Beyond Immunotherapy: New RCC Hope With TPST-1120 and Nivolumab Combo

Bruno Bastos, MD

Many unmet needs exist across the treatment landscape of renal cell carcinoma (RCC), and resistance to immunotherapy is a primary space of interest. Many patients do not respond to or develop resistance to the available immunotherapies for RCC, creating a pressing need for alternative options.

Bruno Bastos, MD, considers TPST-1120, a first-in-class treatment targeting fatty acid metabolism, to show promise, both as a single-agent and combined with immunotherapy. Bastos co-authored a phase 1 study that was presented at the 2024 ASCO Genitourinary (GU) Cancers Symposium. 

“Based on these findings, in seeing the gene expression and lipid changes that have been associated with the mechanism of action of TPST-1120, we notice in this patient that the clinical response and modulation of those genes that have been appropriate with the treatment. The use of targeted agents to this [peroxisome proliferator-activated receptor alpha [PPAR-α], which mainly is involved in fatty acid oxidation in renal cell carcinoma, may be a relevant therapeutic interest,” Bastos told Targeted Oncology^TM, in an interview.

In the interview, Bastos, medical oncologist at the Miami Cancer Institute, Baptist Health South Florida, and member of the GU oncology and phase 1 multiple tumor teams, discussed findings from the trial and next steps in this treatment field.

Targeted Oncology: What unmet needs in the RCC space prompted the study for the poster you presented at ASCO GU?

Bastos: For metastatic renal cell carcinoma, the 2 major components of the treatment is the immunotherapy, which was an anti-PD1/PD-L1 inhibitor in combination with immune-checkpoint inhibitors in combination with VEGF [tyrosine kinase inhibitors (TKIs)]. That's the majority of first-line treatments or a combination of both. [One] can have a combination of immunotherapy or a combination of immunotherapy with VEGF TKIs.

After this, second- and third-line options for treatment are limited. The response rates that patients have after this combination usually are not very robust. What we are trying to understand in this trial is to create new a modality of treatments for patients with renal cell carcinoma post-immunotherapy, post-anti-VEGF TKI, and that's the reason these ideas of combining a new agent, which is the 1 that we use it for this patient cases in the poster presentation, which is an agent called TPST-1120.

TPST-1120 is a new agent and it's a first-in-class drug. This was a phase 1 clinical trial. It's a medication that’s an antagonist of a receptor called PPAR-α. This is a fatty acid-like activated prescriptive factor that controls multiple genes in the cell involved—mainly fatty acids, fatty acid oxidation, angiogenesis, inflammation. The use of TPST-1120 is supposed to block the activity of PPAR-α. That, in combination with immunotherapy, which was the case we used in this poster, and TPST-1120 in combination with nivolumab [Opdivo] was the idea, to enhance the activity of the immunotherapy through the blockade of the fatty acid oxidation.

Could you summarize the findings?

Renal cell carcinoma may have alterations in the lipid of fatty acid metabolism. Stem cells [that are] derived from fatty acid oxidation for energy in the renal cell carcinoma may be 1 of those tumors. The idea to use an agent that blocks that fatty acid oxidation for fatty acid is very interesting. In this trial, we used this drug TPST-1120, which blocks the PPAR-α, in multiple doses in phase 1. Then, when we reached a dose that was considered to be safe, the recommend phase 2 dose, 400 mg [by mouth twice a day], we combine [that] with nivolumab in a new cohort. In this combination, we had 2 patients with renal cell carcinoma who had the response. One of them is the 1 that I [showed] this poster [on]. It had around a 53% reduction in tumor size, just with the first 2 cycles of the combination of the TPST-1120 with nivolumab.

In the in the poster, we showed not only the images of this response but also pharmacodynamic changes in the many genes. We did use some genes, which are PPAR-α-associated genes. We were able to analyze that gene before and after treatment, and we could see that this patient who had a response had reduction below baseline and the expression of the 5 to 6 PPAR-α-associated genes, which corroborates the idea that there was a treatment effect. It has been associated with the target changes in the genes or gene modulation based on the TPST-1120 activity.

What are the next steps that you see?

Based on these findings, in seeing the gene expression and lipid changes that have been associated with the mechanism of action of TPST-1120, we notice in this patient that the clinical response and modulation of those genes that have been appropriate with the treatment. The use of targeted agents to this PPAR-α, which mainly is involved in fatty acid oxidation in renal cell carcinoma, may be a relevant therapeutic interest.

Future phase 2 clinical trials of this combination renal cell carcinoma or other agents that block the PPAR-α or studies are needed to know whether or not this experience we see in this particular clinical trial could be seen on a large scale.

What future work with TPST-1120 in RCC or in other GU cancers can we expect to see in the coming years?

There are few agents in development. This medication, TPST-1120, is already moving into phase 2 to be studied in [gastrointestinal] malignancies. But this is an area of a need. There are not many drugs, as far as I can tell right now, that are in the arena. Like I said, this is first-in-class. I think it's an urge that we have to have better drugs and to analyze the use of these agents in cancer treatment. Hopefully, we will be able to see more advances in the renal cell arena or in combination with the novel agents.