Tailoring Treatment Strategies Is Paramount in the Sarcoma Space

Sandra P. D'Angelo, MD

Memorial Sloan Kettering Cancer Center

When treating sarcoma, it is necessary to adjust treatment based on disease subtype, according to Sandra P. D’Angelo, MD. In addition to deciding whether surgery should be paired with chemotherapy or radiotherapy, several other classes of agents are being investigated within the sarcoma space, including immune checkpoint inhibitors and CAR T-cell therapies.

In a conversation with CancerNetwork^® during Sarcoma Awareness Month, D’Angelo, a sarcoma oncologist and cellular therapist at Memorial Sloan Kettering Cancer Center, discussed the current treatment landscape, new agents coming down the FDA pipeline, and challenges that need to be addressed to move the needle forward for these patients.

“It’s always helpful to have good partners to be able to push the field forward,” D’Angelo said. “We’ve proven that we can do that in these rare diseases. We shouldn’t shy away from sarcoma as a rich area to develop drugs just because it’s rare. In fact, we can use sarcoma to identify important nuances in drug development, and then allow that to impact care in other diseases that are perhaps more common. I’m pleased with what’s happened so far.”

What is the current treatment landscape for sarcoma?

One of the biggest questions to think about when we approach a patient with sarcoma is understanding if their disease is localized or metastatic. When patients initially present with localized sarcoma, the standard of care is typically surgery with or without radiation therapy, with or without chemotherapy. A lot of factors weigh into the approach but that’s usually the path we can take. When patients present with metastatic sarcoma, then the care shifts more towards systemic therapy, and the systemic chemotherapy we utilize is highly dependent on the type of sarcoma.

When we think about bone sarcomas or for example, GIST [gastrointestinal stromal tumor], the approach can be different systemic therapy wise. For most high-grade soft tissue sarcomas, chemotherapy often consists of doxorubicin or gemcitabine and docetaxel in the frontline setting. Both of those approaches are found to be similar with regard to efficacy and toxicity. That comprises that frontline chemotherapy regimen.

There have been a lot of advancements in the field [for] homing in on the sarcoma subtype and trying to treat the sarcoma based on the underlying histology. One of the challenges of this disease is that sarcoma is not one disease; there are 70 to 80 different types of sarcomas that exist, and how we approach care is becoming more and more specific to that subtype. In the past, we used to conduct clinical trials, and we used to lump all these sarcomas together, and our approach was similar. But now [we are] learning more and more that there are a lot of biological differences that exist among all these sarcomas, therefore, our approach becomes a little bit more tailored based on the underlying sarcoma.

Cytotoxic chemotherapy remains the cornerstone treatment for most sarcomas though, and utilizing those regimens is our go-to in the beginning when a patient is initially diagnosed. More and more, we’re integrating next-generation sequencing into our patients’ care, and that has allowed us to offer alternative options for selected patients. The results of those efforts have also [led to] recent approvals as.

What are some the recently FDA approved treatment options available in the sarcoma space? Are there any other agents on the horizon you think are promising?

Tazemetostat [Tazverik] is a drug that was recently approved for epithelioid sarcoma, based on the fact that these tumors are characterized by INI loss, and using that drug is a logical approach and offers reasonable control for some patients.¹ The field of immunotherapy is blossoming in oncology, although in sarcoma, we’re a little bit behind. Many of the delays in advancements are often unfortunately driven by a lack of interest by larger pharmaceutical companies to support novel trials in these rare diseases, although that hasn’t stopped us as a field.

Our first FDA approval with checkpoint blockade came recently with atezolizumab [Tecentriq] being approved for alveolar soft-tissue sarcoma.² That work was spearheaded by colleagues at the National Institute of Health. That’s an important advancement in the field. There’s a lot of effort with T-cell therapies, specifically focused on synovial sarcoma, [including] afami-cel [afamitresgene autoleucel] which is a T-cell therapy that targets MAGE-A4. There’s also been some work done with lete-cel [letetresgene autoleucel] which is a T-cell therapy that targets NY-ESO and both of those have been studied in synovial sarcoma and myxoid round-cell liposarcoma.

There has been some progress and interest in exploring these T-cell constructs in a number of those specific sarcomas. There’s also some interesting work happening with novel inhibitors, for example, bromodomain-9 inhibitors and synovial sarcoma, which targets the underlying biology of the disease driven by the translocation. There’s a lot happening in the field, and we’re excited that the approach we’re taking now is more tailored and specific. We’re trying to figure out what defines a specific sarcoma subtype and what makes more sense in that disease.

Are there any trials underway that may impact the standard of care in sarcoma?

The phase 2 Afami-cel trial [NCT04044768] has been conducted and completed.³ Afami-cel targets MAGE-A4, and specifically was found to be quite promising in synovial sarcoma. A BLA [biologic license application] is in progress at the moment [for the agent]. We’re optimistic that perhaps it’ll become a new standard of care for patients with synovial sarcoma. I mentioned that we don’t have many immunotherapy approvals, other than atezolizumab for ASTS [alveolar soft-tissue sarcoma], but there’s also an ongoing trial called the phase 2 ENVASARC [NCT04480502], which utilizes a checkpoint blockade called envafolimab, specifically in undifferentiated pleomorphic sarcoma or UPS.⁴ That trial has the prospect of allowing envafolimab to ultimately be FDA-approved.

There’s a phase 3 trial [NCT04967521] ongoing with abemaciclib [Verzenio], which is a CDK4 inhibitor.⁵ Much work has been done with CDK4 blockade in dedifferentiated liposarcoma. Much of that work has been led by my colleague at MSK [Memorial Sloan Kettering Cancer Center,] Mark A. Dickson, MD. This is a pivotal trial, randomizing abemaciclib to placebo and ultimately, hopefully demonstrate improvement over placebo to lead to advancements in dedifferentiated liposarcoma.

There’s also a number of other studies—for example, MDM2 inhibition has been studied extensively in liposarcoma. There’s now a frontline trial comparing an MDM2 inhibitor to doxorubicin [in patients with] dedifferentiated liposarcoma. Those are probably the trials that are furthest along [in terms of] development at the moment, and the ones that we think are perhaps closest to impacting the standard of care in the short term.

What is the most pressing barrier to care within the sarcoma space?

One of the most important things that we encounter in the sarcoma field is appreciating the heterogeneity of the disease. Understanding the disease and having the correct diagnosis becomes essential. Given the complexity of sarcoma as a disease, it’s important and essential that pathology is reviewed at a centralized Center of Excellence, to be sure that the diagnosis is correct. That’s the biggest barrier: ensuring that our patients can access the centers, both from a pathology perspective, but then also from a therapeutic and intervention perspective. If you don’t have the correct diagnosis, identifying the correct plan becomes challenging.

How do you utilize multidisciplinary care in your practice?

At MSK and in most sarcoma centers, multidisciplinary care is the cornerstone of how we approach care for our patients. It’s essential, and it allows us to create the best plan for our patients. In my practice, I work side by side with Samuel Singer, MD, FACS, who’s our chief of surgery on the sarcoma team. We devise plans together, and we integrate our approach very closely. If a patient presents with a high-grade large sarcoma, oftentimes, I’m involved in that patient’s care to determine the need for chemotherapy.

That becomes essential when integrating our expert pathologies, to ensure that chemotherapy is appropriate, and then also integrating our radiation oncology team to determine whether radiation would be necessary, either before surgery or after surgery, and before chemotherapy or after chemotherapy. All of these decisions are made as a group and then reviewed by our tumor boards, to ensure that the plan is appropriate for each patient.

What are some unmet needs you would like to see overcome in the next 5 years?

As a field and as a community, we work very closely together. Our approach continues to be optimized. One of the biggest things is working together as a community to design the correct clinical trials for each individual sarcoma subtype to ultimately impact the standard of care. Our field has done a great job of doing that. It’s something that will continue to happen over time.

The story of afami-cel in synovial sarcoma is a perfect example of how we were able to use a biomarker, namely the presence of HLA, a biomarker in the patient, a biomarker in the tumor, the presence of MAGE-A4 expression, to select a subset of a rare disease and conduct a trial and prove that it’s beneficial for some patients, and what we hope will be an FDA approval soon enough. That’s an exciting story and one that I think can be duplicated on other sarcoma subtypes.

References

1. FDA approves tazemetostat for advanced epithelioid sarcoma. News release. FDA. January 23, 2020. Accessed July 20, 2023. https://bit.ly/3XXNQuf
2. FDA grants approval to atezolizumab for alveolar soft part sarcoma. News release. FDA. December 9, 2022. Accessed July 20, 2023. https://bit.ly/3pP1D9T
3. D’Angelo SP, Van Tine BA, Blay JY, et al. SPEARHEAD-1: a phase 2 trial of afamitresgene autoleucel (Formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. J Clin Oncol. 2021;39(suppl 15):11504. doi:10.1200/JCO.2021.39.15_suppl.11504
4. TRACON Pharmaceuticals announces results of independent data monitoring committee review of 12 week safety data from ENVASARC phase 2 pivotal trial - trial to proceed as planned. News Release. TRACON. October 6, 2022. Accessed July 20, 2023. https://yhoo.it/3RJSgzW
5. Dickson MA, Ballman KV, Weiss MC, et al. SARC041: a phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma. J Clin Oncol. 2023;41(suppl 16):TPS11587. doi:10.1200/JCO.2023.41.16_suppl.TPS11587