Divide and Conquer: Dr Somaiah on Applying Precision Oncology in Sarcoma

The fight against sarcoma is entering an era of precision medicine where identifying unique genetic drivers is the key to unlocking more effective, individualized treatment strategies for subtypes such as osteosarcoma, soft tissue sarcoma, and gastrointestinal stromal tumors (GIST). At the fourth annual Miami Cancer Institute Precision Oncology Symposium on January 30, a presentation titled “Dividing and Conquering Sarcomas” examined the state of targeted therapies and what has changed in the last year.

“By dividing and conquering…we’re seeing responses in multiple different subtypes of sarcoma…and moving toward more of an individualized therapy that we try to design for every patient, where we take into account their specific sarcoma type, their patient characteristics, and also the genomics,” said the presenter, Neeta Somaiah, MD.

Her presentation aimed to cover several practice-changing developments including DR5 agonist therapy in chondrosarcoma, overcoming resistance to targeted therapy in GIST, and efforts to implement promising treatment modalities including immune checkpoint inhibitors, antibody-drug conjugates (ADCs), and cellular therapies across this challenging treatment landscape.

During an interview with Targeted Oncology, Somaiah, professor and department chair in the department of sarcoma medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, discussed the key areas of her presentation and the upcoming trials she sees the most potential in across sarcomas.

Targeted Oncology: What was the background for your presentation on precision oncology in sarcoma?

Neeta Somaiah, MD: Precision oncology in sarcoma is daunting to cover…because sarcoma is just not one disease; it’s multiple different subtypes. I focused on trying to give a snapshot of all the development that we are seeing in the space of sarcoma, both soft tissue and bone sarcomas, and also GIST that highlight the importance of precision oncology in the design of our clinical trials. We focus more on subtypes and targets that we can we can rationally attack with available new therapeutics, which actually lead to much better response rates that we’re seeing in our clinical trials, and leading to new drug approvals in small subsets of sarcoma, which are big wins, because when we combine them together without a specific target, the outcome or the efficacy readout gets diluted by some patients who don’t respond. By dividing and conquering…we’re seeing responses in multiple different subtypes of sarcoma, which is the way to go, and moving toward more of an individualized therapy that we try to design for every patient, where we take into account their specific sarcoma type, their patient characteristics, and also the genomics, where through either next-generation sequencing or other platforms which we think are important for that subtype, and take that into consideration while designing their treatment.

What were the subtypes and targets that you focused on the most in your talk?

Since I was [at the Precision Oncology Symposium] last year, I decided to give a little bit of a background on where sarcoma therapies stand but focus more on the updates from last year that were presented after my talk. When you’re looking at targeted therapy drugs, there have been a few…more practice-changing trials that were reported out last year.

One of them was ozekibart [INBRX-109], a death receptor 5 [DR5] agonist. It mimics DR5 agonist, which is a [TNF-related apoptosis-inducing ligand], and by binding with DR5, it causes multimerization of this receptor on the cell surface and then induces apoptosis. Chondrosarcoma is a subtype of bone sarcomas that we don’t have any good treatments for. For patients [with advanced disease] previously, we didn’t have any therapies, and medical oncologists didn’t know what to do with them. Now we’re coming up with more trials in that space, studying that this tumor type had overexpression of DR5, and the fact that they do not undergo apoptosis that well, [so] it made sense trying this. It’s a new best-in-class, tetravalent DR5 agonist now called ozekibart…that was tested in a randomized phase 2 study [ChonDRAgon; NCT04950075] in advanced chondrosarcomas.¹

[Patients were randomly assigned] to placebo 2:1 because there is no standard treatment, and it met its primary end point of progression-free survival [PFS] by a central independent radiology review, with a [median] PFS of 5.5 months in the treatment arm with ozekibart; [with] placebo it was 2.6 months, but it was a 52% reduction in the risk for progression or death [HR, 0.479; 95% CI, 0.33-0.68; P < .0001]. That is technically practice changing, and we’re hoping that even though it’s a phase 2 randomized study, that this was built as a path to registration, so we might have a drug later this year for this subtype of sarcoma.

The other study I presented was in the targeted space was with pimicotinib (ABSK021) which is another targeted CSF1R inhibitor for tenosynovial giant cell tumor. In this space, we do have other CSF1R inhibitors, so [the MANEUVER study (NCT05804045) of] pimicotinib was the third of the phase 3 studies in this space, resulting in a significant improvement in both tumor volume improvement and improvement in symptoms with joint pain, stiffness and range of motion.² We have better drugs, depending on the safety profile, can be used in that subset of population.

I did cover some immunotherapy data with the checkpoint inhibitors for undifferentiated pleomorphic sarcoma. In the neoadjuvant space, there was SU2C-SARC032 [NCT03092323], a randomized phase 2 study that showed significant improvement in disease-free survival combining pembrolizumab [Keytruda] with radiation instead of radiation alone prior to surgery.³ That has been practice changing, and there are a lot of people adopting it. I think we still need to figure out how it best fits when we have to potentially use chemotherapy as well. There are trials in that space.

I covered a little bit about cellular therapies, because afamitresgene autoleucel [afami-cel; Tecelra] is the only approved cellular therapy in solid tumors [with] an indication in sarcoma. The sarcoma type was synovial sarcoma. It is a T-cell receptor therapy targeting MAGE-A4 in synovial sarcoma. I had covered that last time; this year I covered the aggregate data that was presented last year on letetresgene autoleucel [lete-cel; GSK3377794] which is a T-cell receptor therapy targeting NY-ESO-1 which is another cancer-testis antigen also showing great results both in myxoid/round cell liposarcoma and synovial sarcoma.⁴ It’s not a registrational study, but the idea of aggregating the data is to see if there is a path towards registration for this agent that for some patients can make a dramatic difference in their outcomes with just one infusion.

What other subtypes did you present on?

I did go into some of the data for GIST as well, because GIST is the classic example for targeted therapy and precision oncology. Now there is more coming out with how we sequence these drugs knowing the secondary resistance mutations after we’ve treated patients with imatinib. There are new drugs in that area, and it shows a beautiful story of how precision oncology and knowing these mutations is key in picking the right drugs for patients so that they can have a significant response and a durable response earlier on, which could potentially change the whole trajectory of their disease.

I did cover bezuclastinib [CGT9486] and sunitinib for GIST because the phase 3 study [PEAK; NCT05208047] will be presented at the 2026 American Society of Clinical Oncology Annual Meeting. The press release from last year showed—in a long time, we haven’t seen results like that in GIST, where we’re seeing PFS benefit, which is 16.5 months for the combination vs 9.2 for sunitinib alone.⁵ It’s very likely to completely change how we treat patients in second line. Even though the mutation status is important in the second-line setting, because it’s a combination, it covers a very broad spectrum of secondary mutations, so that has the advantage in the second-line setting.

I did talk about the other trials in the second-line setting, which include IDRX-42 for which a phase 3 study vs sunitinib [NCT07218926] just opened, and this drug will also be tested in the first-line setting. There is no other drug that’s gone up against imatinib in the frontline setting so far. IDRX-42 is a very good candidate to do that.

How has the role of genomic testing advanced in treating patients with sarcoma?

I think it’s still evolving. In my own practice, I have seen that it is being used more even in the community setting, because previously it was mostly restricted to only a few centers that sent it out. In sarcomas, we have to be careful. I think there is a definite role in the advanced disease setting for genomic testing. In the localized setting, it’s limited. It might help in some cases, with helping with subtyping or figuring out the subtype of sarcoma, especially when the genomic test includes fusion testing. A lot of our sarcomas are driven by fusions between 2 [genes]; they come together and form this fusion protein that is the cause of the sarcoma. As we’re doing more of that, we’re defining new fusions that are associated with sarcomas and understanding why treatments did or did not work, because this was not similar to the other types of sarcomas we were considering before. I think it’s being incorporated more and more, and as we see more drugs coming out, I think it’s going to be just getting increasingly more important.

I did present some data about antibody-drug conjugates [ADCs] that I think are very interesting and going to be interesting for certain sarcomas as well. When we’re looking at high expression of these markers, and there are ADCs available, I think it will become increasingly important. There are some subtypes where it is important to know, like TSC1/TSC2 mutations. There’s a whole slew of other alterations that we see that we do have either drugs available to as a standard of care [or] drugs available in clinical trial. For advanced disease or unresectable sarcomas, we’re using it quite a bit. There might be certain subtypes where it is not of value because we have a very good drug, and it doesn’t make sense to do it. We have to be cost sensitive, also. The idea is to do it when it really can make a difference and alter that the course of treatment. In other cases, we’re just waiting for better tests, because there is also a limitation of the type of genomic test. Previously, the spectrum of what they would test for might not always be sarcoma specific, so it’s also limited by that, but it’s going to only be used more and more.

What are the most promising areas of investigation in sarcomas looking forward?

In terms of promising areas of investigation, for GIST, the big questions still looming are going to be [about] persistence—how do we eliminate those cells? Even when we have a good response, there are some cells that seem to persist and later are prone to develop resistance. Also, as we use the broader, better drugs up front...if they do progress, what resistance mutations are we now seeing that might be more challenging to treat because none of our available drugs are going to attack those? I think there is a lot of area of drug development that should be focused in that area of limiting persistence and then figuring out how to tackle those additional resistance alterations that we see.

We also have subsets. The trials that I’m most interested in GIST are those underserved subsets like SDH [succinate dehydrogenase]-deficient GIST. We have NF1 [neurofibromatosis type 1]-related GIST. There are others that are more challenging to treat. FGFR inhibitors have shown great activity in the SDH-deficient GIST, so we’re hoping to have a trial that’s grant-funded. Rare tumors [are] difficult sometimes to gather support to test a drug in a very small subset, but institutions interested in sarcoma coming together are able to do that.

With regards to other sarcomas, [in] each subtype, there is an exciting area of investigation. There’s no one answer fits all there. The ADCs targeting B7-H3 in osteosarcoma is coming up as one where there’s activity.⁶ We’re going to be looking at that. There are ADCs against HER2 for desmoplastic small round cell tumor.⁷ We’re going to see activity with that. We’re looking at more data there. In general, we’re still looking at combinations. There’s doxorubicin and lurbinectedin [Zepzelca] data⁸; there’s an ongoing trial in that space [NCT06088290].

We have over 26 clinical trials in sarcoma opened at MD Anderson. There [are] obviously a lot of avenues of interest...and when you talk about cellular therapies, we have natural killer cell studies that are targeting the cancer-testes antigen, so that’s also an area of interest. There are TEAD inhibitors, that we’re looking at. There [is] how to better combine the newer chemotherapy. There’s that avenue of interest. There is immunotherapy. I put ADCs in their own category, because I think that’s of interest and we’re seeing some new trials that are sarcoma focus, that are coming in through phase 1.

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