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, Brian A. Van Tine, MD, PhD, spoke about the 

FDA accelerated approval of afamitresgene autoleucel

 (afami-cel; Tecelra) for patients with metastatic or unresectable synovial sarcoma expressing MAGE-A4. He discussed the data from the 

supporting the agent’s use in this patient population and highlighted how this approval might pave the way for other potential developments in the sarcoma landscape.

Van Tine, a professor of medicine and pediatrics and a medical oncologist at Siteman Cancer Center of Washington University in St. Louis, detailed results from SPEARHEAD-1

 leading to the FDA’s approval of afami-cel. Based on these findings and the agent’s potential availability as a one-time intravenous fusion, afami-cel may offer improvements in quality of life to patients with synovial sarcoma compared with standard treatment options such as chemotherapy.

Topline data from cohort 1 of the SPEARHEAD-1 trial showed that treatment with afami-cel produced an objective response rate of 43% among 44 evaluable patients, which included a complete response rate of 4.5%. Additionally, the median duration of response was 6 months (95% CI, 4.6-not reached). Of patients with a response, durable responses lasting for 12 months or longer occurred in 39%.

In terms of other potential benefits following the accelerated approval of afami-cel, Van Tine said that the T-cell therapy may increase treatment access to specific subsets of patients. For those who are unable to relocate and live near certain treatment centers during their therapy, afami-cel may offer a more readily accessible alternative that can allow patients to undergo treatment at home. Van Tine also described how this accelerated approval may “open the gateway” for other advancements related to the use of afami-cel and similar agents in solid tumors.

“We’re all working hard to get these therapies open at our institutions,” Van Tine said regarding the next steps for increasing access to afami-cel following the accelerated approval. “Knowing who [has] HLA-A*02–positive [disease], knowing who has synovial sarcoma, and being ready to trigger the screening for MAGE-A4 is in every patient's best interest. If you’re one of the patients who have synovial sarcoma, you need to know your status [to determine] how we’re going to integrate this into your care plan.”

Adaptimmune receives U.S. FDA accelerated approval of TECELRA® (afamitresgene autoleucel), the first approved engineered cell therapy for a solid tumor. News release. Adaptimmune Therapeutics. August 2, 2024. Accessed August 14, 2024. https://tinyurl.com/mw6k4hjh

Brian A. Van Tine, MD, PhD, discusses potential evolutions in the treatment landscape following the FDA approval of afami-cel in metastatic synovial sarcoma.

Afami-cel Approval May Open Gateway for Synovial Sarcoma Advancements

, Brian Van Tine, MD, PhD, spoke about developments in the sarcoma research space and discussed where future research needs to be focused in order to push the needle forward in the treatment of this patient across numerous sarcoma subgroups.

Van Tine, a professor of medicine in the Division of Oncology, Section of Medical Oncology at Washington University School of Medicine’s Siteman Cancer Center, discussed his research on nirogacestat as a treatment for desmoid tumors as part of the 

 as well as sitravatinib for managing well-differentiated or dedifferentiated liposarcoma.

He also spoke about other areas of interest in the sarcoma space, including the development of an adoptive T-cell therapy for patients with synovial sarcoma in a phase 1 trial (NCT03132922). Moreover, in the advanced leiomyosarcoma space, he indicated that investigators are assessing unesbulin in combination with dacarbazine as part of another phase 3 trial (NCT05269355).

Concerning the potential next steps in the sarcoma space, Van Tine highlighted several possible developments including research centered on circulating tumor DNA, metabolic therapies, and immunotherapies. He also voiced his hope of advancing vaccine-based technologies in the field within the next 5 years with the hope of delivering individualized neoantigens via injection to sarcomas.

“The best part is when, all of a sudden, you see that look in a patient's face when you get to tell them that they tried something that was ultra-new, and it worked,” Van Tine commented when discussing the development of new treatment options for patients with sarcomas. “We don't do this for us. We do this because we're dedicated to this community. When you actually get the opportunity to see it work, it's almost as exciting for us as it is for the patient.”

Don’t forget to subscribe to the “Oncology On-The-Go” podcast on 

Sarcoma Awareness Month

Brian Van Tine, MD, PhD, speaks about several agents and combination regimens that are currently under investigation in the sarcoma space, and potential next steps in research including immunotherapies and vaccine-based treatments.

Sarcoma Awareness Month 2023 with Brian Van Tine, MD, PhD

As part of our coverage of the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago, we are joined by Sant P. Chawla, MD, a medical oncologist who specializes in the treatment of sarcoma at the Sarcoma Oncology Center in Southern California. At the ASCO meeting, Dr. Chawla presented results of a phase III clinical trial 

that compared aldoxorubicin to investigators’ choice of therapy for the treatment of relapsed or refractory soft-tissue sarcoma.

First, Dr. Chawla, can you tell us about aldoxorubicin? What is its mechanism of action?

Aldoxorubicin is classical doxorubicin. So doxorubicin as we all know was discovered in the 1970s and has the added complication of cardiac toxicity. There are a few anthracyclines that have been developed-and they may have been a little bit less cardiotoxic-but they still have cumulative cardiac toxicity and all of them are less effective.

Here, we took the classical doxorubicin and added a linker, and the linker attaches to albumin, which is taken up by the cancer cells. In the low pH-in the lysosomes-that linker disassociates from doxorubicin. And by this mechanism, we were able to give two to three times the amount of doxorubicin with each dose. So rather than the usual dose of doxorubicin-about 75 mg/m

-we were administering more than 200 mg/m

 of doxorubicin, in the form of aldoxorubicin.

Can you tell us about the design of this phase III study?

The design is a 433-patient study. One half of the patients were given aldoxorubicin at 350 mg/m

 per course, which is equivalent to about 250 mg/m

 of doxorubicin. The control arm was an investigators’ choice of therapy-one of five currently available chemotherapy regimens, which include pazopanib, doxorubicin, dacarbazine, gemcitabine/docetaxel, or ifosfamide. So, in this study, all patients had failed prior chemotherapy and could be given aldoxorubicin or one of these conventionally available chemotherapies.

What are the important results and can you put these into context in terms of the currently available therapies for patients with soft-tissue sarcoma?

As far as efficacy is concerned, the trial showed a superiority of progression-free survival in the total group, but the 

-value was only .08, so it missed the significance level cut-off. But aldoxorubicin was significantly more effective in liposarcoma and leiomyosarcoma. Similarly, the objective response was almost double in the aldoxorubicin arm compared to the control arm. Progression-free survival at 4 months and 6 months was also superior in the aldoxorubicin arm. And so overall, there was a superior efficacy in the aldoxorubicin arm.

As far as cardiac toxicity, there was no dose-limiting cardiac toxicity in the aldoxorubicin arm when a doxorubicin equivalent dose of over 1,000 mg/m

 was administered. In the control arm, the only drug that we could compare cardiac toxicity with was doxorubicin, and the median dose there was only 300 mg/m

. In spite of that, the decrease in ejection fraction was below 50% in 3% of patients in the aldoxorubicin arm, but between 19% and 20% in the doxorubicin arm. That means that doxorubicin is more toxic, less effective, and you cannot give more than 500 mg/m

, while aldoxorubicin is more effective and has no cumulative cardiac toxicity.

Also, we were surprised that aldoxorubicin did not cause any hair loss. I don’t understand the mechanism, because doxorubicin should cause hair loss, but because of the linker attaching to the albumin it did not cause hair loss.

What is next for this drug for the treatment of patients with sarcoma? Are there other studies that are ongoing or planned?

This is a pivotal phase III study. The company will be submitting the data to the US Food and Drug Administration for approval under the provisional 505(b)(2) application, because this drug is less toxic and equally or more effective than doxorubicin.

We hope that the drug will be approved, and if it is approved, it will be for soft-tissue sarcoma. And then, it will hopefully replace all other indications where doxorubicin is used. Doxorubicin is widely used in breast cancer, ovarian cancer, lung cancer, all bone sarcomas, childhood tumors, and other indications. Doxorubicin is a very widely used drug. And hopefully, the cardiac toxicity will be eliminated. As far as this company is concerned, they are doing trials in small-cell lung cancer, and there is a combination study of ifosfamide and aldoxorubicin in sarcoma, which is ongoing right now.

Thank you so much for joining us today, Dr. Chawla. 

In this interview we discuss the phase III trial of aldoxorubicin in patients with advanced soft-tissue sarcoma, which showed improved efficacy and reduced toxicity over doxorubicin. 

Aldoxorubicin Shows Promise in Advanced Soft-Tissue Sarcoma

Data from a phase 1/2 trial demonstrate the potential antitumor activity of FOG-001 in patients with desmoid tumors.

FOG-001 Earns FDA Fast Track Designation in Desmoid Tumors

A median OS of 22.9 months was observed with mecbotamab vedotin plus nivolumab in patients with soft tissue sarcoma. 

Mecbotamab Vedotin Shows Positive OS Results in Soft Tissue Sarcoma

Investigators are currently assessing ADCE-D01 among those with metastatic and/or unresectable soft tissue sarcoma in the phase 1/2 ADCElerate1 trial.

ADCE-D01 Earns FDA Fast Track Designation in Soft Tissue Sarcoma

Experts discussed diagnosing and treating epithelioid sarcoma, emphasizing the importance of clinical history and the role of multiple multidisciplinary clinicians in care.

Diagnosing and Treating Patients With Epithelioid Sarcoma 

Twenty-two of 27 injected tumors across all patients with soft tissue sarcoma in the study showed complete or partial ablation.

Tigilanol Tiglate Exhibits Positive Efficacy in Soft Tissue Sarcoma

microRNA-Based Model Predicts SBRT Outcomes in Soft Tissue Sarcomas

2025 American Society of Clinical Oncology Annual Meeting

, Joanne Weidhaas, MD, PhD, MBM, shared a poster on a study that explored the potential of microRNA-based single-nucleotide polymorphisms (mirSNPs) to predict outcomes stemming from preoperative hypofractionated stereotactic body radiotherapy (SBRT) in patients with soft tissue sarcomas.

Ultimately, the study found that mirSNP-based models were able to identify those with favorable vs unfavorable responses. This demonstrated the capability of these signatures to aid clinicians in deciding whether patients should receive preoperative SBRT or hypofractionated standard radiation.

Weidhaas, a professor in the Department of Radiation Oncology, vice chair of the Division of Molecular and Cellular Oncology, and director of translational research at the David Geffen School of Medicine at UCLA Health Jonsson Comprehensive Cancer Center; cofounder of MiraDx; and founder of MiraKind, stated that the biomarkers were able to predict major wound toxicity.

Identifying which patients are at risk of distant failure and for whom neoadjuvant radiation should be considered would be, in Weidhaas’ words, “very important.”

We previously looked at a small group of patients treated this way—these are big doses of radiation before surgery—and we found that these biomarkers could predict major wound toxicity. After surgery, [there are] difficulties with the surgical site healing.

In this analysis, it was a larger, continued collection of patients treated this way, and we extended the work and, in addition, looked at any late toxicity. Those are toxicities 2 years out, where there could be difficulty, [such as] fibrosis with the leg or joint, or a fracture, or things like that. Distant recurrence, that’s when the tumor, after these interventions—radiation and surgery—has spread elsewhere, as well as the response rate at the time of surgery and any local failure in the surgical bed; those are some additional end points that are important in sarcoma.

In the case of those identified at risk of distant failure, it’d be very important to consider incorporating neoadjuvant chemotherapy, which is being done in the second part of the clinical trial going on at UCLA. To identify the patients for whom that will be beneficial would be very important. Historically, radiation wasn’t part of sarcoma care and we weren’t able to salvage the limb—there weren’t limb salvage approaches. Radiation has enabled smaller surgeries and [the possibility to] salvage the limb. In the great majority of cases, one form of radiation will be safe for patients—we've seen that in other cancers. It is probably safe for 99% of people, but it could be that big doses are safer for [some patients] than small doses and vice versa. This is all a move toward making radiation personalized. Everyone's scared of radiation, but honestly, it's quite safe for most people if we just put our heads together and apply some biomarkers to identify which course is the safest.

Weidhaas JB, McGreevy K, Nikitas J, et al. microRNA-based biomarkers of outcome in soft tissue sarcoma treated with hypofractionated preoperative radiation therapy. 

. 2025;43(suppl 16):11538. doi:10.1200/JCO.2025.43.16_suppl.11538

Identifying which patients are at risk of distant failure may assist oncologists in deciding who should receive neoadjuvant radiation, according to Joanne B. Weidhaas, MD, PhD, MBM. 

Conference

Afami-cel Approval in Sarcoma May Offer More Readily Accessible Therapy

Van Tine AA 2

(afami-cel; Tecelra), and how this regulatory decision may increase access to treatment for patients with unresectable or metastatic synovial sarcoma.

According to Van Tine, a professor of medicine and pediatrics and a medical oncologist at Siteman Cancer Center of Washington University in St. Louis, the screening process for patients with synovial sarcoma may take up to 1 month before they are eligible to begin therapy, which may involve multiple agents as part of the treatment course. With the accelerated approval of this engineered cell therapy, patients may be able to receive more readily available treatment at home, thereby expanding access to those who may be unable to relocate to larger cities where certain treatment centers operate.

As patients with synovial sarcomas begin to appear in my clinic, I’m getting the screening, which does take a while. There’s a month or so that it takes between identifying a patient, getting their HLA determined, getting their MAGE-A4 status determined, [conducting apheresis], infusing them, and the manufacturing in between, which means that they need to be on another therapy for that. This is because synovial sarcomas are usually not an endoglin disease upfront, and so you don’t want to lose control of a disease while getting [patients] a T-cell therapy.

Patients who may have not lived near a center where they could have gotten access to this [therapy] can now get access to this more readily at home. The biggest difference between how we practice now on trial and how we will practice in the future is that [patients] will probably come to a center like mine and have [their] therapy done, but then be followed completely locally. That may expand access and make this a lot easier for patients who have issues with having to come to one of the larger cities just to have this done.

Adaptimmune receives U.S. FDA accelerated approval of TECELRA® (afamitresgene autoleucel), the first approved engineered cell therapy for a solid tumor. News release. Adaptimmune Therapeutics. August 2, 2024. Accessed August 13, 2024. https://tinyurl.com/mw6k4hjh

Accelerated approval of afami-cel may expand access to therapy for patients who are unable to live near certain treatment centers.

“Exciting” Response Durability Data Support Afami-cel Approval in Sarcoma

Van Tine AA 1

, Brian A. Van Tine, MD, PhD, discussed how the 

(afami-cel; Tecelra) may improve the treatment landscape for patients with metastatic or unresectable synovial sarcoma.

Specifically, Van Tine, a professor of medicine and pediatrics and a medical oncologist at Siteman Cancer Center of Washington University in St. Louis, highlighted response data from the 

 which supported the agent’s approval in this indication. Topline data showed that 39% of those with a response to afami-cel had responses lasting for at least 12 months.

In terms of other potential benefits, Van Tine said that treatment with afami-cel, which was administered as a single intravenous infusion in SPEARHEAD-1, may offer a higher level of quality of life compared with continuous chemotherapy or other treatment courses when managing a patient’s tumor burden.

Synovial sarcoma is associated with the expression of an embryonic tumor antigen called MAGE-A4, and [approximately] 60% to 80% of every patient with synovial sarcoma expresses this antigen. In the context of an HLA-A*02 subtype of an immune system, a peptide from the MAGE-A4 gets expressed on HLA-A*02. We have used that in a clinical trial to use an engineered T cell to attack synovial sarcoma. In this subset of patients with the right immune system, and through expressive protein, we now have the first modified T-cell therapy for a solid tumor.

If you really get into the results of the clinical trial, [approximately] one-third of the patients had these extreme, deep responses. [The trial meets] an unmet need for this patient population because [with afami-cel], it’s one and done. You treat them, you put the cells in, and then the patient treats themselves, sometimes for years. That’s kind of a fantasy in the solid tumor world, where we can go after a solid tumor with a fancy immunotherapy, have it work, and have it be durable. It’s that durability [of response] in [approximately] one-third of the patients that’s really exciting because I’ve had some patients years into the [SPEARHEAD-1] trial who are still there, and I have had to treat them again. That gives the patient the highest quality of life that’s possible without putting them on constant chemotherapy or some sort of oral therapy just to maintain their tumor burden.

Adaptimmune receives U.S. FDA accelerated approval of TECELRA

 (afamitresgene autoleucel), the first approved engineered cell therapy for a solid tumor. News release. Adaptimmune Therapeutics. August 2, 2024. Accessed August 13, 2024. https://tinyurl.com/mw6k4hjh

Treatment with afami-cel may offer improved quality of life to patients with metastatic synovial sarcoma compared with continuous chemotherapy.

Nirogacestat Approval Offers Choice to Desmoid Tumor Population

Van Tine AA

In an interview with CancerNetwork®, Brain Van Tine, MD, PhD, spoke about how the 

in progressing desmoid tumors may offer patients a choice when it comes to managing their disease.

Van Tine, a professor of medicine in the Division of Oncology, Section of Medical Oncology at Washington University School of Medicine’s Siteman Cancer Center, discussed how nirogacestat may have a different adverse effect (AE) profile compared with sorafenib (Nexavar), which may produce rashes and some nausea. Although nirogacestat may cause ovarian failure in some younger female patients, he stated that this wouldn’t be a concern in male patients or those who have undergone menopause. He continued to say that nirogacestat’s approval will allow for patients to decide which agent would be more suitable for them as part of a patient-centered discussion.

Supporting data for the approval of nirogacestat came from the 

in which the agent elicited a statistically significant progression-free survival (PFS) benefit compared with placebo in those with desmoid tumors (HR, 0.29; 95% CI, 0.15-0.55; 

I think the most important thing that comes out of having a second active drug and the first FDA-approved drug for the treatment of desmoid tumors is that patients actually have choices. The [adverse] effect profile of these two drugs is different.

Sorafenib is a drug that you have to use carefully because [patients] can get rashes on [their] hands and feet; you have some tolerance for nausea and some tolerance for fatigue. Nirogacestat has a different adverse effect profile and some things you have to watch for. Overall, it is something that may be more appealing to the average patient. There is some concern that this can induce ovarian failure in younger women, but for older women and male patients, this is not a concern. There may be a selective advantage for one drug over the other depending on a patient-centered discussion of which drug they'd like to try. The biggest thing that comes out of an FDA approval here is actually choice.

FDA approves nirogacestat for desmoid tumors. News release. FDA. November 27, 2023. Accessed November 27, 2023. https://tinyurl.com/3zezwe53

Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. 

 2023;388:898-912. doi:10.1056/NEJMoa2210140

The difference in adverse effect profiles between sorafenib and nirogacestat may make one treatment more appealing than the other for certain patients with desmoid tumors, says Brian Van Tine, MD, PhD.

Sarcoma

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