Jonathan C. Trent, MD, PhD, discusses recent advances and ongoing research in the field of soft tissue sarcoma.
Jonathan C. Trent, MD, PhD
Soft tissue sarcoma treatments have significantly advanced within the past year with new available agents, others in the pipeline, and the continued search for biomarkers to make treatment more personalized for patients, explained Jonathan C. Trent, MD, PhD.
Sarcoma has seen some recent approvals and regulatory decisions from the FDA. In January 2020, the FDA approved tazemetostat (Tazverik) for the treatment of adult and pediatric patients aged ≥16 years old with metastatic or locally advanced epithelioid sarcoma that is not eligible for complete resection.
Furthermore, in December 2019, the FDA granted a Regenerative Medicine Advanced Therapy (RMAT) designation to ADP-A2M4 (MAGE-A4) as a treatment for patients with synovial sarcoma, as well as a fast track designation to the potent reversible LSD1 inhibitor SP-2577 (seclidemstat) for the treatment of patients with relapsed/refractory Ewing sarcoma.
Early evidence for immunotherapy has emerged in some sarcoma subtypes, though there are currently no known biomarkers to identify patients who will benefit from this type of treatment. Research has indicated that circulating tumor (ct)DNA can also be used to detect biomarkers in patients with sarcomas, Trent explained.
In an interview with OncLive, Trent, a professor and associate director for Clinical Research at the Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed recent advances and ongoing research in the field of soft tissue sarcoma.
OncLive: What ongoing research is taking place in sarcoma?
Trent: Immunotherapy is really becoming useful in the management of certain types of patients with certain types of sarcomas. For instance, a recent publication in Lancet Oncology showed that patients with a type of sarcoma known as out alveolar soft part sarcoma may benefit from immunotherapy with a checkpoint inhibitor plus a TKI. In this study, the authors used axitinib (Inlyta) plus pembrolizumab (Keytruda) and found that there was a 50% partial response rate, which is remarkable for a disease that is known to be resistant to chemotherapy.
What are some recent advances in sarcoma?
There have been other advances in immunotherapy for sarcoma. For instance, cutaneous angiosarcoma seems to be responsive to immune checkpoint inhibitors. In a study published in the Journal of the Immunotherapy for Cancer, results showed that immune checkpoint inhibitors resulted in an approximate 70% complete or partial response rate when immune checkpoint inhibitors were used to treat patients with angiosarcoma. Of note, the patients with cutaneous angiosarcoma seem to benefit the most [from immunotherapy]. However, aside from those 2 sarcoma types, potentially pleomorphic sarcoma and the differentiated liposarcoma, we still have a lot of progress that we need to make in bringing immuno-oncology into the day-to-day management for patients with soft tissue sarcoma.
What criteria are you looking for in patients when deciding to treat them with immunotherapy?
Immunotherapy for sarcomas is not standard of care. However, early evidence in some histologic subtypes such as cutaneous angiosarcoma, alveolar soft part sarcoma, dedifferentiated liposarcoma, pleomorphic sarcoma, and potentially synovial sarcoma may be histologic subtypes in which immuno-oncology approaches could be useful. Other than those histologic subtypes, we don't have any biomarkers that have helped us identify which patients will benefit from immunotherapeutic approaches.
What are your thoughts on the January 2020 approval of tazemetostat?
Recently, the FDA approved tazemetostat for the use of patients with epithelioid sarcoma that's not amenable to surgical resection. Importantly, the treatment is for patients aged at least 16 years old. Epithelioid sarcoma is an aggressive type of sarcoma. Even when small, the potential for local recurrence and distance spread is very high. Chemotherapy has not been effective in epithelioid sarcoma. Tazemetostat is the first targeted therapy for epithelioid sarcomas that has shown efficacy.
There have also been some early regulatory moves in the space. What are your thoughts on the RMAT designation of ADP-A2M4?
Another promising agent on the horizon is ADP-A2M4, which may be developed for patients with synovial sarcoma. This is a critical development for these patients, especially when their disease becomes metastatic because, after standard chemotherapy approaches, there's really no known effective therapies.
Could you also provide your thoughts on the Fast Track Designation of SP-2577 in Ewing sarcoma?
Ewing sarcoma is a very aggressive type of cancer, also known in the category of small round blue cell tumors. These cancers have a very aggressive histology, a very early metastatic spread, and are difficult to manage when metastatic. Ewing sarcoma can be managed with standard cytotoxic chemotherapy initially, but most patients with metastatic disease become resistant. We don't really have effective therapies after standard chemotherapy. There's no targeted therapy; there are no immunotherapies. However, SP-2577 is a promising new agent that is an LSD1 inhibitor and may be able to provide a targeted therapy by way of interfering with the EWS-FLI1 translocation binding to DNA.
Are other agents showing promise across bone tumors or sarcomas?
Recently, the FDA approved avapritinib (Ayvakit) for the treatment of patients with PDGFRA D842V—mutant gastrointestinal stromal tumor (GIST). This is a targeted agent that is approved by the FDA for patients with a specific type of GIST.
This mutation has been historically resistant to other TKIs, such as imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga), and these patients have had no known effective therapy. However, avapritinib showed an approximate 90% response rate when used in patients with advanced PDGFRA D842V—mutant GIST. This really underscores the need for mutation testing in any patient with GIST, in which you're considering systemic therapy.
What challenges remain in the sarcoma space and how are they being addressed?
There are many challenges that remain in the sarcoma space. For instance, many of the common types of sarcoma, such as leiomyosarcoma, osteosarcoma, and pleomorphic sarcoma do not have any driver mutations that have been well defined or have been able to be treated with a targeted therapy. These are also fairly resistant to immunotherapy.
We have a long way to go in understanding the biology of these common types of sarcomas in order to define new therapies. There are increasing numbers of investigators trying to understand the biology of what's driving these tumors. What is driving the immunology—the resistance to the immune system? What is driving it in an epigenetic space? What's driving these tumors in terms of possibly unidentified mutations that could be targeted? All of this research and understanding that these more common types of sarcomas is desperately needed to identify new treatments for these patients.
Are there any precision medicine efforts in sarcoma?
Sarcoma is really a collection of 175 different types of cancer. For instance, chondrosarcoma is as different from liposarcoma as breast cancer is from colon cancer. They have different metastatic patterns, different treatments, and different ideologies. It has taken a long time to make advances in understanding the driver mutations and the biology of all of these different diseases. However, in recent years, a number of different driver mutations have been identified in several different types of sarcoma, some of which can be targeted therapeutically.
For instance, the gene isocitrate dehydrogenase is a component of the cell cycle, and when mutated, the protein now converts alpha-ketoglutarate into 2-hydroxyglutarate. 2-hydroxyglutarate epigenetically deregulates the cell and turns it into a cancer cell. This is important not just because it's fascinating biology, but also because there are a series of new IDH inhibitors that are FDA approved and are also in development to treat patients with IDH-mutant chondrosarcoma.
You recent published some work in Discovery Medicine about precision medicine efforts in GIST. What are the key points from that research?
GIST is one of the more common types of soft tissue sarcoma. There may be somewhere around 3000 to 5000 new patients diagnosed each year. For many years, we have thought of GIST as 1 disease. We found that, over recent years, that GIST is a collection of many different molecularly defined diseases. The most common type of GIST is KIT-mutated GIST, which is often an exon 11 or exon 9, but can also have mutations in exon 13 or exon 17 as primary mutations.
However, GIST may also be driven by PDGFR, often PDGFRA D842V, which is resistant to most TKIs. GIST may also be caused by a loss of SDH. There is also RAF-mutant GIST, and NTRK-translocated GIST.
Why are these different types of GIST important? They're very important because each of those mutations I discussed have a specific targeted therapy. For instance, patients with KIT-mutated GIST with exon 11 is treated with 400 mg of imatinib, whereas exon 9—mutated GIST is treated with 800 mg of imatinib. Patients with PDGFRA D842V-mutant GIST should be treated with avapritinib, and those with NTRK-translocated GIST should be treated with an NTRK inhibitor, such as larotrectinib (Vitrakvi) or entrectinib (Rozlytrek), and others that are in development. SDH-deficient GIST is a little more difficult to manage, but there is some anecdotal evidence that these might respond to multikinase inhibitors that can also inhibit the VEGF receptor pathway.
GIST is a collection of molecularly driven diseases for which mutation testing plays a key role in order to provide optimal treatment of patients. We recently looked at the SEER-Medicare database and found that only 30% of patients with GIST are getting KIT testing, whether it's metastatic or primary.
Patients with metastatic GIST are treated with these TKIs. Patients with metastatic GIST may have any of the mutations that I discussed; yet, in the United States, only 30% of our patients are receiving the mutation testing that allows us to identify the best treatment for them. We need to work collectively throughout the United States and throughout our healthcare system in order to perform mutation testing, to define what's driving these GIST tumors, so that we can identify the right medication for the right patient.
How is ctDNA being used in sarcoma?
ctDNA is a new technology where blood can be tested in a patient and we can identify the mutation in DNA that is shed from a tumor cell. For instance, in GIST, our group recently evaluated 143 patients with GIST and found that ctDNA could be detected. The majority of patients could be detected at a very high sensitivity rate with large tumors that are growing and resistant to TKIs.
ctDNA could be very important in the future when one is selecting subsequent therapies for patients with GIST after imatinib resistance. For instance, patients with KIT exon 13—mutant,
secondary resistant GIST seem to be sensitive to sunitinib, but is resistant to other TKIs. On the other hand, patients whose GIST is resistant to imatinib in the setting of a KIT exon 17 resistance mutation might be potentially sensitive to other TKIs, such as regorafenib. In the future, we may be able to define the optimal second-line therapy for patients with GIST, based on ctDNA.