosarcoma, they have homologous recombination deficiency. It does appear that it could be targetable with a novel class of drugs called PARP inhibitors, which I think is 1 of the most recent exciting advances in how we treat the most common type of uterine sarcoma, which is the uterine leiomyosarcoma.

Matthew Ingham, MD, discusses understanding the genomics of sarcomas and how molecular testing can be useful in this space.


Molecular Testing to Treat and Diagnose Uterine Sarcoma

Matthew Ingham, MD, an assistant professor of Medicine in the Division of Hematology and Oncology at New York Presbyterian Hospital/Columbia University Medical Center, discusses the unique biology of uterine sarcomas.

 With uterine sarcoma, I think we tend to think it reflects sarcoma as a whole, which means it's a rare disease, and it has many different subtypes within it. And all these subtypes of uterine sarcoma are quite different biologically and clinically. And so really, what we need to do is try to understand them individually so that we can treat them individually as well. So, when we think about uterine sarcoma, the most common subtype is leiomyosarcoma [LMS], which is a sarcoma that comes from the smooth muscle of the uterus. That accounts for the majority of uterine sarcomas, maybe about 70% to 80%. It's a difficult disease to treat even after we remove it by surgery, it has a high risk between 50 and 60% of unfortunately have coming back in the lungs or elsewhere in the body. So, it does have a high rate of metastatic relapse.

 One of the unmet needs and sarcoma researchers to develop better systemic therapies for advanced uterine LMS. Then the other types of uterine sarcoma are a little bit less common. There are high-grade and endometrial stromal sarcomas, there's a low-grade endometrial stromal sarcoma, and we have less common subtypes, which are adenosarcoma. Sometimes we'll see a type called PEComa, which arises in the uterus. Even after those, there are several ultra-rare uterine sarcomas. I think the challenge is just that it's a collection of rare diseases that are very distinct.

Matthew Ingham, MD, discusses the unique biology of uterine sarcomas.

Ingham Discusses Uterine Sarcoma Subtypes

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Experts discuss advances in gastrointestinal stromal tumors (GIST) and dive into the evolving landscape and ongoing unmet needs. 

GIST

Advances in Later-Lines of Therapy for GIST

Gary K. Schwartz, MD, professor of medicine, chief of the Division of Hematology/Oncology, ​and deputy director at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, discusses adverse events (AEs) seen in patients with metastatic sarcoma participating in the Alliance A091401 trial (NCT02500797).

According to Schwartz, before this study there were relatively low rates of treatment-related AEs in this setting of 10% to 15%. The design of Alliance A091401, which investigated nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with gastrointestinal stromal tumor, undifferentiated pleomorphic sarcoma (UPS), and dedifferentiated liposarcoma (DDLS), used a lower dose of ipilimumab. The standard dose for melanoma is 3 mg/kg of ipilimumab and 1 mg/kg of nivolumab. This study did the opposite, with 1 mg/kg of ipilimumab and 3 mg/kg of nivolumab.

The reduction of dosing with ipilimumab reduced immune-related AEs in the DDLS and UPS groups. Schwartz says this outcome shows this regimen is a much safer approach for patients with sarcoma; he says AEs in this patient population are always a problem because physicians have to decide if the value of ipilimumab merits the increased immune-related toxicities.

In patients with melanoma, those concerns remain, and trials looking into it now are showing that any dose of ipilimumab does not make a difference, Schwartz says. This study, however, demonstrated reduced toxicity with the lower dose of ipilimumab and improved benefit in response rate.

<< View more resources and information regarding sarcomas

Gary K. Schwartz, MD, discusses adverse events seen in patients with metastatic sarcoma participating in the Alliance A091401 trial.

Investigators Observe Differences in Toxicity for Sarcoma Due to Dosing

Alessandro Gronchi, MD, chair of the Soft Tissue Sarcoma Committee of the Italian Sarcoma Group (ISG) and chair of the Sarcoma Service at the Istituto Nazionale Tumori, discusses a phase 2 trial (NCT02275286) of trabectedin (Yondelis) and radiotherapy in patients with soft-tissue sarcoma.

Gronchi says trabectedin alone and radiotherapy alone achieved tumor shrinkage in as many as 40% to 50% of patients with myxoid liposarcoma, which is good for this setting. Both of these agents together have less adverse events compared to other drugs for these patients. The combination of the 2 therapies achieved responses in about 70% of patients in this study.

The tumor pathologic response observed for these patients was impressive, according to Gronchi. Over 90% of patients who received trabectedin and radiotherapy had less than 10% viable remaining tumor on their surgical specimen. This is indicative of significant activity when treating with these drugs together. The international prospective trial concluded that this combination could become an alternative to anthracycline and ifosfamide (Ifex) concurrent to radiotherapy in the high-risk localized myxoid liposarcoma population.

Alessandro Gronchi, MD, discusses a phase 2 trial of trabectedin and radiotherapy in patients with soft-tissue sarcoma.

Evaluating the Activity of Trabectedin and Radiotherapy in Sarcoma

Christina L. Roland, MD, PhD, chief of Sarcoma Surgery and assistant professor in the Department of Surgical Oncology, Division of Surgery, and associate medical director of the Sarcoma Center at The University of Texas MD Anderson Cancer Center, discusses the preliminary results of neoadjuvant checkpoint blockade—nivolumab (Opdivo) or nivolumab plus ipilimumab (Yervoy)—in patients with surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS).

This phase 2 study (NCT03307616) had 23 patients that have been reported on and data from 4 more that have been treated but did not have enough data at the time of the data cut-off for the presentation at the 2020 American Society of Clinical Oncology Virtual Scientific Program, according to Roland. Of the 23 patients, 14 had DDLPS and 9 had UPS. She says the most exciting findings are in the UPS cohort.

For the UPS arm, there was not much difference between nivolumab compared with nivolumab plus ipilimumab, except for more toxicity with the doublet. As for the efficacy, 8 of the 9 patients had less than 15% residual tumor remaining. When looking at the historical data before designing the study, the median amount of hyalinization for radiation alone or chemotherapy and radiation was about 5% to 10%. For this study, it was about 90% for the UPS cohort. Although there was not a group in this study receiving radiation alone, the historically data worked as a reference.

There was not as much historical data for the DDLPS cohort, but the median amount hyalinization in this group was around 20% to 25%. Though it’s not as much as the UPS group, this therapy could still be considered as an alternative to chemotherapy and other regimens for this patient population, Roland says.

<< View more of Targeted Oncology's coverage from the 2020 ASCO Virtual Annual Meeting

Christina L. Roland, MD, PhD, discusses the preliminary results of neoadjuvant checkpoint blockade—nivolumab or nivolumab plus ipilimumab—in patients with surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

Conference News

Neoadjuvant Blockade Demonstrates Significant Clinical Activity in UPS

Neeta Somaiah, MD, an assistant professor in the Department of Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center, discusses the evolution of treatment options for patients with a unique sarcoma.

Neeta Somaiah, MD, discusses the evolution of treatment options for patients with a unique sarcoma.