Biomarker-Driven Research Accelerates Drug Discovery and Precision Medicine Approaches in Sarcoma

Over the past 5 years, advancements in identifying specific biomarkers within sarcoma subtypes have paved the way for targeted therapies that could potentially replace traditional chemotherapy-based approaches, according to Neeta Somaiah, MD, who adds that such progress in precision medicine is greatly enhancing patient outcomes, particularly for those with rare sarcoma subtypes.1

The FDA approval of afamitresgene autoleucel (afami-cel; Tecelra) in August 2024, which marked the first T-cell therapy for patients with advanced synovial sarcoma, is emblematic of the shift towards more tailored treatment in sarcomas.2 The genetically modified autologous T-cell immunotherapy is indicated for adult patients with unresectable or metastatic synovial sarcoma who were previously treated with chemotherapy; were HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive; and whose tumors express MAGE-A4, identified by FDA-approved or -cleared companion diagnostics.

“We have seen [a growing number of] drug approvals in [sarcoma] in the past 5 years, and this has helped [improve patient outcomes],” Somaiah said. “The extent of benefit [with these regimens] has been much higher, even though we're going after a smaller subgroup of patients.”

In an interview with OncLive®, Somaiah highlighted key points from her presentation on sarcoma at the 3rd Annual Miami Cancer Institute Precision Oncology Symposium, the impact of precision oncology on patient outcomes in sarcoma, and novel, more targeted therapies coming down the pike.

Somaiah is a professor and deputy department chair of the Department of Sarcoma Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas.

OncLive: How has the identification of specific biomarkers within sarcoma subtypes influenced drug development and improved patient outcomes?

Somaiah: Understanding each of the nuances of these different [sarcoma] subtypes helps us find homogenous subtypes with specific biomarkers that can lead to easier and faster identification of drugs. Once we've started dividing our sarcoma subtypes [we will start] having clinical trials specific to these rare subtypes.

Sarcoma is a space where, if you identify the subtype and have a target, investigators shouldn't be worried about investigating a rare tumor. If we come together to perform trials, we can get a drug approval much faster, and we will see the benefits [much quicker. Some patients are very young, and being able to [offer them] targeted therapy options that provide fewer adverse effects and better quality of life can make a dramatic difference [in outcomes].

Sarcomas have historically been treated with chemotherapy, radiation therapy, and surgery. How are precision medicine approaches reshaping the traditional treatment paradigm?

We have a small number of chemotherapy options that we treat sarcoma patients with, and that list has not expanded significantly in the past 5 years. It's the same drugs with a few shifts. The majority of [patients with] sarcomas are still [receiving] chemotherapy as their mainstay [treatment] for advanced or locally advanced disease. However, when you look at the growing list of targeted therapies and immunotherapy agents, that list is quite large and is still expanding.

It's encouraging to know that as we're identifying these subtypes [of sarcoma], are finding biomarkers, and a able to match [them with] targeted drugs, we have seen an improvement in outcomes for some of these rare subtypes. We still use chemotherapy to begin with, but there are a lot of targeted therapy options and clinical trials that we consider. For some of the disease subtypes, these targeted therapies have replaced chemotherapy, which is quite exciting.

What are some of the key challenges in developing novel therapies for sarcoma? How can early evaluations and multidisciplinary care address some of these difficulties?

For sarcoma, I think the biggest challenge that remains is the rarity of the disease. With this also comes the path diagnosis of the subtypes [of sarcoma]. The big push is still to make sure that [patients with] sarcomas get at least an early opinion at an expert center that also involves a pathologic review. We still need to consider that some people will send off the next-generation sequencing up front, which is happening quite a bit but is absolutely essential. We also need to match it with the pathologic diagnosis because there are nuances within sarcoma based on where the tumors arise, where they're going to metastasize, which ones need early systemic therapy, and where you can delay those therapies. Having a multidisciplinary approach [is necessary] to treat [patients with] these sarcomas. The challenge is getting [patients] to an expert center that understands these nuances and [provides] an accurate diagnosis.

We can make great progress if we can institute the right treatment early, which is why an early opinion does help guide the care of these patients. In terms of the rarity [of sarcomas], the other challenge is that when we do large trials, they are registrational—we're trying to get drugs approved. We have to work with expert sarcoma centers within the United States as well as globally. The good thing is that we can perform these trials quickly when there is a good drug and the subtypes are there, even if the incidence of the tumor is [rarer].

What ongoing research with novel agents and tailored treatment approaches could advance the sarcoma treatment paradigm?

In the sarcoma world, there are some targeted therapies, like you'll see for desmoid sarcoma. There's a new gamma secretase inhibitor that's being looked at. There's more work done with specific mutations that are not sarcoma-specific but across different subtypes. Last year, the first T-cell therapy [afamitresgene autoleucel] was FDA approved for [advanced synovial] sarcoma. That field is still nascent, and we're going to see a lot of work in that field moving forward because there are more cellular therapies that are going to emerge. The goal would be to expand [these agents] to more sarcoma subtypes with the same markers, as well as to patients with HLA subtypes that are beyond what the current T-cell therapies are approved for.

[It’s important to understand the optimal application of] immunotherapy in terms of which patients benefit and what the right combinations are. Are there some CTLA-4 [therapies] that are better than other others, that will [show] a response in sarcomas that are traditionally cold? How do we identify those patients and [disease] subtypes better, and actually get some of these newer agents that we're seeing in clinical trials targeting sarcomas? That field is going to expand, and we're going to see a lot there.

The field of antibody-drug conjugates [ADCs], though not specific to sarcomas, is also quite exciting. As we see these phase 1 trials come along, we'd be interested in seeing [research with] sarcomas that have applicable targets for these ADCs. I am seeing a lot of trials in that space, so I'm excited to see what that brings this year.

We're talking about sarcomas, but [gastrointestinal stromal tumors (GIST)] are another big category [of interest]. That field is going to see some practice-changing drugs [emerge], and perhaps a change in the way we sequence drugs for the treatment of GIST, is yet to come.

References

1. Somaiah N. Dividing and conquering sarcomas. Presented at: Third Annual Miami Cancer Institute Precision Oncology Symposium; February 7-8, 2025; Coral Gables, FL.
2. FDA approves first gene therapy to treat adults with metastatic synovial sarcoma. FDA. August 2, 2024. Accessed February 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-afamitresgene-autoleucel-unresectable-or-metastatic-synovial-sarcoma