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Kevin Kalinsky, MD, MS; Komal Jhaveri, MD, FACP; Reshma L. Mahtani, DO; Kelly McCann, MD, PhD

Coffee Talk™: Navigating the Impact of HER2/3, TROP2, and PARP from Early Stage to Advanced Breast Cancer Care

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

Tiffany A. Traina, MD, FASCO; Demetria Smith-Graziani, MD, MPH

Community Practice Connections™: Case Discussions in TNBC… Navigating the Latest Advances and Impact of Disparities in Care

Annual Hawaii Cancer Conference

In this episode of Targeted Talks, Edwin Choy, MD, PhD, director of the sarcoma program at the Division of Hematology Oncology at Massachusetts General Hospital, a founding member of Mass General Brigham, and associate professor of medicine at Harvard Medical School, delves into the recent approval of afamitresgene autoleucel (afami-cel; Tecelra) for the treatment of patients with advanced synovial sarcoma.

“Afami-cel is a T-cell receptor therapy. What we do is we harvest the cell to the patient and then we modify the receptor to target a cancer protein called MAGE-A4. Once the T-cell receptor is genetically modified, we can reinfuse the T cells back into the cancer patient,” explains Choy.

The engineered T-cell receptor therapy gained 

 on August 1, 2024, for the treatment of adult patients with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or -cleared companion diagnostic devices.

Findings from the phase 2 SPEARHEAD-1 trial (NCT04044768) supported this approval with approximately 39% of patients with heavily pretreated synovial sarcoma responding to afami-cel. In this cohort, the median duration of response was approximately 12 months, and the median overall survival was approximately 17 months.

“The fact that we now have a treatment that has a 39% response rate in synovial sarcoma is a significant advantage over what we had available before this drug,” adds Choy.

1. Adaptimmune receives U.S. FDA accelerated approval of TECELRA® (afamitresgene autoleucel), the first approved engineered cell therapy for a solid tumor. News release. Adaptimmune. August 1, 2024. Accessed August 13, 2024. 

2. Adaptimmune reports better outcomes for people with synovial sarcoma who received afami-cel compared to historical control. News release. Adaptimmune. October 31, 2023. Accessed August 13, 2024. 

3. Spearhead 1 study in subjects with advanced synovial sarcoma or myxoid/round cell liposarcoma. ClinicalTrials.gov. Updated August 15, 2023. Accessed August 13, 2024. 

https://classic.clinicaltrials.gov/ct2/show/NCT04044768

In this episode of Targeted Talks, Edwin Choy, MD, PhD, discussed the FDA approval of afamitresgene autoleucel for the treatment of patients with advanced synovial sarcoma.

Breaking New Ground in Synovial Sarcoma: Choy on the FDA Approval of Afami-cel

In season 4, episode 5 of Targeted Talks, Alice P. Chen, MD, medical officer in the Target Therapeutics 1 Section of the Investigational Drug Branch of the Cancer Therapy Evaluation Program at the National Cancer Institute, discusses important studies that are investigating treatment options for alveolar soft part sarcoma (ASPS).

According to Chen, there is only one therapy specifically granted FDA approval to treat ASPS.

“Alveolar soft part sarcoma is an extremely rare tumor. It occurs in less than 1% of all sarcomas, which, in general, is not that common to start with. Alveolar soft part sarcoma is one that is seen primarily in young adults,” explain Chen.

Atezolizumab (Tecentriq) was approved in December of 2022 based on findings from an open-label, single-arm study (Study ML39345; NCT03141684) of 49 adult and pediatric patients with unresectable or metastatic ASPS.

The findings showed that at the 1200 mg. dose for adult and 15 mg for children, atezolizumab achieved an objective response rate of 24% (95 CI, 13%-39%) with a duration of response (DOR) of 6 month or more in 67% of patients. Moreover, 42% of patients had a DOR of 12 months or more. The most common adverse events shown with atezolizumab during the study included musculoskeletal pain (67%), fatigue (55%), rash (47%), cough (45%), as well as nausea, headache, and hypertension (43% each). 

Today, atezolizumab is being investigated multiple studies in combination with other therapies. One study is evaluating 

atezolizumab with or without bevacizumab (Avastin) in adult and pediatric patients

 aged 2 years or older to further understand the efficacy, safety, and pharmacokinetics of the agent (NCT03141684). On another study (Axiom; NCT05333458), atezolizumab is being administered with or without selinexor (Xpovio) in adult aged 18 years or older, explain Chen.

FDA grants approval to atezolizumab for alveolar soft part sarcoma. News release. FDA.gov. December 9, 2022. Accessed April 26, 2023. https://bit.ly/3LcwZh6

In season 4, episode 5 of Targeted Talks, Alice P. Chen, MD, discusses important studies that are investigating treatment options for alveolar soft part sarcoma.

Advancing the Treatment of Alveolar Soft Part Sarcoma

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

The phase 3 INVINCIBLE-3 study of INT230-6 for soft tissue sarcomas continues without changes following Data Monitoring Committee safety review.

DMC Recommends Continuation of Phase 3 INVINCIBLE-3 Sarcoma Study

The FDA’s breakthrough therapy designation for GSK’227 underscores its potential to address the critical unmet needs of patients with relapsed/refractory osteosarcoma.

FDA Grants B7-H3–Targeted ADC Breakthrough Status in Osteosarcoma

Elraglusib is undergoing investigation in an open-label, multicenter, phase 1/2 trial for the treatment of patients with Ewing sarcoma.

Elraglusib Gains FDA Rare Pediatric Disease Designation in Ewing Sarcoma

In an interview with Targeted Oncology, Jacob Stein, MD, MPH, discussed nab-sirolimus and its impact on patients with advanced PEComa.

Exploring the Benefits of Nab-Sirolimus in Advanced PEComa Treatment

The FDA granted orphan drug designation for elraglusib, a novel drug for treating advanced soft tissue sarcoma.

FDA Grants Elraglusib Orphan Drug Designation in Soft Tissue Sarcoma

Afami-cel’s Mechanism of Action and Role in Synovial Sarcoma 

Edwin Choy, MD, PhD, director of the Sarcoma Program at the Division of Hematology Oncology at Massachusetts General Hospital, a founding member of Mass General Brigham, associate professor of medicine at Harvard Medical School, discusses the mechanism of action of afamitresgene autoleucel (afami-cel; Teclera) and the recent 

 for patients with advanced synovial sarcoma.

 Afami-cel is a T-cell receptor therapy. What we do is we harvest the cell to the patient and then we modify the receptor to target a cancer protein called MAGE-A4. Once the T-cell receptor is genetically modified, we can re-infuse the T cells back into the cancer patient.

 In theory, these T cells can now target the tumor because they are attracted to the MAGE-A4 target. And it is a form of immunotherapy, so people can have the same type of [adverse] effects [AE] as seen with other immuno-therapeutic drugs. Cytokine release syndrome occurred in the majority of these patients to some degree. Most of them were grade 1 and 2. There was 1 patient with a grade 3 [AE], and then, one can also develop cytopenias with low neutrophils, lymphocytes. You can have other autoimmune type effects from this. But overall, I think the study found the treatment to be relatively tolerable, sort of in line with other T cell therapies.

To even qualify for afami-cel, you have to meet 2 criteria. First of all, the disease itself has to express the target, otherwise treatment would be useless. You have to detect the tumor for MAGE-A4. I think the field is probably moving toward a standard operating procedure where all synovial sarcomas, once the diagnosis is made, will also be tested for MAGE-A4 expression in the same way others sarcomas, like GIST [gastrointestinal stromal tumor] is almost always tested for 

expression. That is a target for GIST treatment. Similarly, we will look at synovial sarcoma as a MAGE-A4-expressing tumor that is amenable to this type of therapy.

I think MAGE-A4 will be tested almost right off the bat by pathology. For the community and colleges, if you know your patients have synovial sarcoma, I would encourage testing early for something called HLA. HLA is the immunotype that will determine whether or not this product can be used or not at all for the patient. This product was developed for patients with specific HLA-A*02 subtypes. Maybe around 50% of the Caucasian population expresses HLA-A*02, and then less so in the non Caucasian population. I would encourage community oncologists to know a patient has the diagnosis to test early for both the HLA and the MAGE-A4.

Videos

Edwin Choy, MD, PhD, discusses the mechanism of action of afamitresgene autoleucel and the recent accelerated approval from the FDA for patients with advanced synovial sarcoma.


News

This study presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting investigated the impact of nirogacestat (Ogsiveo) on ovarian function in young women with desmoid tumors. The study found that 75% of women treated with nirogacestat experienced ovarian toxicity, which could potentially affect their fertility.

However, in most cases, the ovarian toxicity was temporary. When women stopped taking the drug, their ovarian function typically returned to normal. This suggests that nirogacestat may still be a viable treatment option for some women, as long as they are aware of the potential adverse effects.

The study also highlights the importance of monitoring ovarian function during cancer treatment, especially for young women who may want to have children in the future. There is currently no standard approach for monitoring ovarian toxicity, but this study suggests that a combination of hormone tests and symptom tracking could be helpful.

Here Elizabeth Loggers, MD, PhD, presenter of the study and associate professor in the Clinical Research Division at Fred Hutch Cancer Center, discusses the study's findings and implications. 

There are approximately 1.4 million females under the age of 45 who will be diagnosed with cancer annually. And here in the United States, there are approximately 45,000 fertile females. And so this topic is important because the incidence of early onset cancers is increasing in our fertile populations. And our treatments are getting better, and so people are going to live longer, and ovarian toxicity is going to be more important. So investigators need to start paying more attention to this. And we need to do a better job collecting data.

One of the ways that we tried to demonstrate the importance of this was by focusing on the results from the device study, which was a phase 3 study of nirogacestate, which is an oral gamma secretase inhibitor used in desmoid tumors. And over the course of that trial, we learned that ovarian toxicity was a safety signal, and therefore needed to do more in depth study of toxicity and its resolution. And so, for example, in that study, we saw that 75% of females of reproductive potential actually experienced ovarian toxicity. We learned through this process of measuring ovarian toxicity and assessing its resolution that 78% of those women were going to have the resolution of that toxicity. And of those, 100% would resolve once they stopped the treatment for any reason. And then 71% actually had resolution of their ovarian toxicity still on treatment. So it's an interesting story. And it teaches us to be more consistent in the way that we measure ovarian toxicity.

One of the key points of this abstract was to highlight ASCO's clear recommendations in this area. ASCO had 3 primary recommendations. The first was to include measures of ovarian toxicity all clinical trials. They recommend to doing that at baseline and at 12 to 24 months after completion of the trial. And then to include both clinical measures like menstrual diaries, as well as hormonal measures like anti-Mullerian hormone and other things that help us assess the toxicity. So I think it's just important that clinical trial lists begin to incorporate these measures in the early design of their studies to ensure that this is done in an efficient and an effective way, so that we can use that information when we're counseling patients in the future.

Transcription created with AI and edited for clarity. 

Elizabeth Logers, MD, PhD, discusses the implications of ovarian toxicity on female patients of reproductive age being treated with nirogacestat for desmoid tumors. 

Conference News

Nirogacestat Shows Promise With Manageable Fertility Concerns in Young Women

Mark Agulnik, MD, discusses advances in determining the molecular drivers of the tumor in the sarcoma space

Examining Molecular Targets in Sarcoma 

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, discusses advances in determining the molecular drivers of the tumor in the sarcoma space.

Often when patients are coming to see us, the question they often have is why do they have this happening? For most sarcomas, we don't see a cause. With respect to other tumors, we may see some environmental causes, or some factors related to perhaps smoking or alcohol. The second thing is whether or not there's a genetic driver of this. I sort of piece that into 2 different compartments. One is the genetics that we're born with, and one's the genetics that we acquire over time. I often feel that for our patients there are some patients, whereby there is a genetic component with respect to the genes that are passed to them. And for me, that's often what I think of like Li-Fraumeni syndrome. Then there are acquired mutations that cause the tumors, and those are the ones that often we are searching for using different platforms like next-generation sequencing platforms.

When we're sending off a tumor to specifically look for the genetic markers of the tumor, we're specifically looking for the drivers. I sort of categorize it into 2 different components. It's almost like a car, there's drivers and passengers. If something happens to the passenger, nothing happens to the car. But if you're able to impact the driver, then you're able to stop the car from going which is essentially stopping the tumors. We tried very hard using molecular profiles to find drivers. We've been successful with some drivers that actually do have drugs for it like and 

We also have other drivers that will mimic other diseases. So we have lung cancer, where there are several drivers that drive it. If we see the same markers in our sarcoma patients, then we will target those with lung cancer drugs. We are looking at different factors to see whether or not they would benefit from immunotherapy. All of those are reasons that we would do sequencing of our patients who have metastatic disease, to really specifically look for what is driving their tumor. If we're able to find the driver, we're able to find and tailor a therapy that's more unique to their tumor vs a therapy that would be for every patient walking in the door with the same diagnosis.

Mark Agulnik, MD, discusses advances in determining the molecular drivers of the tumor in the sarcoma space.


Lisa B. Ercolano, MD, orthopedic oncologist and chief of musculoskeletal oncology at Allegheny Health Network, discusses some of the advances that have been seen in the treatment of sarcomas.

Over the past few years, there has been an increase in the number of therapies available for the treatment of patients with sarcoma. Some of these recent advances include CDK4 inhibitors and MDM2 inhibitors for patients with liposarcomas and desmoid sarcomas, gamma secretase inhibitors for patients with Kaposi sarcoma, and 

Lisa B. Ercolano, MD, discusses some of the advances that have been seen in the treatment of sarcomas.


SARCOMA

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