First-Line TPST-1120 Plus Atezolizumab/Bevacizumab Improves Responses in Unresectable or Metastatic HCC

The addition of TPST-1120 to the combination of atezolizumab and bevacizumab led to improved responses vs atezolizumab plus bevacizumab alone in the first-line treatment of patients with unresectable or metastatic hepatocellular carcinoma.

The addition of TPST-1120 to the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) led to improved responses vs atezolizumab plus bevacizumab alone in the first-line treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC), according to data from a phase 1b/2 trial (NCT04524871).1

Findings showed that at a median follow-up of 9.2 months, patients treated with TPST-1120 plus atezolizumab and bevacizumab (n = 40) achieved a confirmed objective response rate (ORR) of 30%. At a median follow-up of 9.9 months, those given atezolizumab plus bevacizumab alone (n = 30) experienced a confirmed ORR of 13.3%. The median duration of response (DOR) had not been reached in either arm.

Although survival data were not mature, trends favoring the TPST-1120 regimen were observed for both progression-free survival (PFS; HR, 0.7) and overall survival (OS; HR, 0.59). The median PFS was 7 months (95% CI, 5.6-13.8) for the triplet vs 4.27 months (95% CI, 2.8-7.3) for atezolizumab/bevacizumab. The median OS was not reached (95% CI, 10.84–not evaluable [NE]) for the TPST-1120 arm vs 15.1 months (95% CI, 7.49-NE) for the doublet arm.

“This comprehensive analysis of more mature clinical data shows an even greater benefit than the earlier interim analysis of the TPST-1120 triplet therapy over standard of care alone, both for the entire study population and in subpopulations of patients, the latter of which was predicted by TPST-1120’s proposed mechanism of action,” Stephen Brady, president and chief executive officer of Tempest, stated in a news release. “First-line HCC remains an indication with substantial opportunity to improve patient outcomes and, based upon these data, we are excited about the opportunity to move TPST-1120 into a pivotal study. Given these new data and the phase 1 evidence of activity beyond HCC, we look forward to advancing discussions with potential partners who share our vision for TPST-1120.”

Data for TPST-1120, which is an oral, small molecule, selective PPARα antagonist, have suggested that the agent directly targets tumor cell metabolism and modulates immune suppressive cells and angiogenesis in the tumor microenvironment.

The phase 1b/2 trial is an open-label, multicenter, randomized umbrella study enrolling patients with advanced liver cancers, and it is designed with the flexibility to open new treatment arms as new treatments become available and close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity.2

Stage 1 of the study is enrolling patients at least 18 years of age with histologically or cytologically confirmed, locally advanced or metastatic, and/or unresectable HCC whose disease is not amenable to curative surgical and/or locoregional therapies and who have not received prior systemic treatment for HCC. Key inclusion criteria include an ECOG performance status of 0 or 1, Child Pugh class A, and a life expectancy of at least 3 months.

Key exclusion criteria include prior treatment with CD137 agonists or immune checkpoint inhibitors; treatment with investigational therapy within 28 days of enrollment; treatment with locoregional therapy to the liver within 28 days of the study; untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding; and prior bleeding events due to esophageal and/or gastric varices within 6 months prior to enrollment.

Patients were randomly assigned to receive 1200 mg of oral TPST-1120 once per day on days 1 through 21 plus 1200 mg of intravenous (IV) atezolizumab on day 1 and 15 mg/kg of IV bevacizumab on day 1 of each 21-day cycle; or atezolizumab plus bevacizumab alone.

ORR is serving as the trial’s primary end point, and secondary end points include PFS, OS, and DOR.1

The randomized arms were generally well balanced. Additional data showed that patients with β-catenin mutations in the TPST-1120 arm (n = 7) experienced a confirmed ORR of 43% and a disease control rate of 100%. In patients with PD-L1–negative tumors, the TPST-1120 regimen elicited a confirmed ORR of 27% compared with 7% for atezolizumab/bevacizumab alone.

At data cutoff, treatment was ongoing for 40% of patients in the TPST-1120 arm compared with 16.7% of those in the doublet arm. Additionally, 72.5% of patients in the experimental arm were still on study compared with 46.7% of patients in the control arm.

Safety data showed that TPST-1120 was well tolerated, and toxicities were comparable between the two arms.

References

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