TPST-1120 shows promise in solid tumors, including renal cell carcinoma
In the monotherapy cohort of TPST-1120, 53% of patients achieved a best response of stable disease, with 5 of those patients remaining on treatment for more than 5 months.
The oral, selective PPAR⍺ inhibitor TPST-1120 was well-tolerated and demonstrated preliminary anti-tumor activity as both a monotherapy and in combination with nivolumab (Opdivo) in patients with advanced solid tumors, including renal cell carcinoma (RCC), according to data from a phase 1 trial (NCT03829436) of the therapy published in Cancer Research Communications.1
In the combination arm, the objective response rate was 23% across all dose levels.
“In this phase 1 study of TPST-1120, we saw the first evidence of anti-tumor activity in multiple cancer types, affirming our belief that PPARα inhibition is an exciting and novel approach for cancer treatment. These early-phase data are supported by the positive top line results of the ongoing randomized phase 1b/2 trial in first-line [hepatocellular carcinoma]. We believe there is tremendous potential for TPST-1120 to make a meaningful impact for patients and we look forward to providing updated data this year,” said Sam Whiting, MD, PhD, in a news release on the findings.2 Whiting is the chief medical officer and head of R&D at Tempest Therapeutics, the developer of TPST-1120.
The study included heavily pretreated patients with RCC, hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). In total, 38 patients were treated in the study, of which 20 received TPST-1120 monotherapy and 18 received TPST-1120 in combination with nivolumab.
Overall, treatment with TPST-1120 was well-tolerated in both cohorts. The most common treatment-related adverse events (TRAEs) were grade 1 or 2 nausea, fatigue, and diarrhea. No grade 4 or 5 TRAEs nor any dose-limiting toxicities were observed.
In the monotherapy arm, 53% of patients (10 of 19) achieved a best response of stable disease, with 5 of those patients remaining on treatment for more than 5 months. Further, 21% of patients (4 of 19) experienced tumor shrinkage of target lesion, and 3 additional patients achieved a best response of no target lesion growth.
In the combination arm, the objective response rate (ORR) was 23% across all dose levels, and 30% among those treated at the 2 highest dose levels (≥ 400 mg twice daily) of TPST-1120. These responses included a 50% ORR among patients with RCC (2 of 4 evaluable patients) who had previously progressed on anti-PD-1 therapy, as well as 1 patient with CCA.
Further, data showed that changes in expression of PPAR⍺-associated immune genes via whole blood specimen analyses were linked to TPST-1120 dose levels. The investigators noted that some of these changes were only observed in patients who achieved a partial response, indicating that TPST-1220 biological activity is linked to clinical outcomes.
To be included in the study, patients needed to have an ECOG performance score of 0-1, at least 1 measurable lesion per RECIST v1.1, and progressive or previously untreated tumors for which no standard therapy exists or that are treatment naïve. At the time of study entry, patients had received a median of 3 prior lines of therapy.
The primary end points for the study are the incidence of dose-limiting toxicities, the incidence of treatment-emergent adverse events, and an identification of the maximum tolerated dose. Secondary outcome measures include pharmacokinetics and objective response rate.3
In addition to the current study, TPST-1120 is also being assessed in combination with atezolizumab (Tecentriq) and bevacizumab (Avastin) as a first-line treatment for patients with advanced HCC in an ongoing phase 1b/2 study (NCT04524871). Updated data from the study were presented in October 2023, showing clinical superiority of the TPST-1120 arm across multiple study end points.4 Tempest is now preparing to move into a phase 3 trial of TPST-1120 in HCC.
References
1. Yarchoan M, Powderly JD, Bastos BR, 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. 2024. doi:10.1158/2767-9764.CRC-24-0082
2. Tempest announces publication of positive data from phase 1 trial of TPST-1120 in patients with advanced solid tumors in Journal of Cancer Research Communications. News release. Tempest Therapeutics. Published online and accessed April 4, 2024. https://ir.tempesttx.com/news-releases/news-release-details/tempest-announces-publication-positive-data-phase-1-trial-tpst
3. TPST-1120 as monotherapy and in combination with nivolumab in subjects with advanced cancer. ClinicalTrials.gov. Last updated July 3, 2023. Accessed April 4, 2024. https://clinicaltrials.gov/study/NCT03829436
4. Tempest releases new data demonstrating superiority of TPST-1120 arm across multiple study endpoints in randomized first-line HCC study. News release. Tempest Therapeutics. October 11, 2023. Accessed April 4, 2024. https://ir.tempesttx.com/news-releases/news-release-details/tempest-releases-new-data-demonstrating-superiority-tpst-1120
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