TPST-1120 Plus Nivolumab Offers New Treatment Potential in RCC

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The novel PPAR-α inhibitor TPST-1120 shows promise for solid tumors, including renal cell carcinoma, as monotherapy and in combination with nivolumab.

3D rendering of human kidneys

3D rendering of human kidneys

TPST-1120, a first-in-class oral inhibitor of peroxisome proliferator activated receptor α (PPAR-α), appeared to be well tolerated as both monotherapy and in combination with nivolumab (Opdivo), in patients with PD-1 inhibitor-refractory cancers, including renal cell carcinoma (RCC).1

Five patients (28%) with RCC were included in the combination TPST-1120 plus nivolumab arm, and 2 patients experienced responses. Both patients had previously progressed on anti-PD-1 therapy. In the combination group, the objective response rate (ORR) was 20% across all dose levels and 30% with a TPST-1120 dose of 400 mg or higher twice daily. In the monotherapy arm, 53% of patients (n = 10) had a best objective response of stable disease.

“[With] this combination, we had 2 patients with renal cell carcinoma who had the response. One of them…had around a 53% reduction in tumor size, just with the first 2 cycles of the combination of the TPST-1120 with nivolumab,” said Bruno Bastos, MD, medical oncologist at the Miami Cancer Institute, Baptist Health South Florida, and member of the genitourinary oncology and phase 1 multiple tumor teams, in an interview with Targeted OncologyTM. Bastos was an author and investigator of this study and presented a poster from this analysis at the 2024 Genitourinary Cancers Symposium held in January 2024.

Regarding safety, there were no dose-limiting toxicities observed during the dose-escalation phase, and a maximum tolerated dose (MTD) was not established. Within the monotherapy arm, 50% of patients (n = 10) experienced an adverse event (AE) related to TPST-1120. Treatment-related AEs in the monotherapy arm included nausea (20%), fatigue (15%), and diarrhea (10%), all of which were grade 1 to 2. An incidence of grade 3 hypertension was reported in a patient who received 600 mg twice daily of TPST-1120. Further, no grade 4 or 5 TRAEs were reported in the monotherapy arm, and no patients discontinued treatment due to an AE.

A total of 14 patients (77.8%) experienced TRAEs related to nivolumab or TPST-1120 in the combination therapy arm. The most common TRAEs were fatigue (33.3%), diarrhea (22%), and nausea (17%), and all were grade 1 or 2. Three grade 3 TRAEs were reported, includingarthralgia at the 400-mg TPST-1120 dose, increased hepatic enzyme at the TPST-1120 600-mg dose, and muscle spasms, also at the 600-mg dose. Only the patient who had increased hepatic enzymes discontinued treatment.

Behind the Phase 1 Study of TPST-1120

The trial (NCT03829436) was a phase 1, first-in-human, open-label, dose-escalation study with a 3+3 design. The primary end points were safety and tolerability and identifying the MTD or optimal biological dose of TPST-1120 as monotherapy and in combination with nivolumab. Secondary points included pharmacokinetics, pharmacodynamics, and preliminary assessments of anticancer activity.

Patients with castration-resistant prostate cancer, cholangiocarcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, pancreatic cancer, and RCC were included. Patients were required to have advanced or metastatic disease that was previously treated with standard systemic therapy, an ECOG performance status of 0 or 1, an estimated life expectancy of at least 12 weeks, and adequate organ function to be eligible for study enrollment.

Monotherapy TPST-1120 was administered orally in 21-day cycles until disease progression or unacceptable toxicity with a starting dose of 100 mg twice daily (BID) (200 mg/day). In a standard 3+3 design, patients were sequentially enrolled at progressively higher dose levels of TPST-1120, evaluating 100, 200, 300, 400, and 600 mg BID. Dose-escalation of TPST-1120 in combination with nivolumab was initiated after the 300 mg BID (600 mg/day) monotherapy cohort successfully cleared the dose-limiting toxicity evaluation period. TPST-1120 was evaluated in 28-day cycles at progressively higher dose levels of 200, 300, 400, and 600 mg orally BID in combination with standard dose nivolumab (480 mg intravenous infusion every 4 weeks). Treatment continued until disease progression or unacceptable toxicity.

About TPST-1120

“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 fatty acid oxidation for fatty acid is very interesting,” said Bastos.

PPAR-α is a fatty acid ligand-activated transcription factor responsible for controlling the expression of over 100 genes involved in fatty acid oxidation, angiogenesis, and inflammation, making it an attractive target for anticancer therapies.

TPST-1120 is aPPAR-α inhibitor with high specificity. In xenograft and syngeneic tumor models, TPST-1120 monotherapy inhibited tumor growth, while the combination of TPST-1120 and nivolumab demonstrated synergistic tumor reduction and antitumor immunity in murine models.

REFERENCE:
1. Yarchoan M, Powderly J, Bastos B, et al. First-in-human phase I trial of TPST-1120, an inhibitor of PPARα, as monotherapy or in combination with nivolumab, in patients with advanced solid tumors. Cancer Res Commun. Published online March 29, 2024. doi:10.1158/2767-9764.CRC-24-0082
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