Targeted Therapies Begin to Transform the Treatment of Sarcomas

Neeta Somaiah, MD

A decade ago, there were few drugs for the treatment of sarcomas, and most of them were chemotherapies, according to Neeta Somaiah, MD. Sarcomas have more than 50 subtypes, therefore, precision medicine was an unmet need until recently.¹

During a presentation at the Inaugural Miami Cancer Institute Precision Medicine Oncology Symposium, Somaiah, an associate professor and deputy department chair, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, talked about the use of precision oncology to conquer sarcoma treatment. She explained that the introduction of these targeted therapies started with gastrointestinal stromal tumors (GIST).

“GIST is the first tumor type of sarcoma where precision oncology made a huge impact with the approval of imatinib [Gleevec] way back in 2002. Since then, we have discovered we have had 3 drug approvals, and in the last 2 years, we have 2 additional drugs approved by that target KIT and PDGFR mutations more effectively. We have been able to get patients to respond even in the later lines of therapy,” Somaiah told Targeted Oncology™, in an interview.

After imatinib, the FDA also approved sunitinib (Sutent), regorafenib (Stivarga), ripretinib (Qinlock), and avapritinib (Ayvakit) for the treatment of GIST. For patients who do not respond to these therapies, there are other tyrosine kinase inhibitor options, including pazopanib (Votrient), nilotinib (Tasigna), and dasatinib (Sprycel).²

For other forms of sarcoma, both pazopanib and the EZH2 inhibitor, tazemetostat (Tazverik), are available targeted therapies.³

During the interview, Somaiah explained how targeted therapies have started to re-shape the treatment of sarcomas and discussed the potential role of immunotherapy in the future.

TARGETED ONCOLOGY: What did you discuss during the Inaugural Precision Medicine Oncology Symposium?

Somaiah: I am a sarcoma medical oncologist, and I was assigned to discuss how precision oncology is making a difference in the care of patients with sarcoma. We divided the sarcomas into gastrointestinal stromal tumors and the rest of the sarcomas. I gave an overview on sarcoma treatment, how we're making progress by dividing and conquering the different subtypes, and the molecular histologies that we see in sarcoma.

What does the treatment landscape for sarcoma look like right now? What targeted therapies are coming down the pipeline?

What is interesting in the treatment landscape of sarcomas is that in the past, we had very few treatment options for majority of the sarcomas. There are more than 50 types of sarcomas, and the treatments were mainly chemotherapy-based, and were not specific to either subtype or molecular histology. In the last 10 years, we have seen a lot more approvals for drugs in the sarcoma space, albeit they are approvals for specific subtypes or molecular histologies.

I think the recent developments are exciting. It's not just 1 or 2 drugs, but there are multiple drugs. There are drugs that are in the targeted space [and are] targeting specific molecular drivers within different sarcoma types, and then there is some progress made with immunotherapy as well with our first approval for a checkpoint inhibitor in a sarcoma subtype.

Can you talk outcomes shown with the available targeted therapies for sarcoma?

The reason why we have seen an uptake in the number of new drugs approved, even though they're for a smaller number of patients, is because by having a biomarker-driven approach, it allows for a much higher response rate, hence the efficacy that we see with the trials that are leading to approvals right now. Instead of the chemotherapy responses that are usually in the 20% range, we're hitting well in the 40%-50% range with these targeted therapies.

In research, what will be some important targets to focus on in the future?

I personally am interested in advancing immunotherapy in the sarcoma space. The challenge there is finding the right subtypes that will respond, and finding the right type of immunotherapy combinations that will be helpful for these patients with sarcoma that are different than some of the carcinomas that we see. I think there are some trials that we'll be seeing in the future that we hope can bring the immunotherapy into the soft tissue and bone sarcoma spaces as well. Right now, immunotherapy is only approved for a small subtype called alveolar soft part sarcoma.

Specifically for GIST, what are the unmet needs and what progress has been seen with precision oncology?

GIST is the first tumor type of sarcoma where precision oncology made a huge impact with the approval of imatinib way back in 2002. Since then, we have discovered we have had 3 drug approvals, and in the last 2 years, we had 2 additional drugs approved by that target KIT and PDGFR mutations more effectively. We have been able to get patients to respond even in the later lines of therapy.

What's interesting is there ate at least 5 new drugs in the space that are better and stronger inhibitors of the mutations and secondary mutations we see in GIST. There is likely to make a significant impact in the GIST treatment landscape in the next coming years.

_REFERENCES:

_{1. Somaiah N. Dividing and conquering sarcomas through precision oncology. Presented at Inaugural Miami Cancer Institute Precision Oncology Symposium; February 3-4, 2022; Coral Gable, FL.}

_{2. Schaefer IM, DeMatteo RP, Serrano C, et al. The GIST of advances in treatment of advanced gastrointestinal stromal tumor. Am Soc Clin Oncol Educ Book. 2022;42:1-15. doi: 10.1200/EDBK_35123}

_{3. Vasella M, Gousopolous E, Guidi M, et al. Targeted therapies and checkpoint inhibitors in sarcoma. QJM. 2022;115(12):793-805. doi: 10.1093/qjmed/hcab014.}