TKI and Immunotherapy Trials Bring ‘Excitement’ to Sarcoma Space

Brian Van Tine, MD, PhD

Washington University in St. Louis

Over the past few years, numerous classes of drugs have been introduced in several sarcoma subtypes that have the potential to expand the armamentarium, including tyrosine kinase inhibitors (TKIs) and immunotherapy agents, as well as combination regimens consisting of TKIs and dual checkpoint inhibitors, and chemotherapy in dual checkpoint inhibitors, according to Brian Van Tine, MD, PhD.

In a conversation with CancerNetwork^® during Sarcoma Awareness Month, Van Tine, a professor of medicine in the Division of Oncology, Section of Medical Oncology at Washington University School of Medicine’s Siteman Cancer Center, discussed several ongoing and establishing trials including studies investigating nirogacestat for desmoid tumors and sitravatinib for well-differentiated or dedifferentiated liposarcoma. He also highlighted more experimental modalities such as the development of a CAR T-cell therapy for synovial sarcoma, neoantigen vaccine–based technologies, and metabolic therapies as novel potential options in patients with sarcoma.

Van Tine also emphasized the importance of establishing a partnership between providers and patients, especially when it comes to clinical research.

“This is a very collegial field, and we as a group have a message that we can only move as fast as the partnership between us and the patients willing to try the drugs,” he said. “This understanding that clinical trials are needed so that we can figure out who to treat and who not to treat and what biology responds to what [treatment] will only be accomplished through a partnership between everybody.”

CancerNetwork^®: As one of the authors of the phase 3 DeFi trial (NCT03785964) investigating nirogacestat as a treatment for patients with desmoid tumors, which is currently under review by the FDA,¹ how might this agent provide benefit to this patient population?

Van Tine: The treatment of desmoid [tumors] has actually been evolving rapidly since thephase 3 Alliance clinical trial [NCT02066181] that first reported the activity of sorafenib.² And in that same study, we found out there was a 20% spontaneous regression rate of this tumor if you do nothing. Our understanding of this tumor has changed and evolved. We've done a lot of work in this area, and what's interesting is we understand there's a β‐catenin mechanism, and nirogacestat gets into that signaling. All of a sudden, not only do we have sorafenib as an NCCN Compendium listing for the treatment of desmoid [tumors],³ but nirogacestat, which is hopefully coming out as an FDA-approved treatment for desmoid [tumors].

The data that came out in the [phase 3 DeFi] trial is reminiscent of that of sorafenib. The [adverse] effect profiles are different between the 2 agents, but having more than one drug for the desmoid population as this treatment paradigm evolves and we now treat these tumors more medically than surgically is good.

You were also an author on another study evaluating sitravatinib in patients with well-differentiated or dedifferentiated liposarcoma.⁴ What do findings from that study suggest about sitravatinib’s efficacy?

When we did all the studies of pazopanib [Votrient], which is a different oral TKI, it went across all of the sarcomas except liposarcoma, which was left without an oral TKI with great activity. What was nice about sitravatinib is that it seems to have activity that is now equivalent to pazopanib in other sarcomas, [including] in dedifferentiated and well-differentiated liposarcoma.

We found what I would consider the missing TKI for dedifferentiated liposarcoma. While the development of sitravatinib is still underway, and it's not quite FDA-approved yet for another indication, we're hoping that we can still push this TKI to the liposarcoma space because it was clearly active and well tolerated. It's a missing drug in our armamentarium for that one specific disease.

We either need to do a dedicated trial in dedifferentiated liposarcoma or wait for one of the other trials sitravatinib is actually being used [in] to read out, and then we can use it as a guideline compendium. This needs to be a partnership, especially with the company that owns this agent, so that hopefully we can continue to develop it in this area.

Are there any other ongoing trials or research in the sarcoma space that appear to be promising?

There are so many amazing clinical trials going on. If we're talking about the largest trials that are going on right now, the first would be the unesbulin with dacarbazine trial [NCT05269355], a registration phase 3 trial that's going on in leiomyosarcoma.⁵ There is an almost ready for FDA approval phase 1 trial [NCT03132922] looking at a T-cell therapy that has been developed for synovial sarcoma, which would be the first T-cell therapy within our space, and I'm quite excited about that.⁶

There is a trial looking in the uterine leiomyosarcoma space with both PARP inhibitor temozolomide [Temodar] or dacarbazine against standard of care, which is a different registration trial. There is about to be a trial that is really geared in my research of arginine deiminase with gemcitabine and docetaxel, which is a metabolic therapy opening up around the world as a registration trial.

And then you get into all the phase 2 trials where we're looking for activity. There are really new trials looking at different agents that are targeted now to the mechanisms of the different sarcomas. There are some different immunotherapies being developed, and there is talk that we're going to expand the TKIs with immunotherapy, which was just reported at the American Society of Clinical Oncology [ASCO] Annual Meeting in different ways, or with chemotherapy in different ways. And then on top of that, you have early trials where there are signals now evolving that will move onto later stage trials with other small molecules against different targets that I can't speak to yet, but I can't wait until when we actually can. This is a very active space where there are a lot of new agents and a lot of new things going on.

Are there any other immunotherapy agents in this space that you think have the potential to impact the treatment paradigm?

If you start looking at the series of things that were looked at ASCO, if you look at the TKIs—whether lenvatinib [Revlimid] or cabozantinib [Cabometyx]—in combination with immunotherapy [we] are beginning to identify subsets where that combination seems to be important for certain sarcomas. There are all the data with trabectedin [Yondelis] and dual checkpoint inhibitors, where that seems to work in a different subset. And then there's all the work of Seth M. Pollack, MD, where he's going frontline with doxorubicin and pembrolizumab [Keytruda], which is going to be a phase 3 trial opening across the country.

[There's also] Breelyn Wilky, MD, who is looking at chemotherapy with dual checkpoint inhibitors, but different than new checkpoint inhibitors, which could potentially be better. We're no longer at the “I wish we could get checkpoints into sarcoma” point; we've moved onto [assessing] which checkpoints are right for which sarcoma. We had classically thought [subsets] like leiomyosarcoma would never have an immunotherapy or that there would be an odd patient here or there. That was the signal in the cabozantinib trial. The classic checkpoints didn't work for synovial sarcoma, and suddenly, there's a T-cell therapy.

There’s a lot of work here. There’s a lot of excitement, and I’m just really privileged to be a part of it.

Where do you see sarcoma research moving in the next few years?

It's neat that when I first entered this field, the number of dedicated sarcoma labs that were funded were few and far in between, and now there's this new generation of active researchers, both on the pediatric side and the adult side where we're looking at leiomyosarcoma in new ways. We're looking at alveolar soft part sarcoma, which is ultra-rare. There are groups of people looking at everything from circulating tumor DNA to metabolic therapies, to immunotherapies, to vaccine-based technologies, to the new idea of taking the COVID-19 vaccine to make cancer vaccines based on neoantigens within our own tumors. If you ask where I think we'll be in 5 years, we’ll hopefully start the conversation where we're actually talking about vaccine-based delivery of neoantigens to [an individual’s] sarcoma.

This is quite a journey. The best part is when all of a sudden you see that look in a patient's face when you get to tell them that they tried something that was ultra-new and it worked. We don't do this for us, we do this because we're dedicated to this community when you get the opportunity to see it work. It's almost as exciting for us as it is for the patient.

References

1. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140
2. Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018; 379:2417-2428. doi:10.1056/NEJMoa1805052
3. NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 2.2023. Accessed July 24, 2023. bit.ly/3Y58VTn
4. Ingham M, Lee S, Van Tine BA, et al. A single-arm phase II trial of sitravatinib in advanced well-differentiated/dedifferentiated liposarcoma. Clin Cancer Res. 2023;29(6):1031-1039. doi:10.1158/1078-0432.CCR-22-3351
5. Ingham M, Blay JY, Baird J, et al. A phase II/III study evaluating the efficacy and safety of unesbulin in advanced leiomyosarcoma (SUNRISELMS). Ann Oncol. 2022;33(7):S1243-S1244. doi:10.1016/j.annonc.2022.07.1917
6. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. 2023;29:104-114. doi:10.1038/s41591-022-02128-z