Atezolizumab

Keytruda's Keynote-689 marks the first positive trial in more than two decades in resected locally advanced head and neck squamous cell carcinoma. Ending a 20-year-plus drought, Merck & Co.’s Keytruda demonstrated that its use around surgery can reduce the risk of certain head and neck cancers from returning.Continuous use of Keytruda—both before and after surgery—reduced the risk of recurrence or death by 27% in patients with stage 3 or 4a, resected, locally advanced head and neck squamous cell carcinoma (HNSCC), according to results from the phase 3 Keynote-689 trial presented at the American Association for Cancer Research Annual Meeting 2025.In the study, Keytruda was added to postoperative radiotherapy with or without chemo. Investigators compared the perioperative Keytruda regimen with the sans-Keytruda standard treatment.Keynote-689 marks the first positive trial in more than two decades in resected locally advanced HNSCC, making Keytruda the first PD-1 inhibitor to mount such a benefit.The study’s findings suggest that the Keyturda regimen represents a new standard of care in this disease setting, Ravindra Uppaluri, M.D., Ph.D., from Brigham and Women’s Hospital and Dana-Farber Cancer Institute, said during a press conference Sunday. Uppaluri is a co-principal investigator of Keynote-689.The 27% event-free survival (EFS) improvement, though statistically significant, isn’t numerically among Keytruda’s best performances in its use around surgery, an approach known as perioperative treatment. In 2023, Keytruda won its perioperative non-small cell lung cancer approval after slashing the risk of disease recurrence, worsening or death by 42% when added to presurgical chemo alone.The 27% number is still clinically meaningful, Marjorie Green, M.D., Merck’s head of oncology global clinical development, said in an interview with Fierce Pharma.At three years, 57.6% of patients in the Keytruda arm remained recurrence free, versus 46.4% in the control arm. That 11.2-percentage-point absolute difference is also clinically meaningful for patients, she added.“There have been uptakes and adoptions of therapies for 2% to 3% absolute difference in outcomes, because we know most of the recurrences that have happened on the study were distant,” which increases the risk of death, she said.Further, Keytruda’s 51.8-month median EFS time was notably longer than the control arm’s 30.4 months. Despite the overall trial win, there remains a question about whether Keytruda is appropriate for patients whose tumors have low to no expression of PD-L1.The magnitude of Keytruda’s EFS benefit deteriorated as patients with lower levels of PD-L1 were included in the analysis. In patients with PD-L1 expression at a combined positive score (CPS) of 10 or above, the EFS risk reduction reached 34%. The number dropped to 30% when those with at least 1 CPS score were included, and then to 27% when PD-L1-negative disease was also counted.Green wouldn’t disclose what level of PD-L1 coverage Merck is seeking in the drug’s FDA label. She did note that Keytruda’s existing perioperative indications in other curative disease settings are broad approvals across the PD-L1 spectrum. In this HNSCC setting, patients with CPS of 10 or greater make up about 65% of the population, and only 5% have CPS below 1. Because of the small number of patients, it would be hard to draw conclusions about the PD-L1-negative group, Uppaluri said during the press conference.“Given that as a whole, I would say yes, this should be for all participants,” Uppaluri said.Another question that Keynote-689 cannot conclusively answer is whether Keytruda is necessary both before and after surgery. That question is even more relevant because Roche’s PD-L1 inhibitor Tecentriq failed in its own study when used as an adjuvant therapy after head and neck cancer surgery.Uppaluri admitted that the contribution of components is clearly a limitation of the study. Before Keynote-689 was launched, some investigator-initiated studies showed the potential of a perioperative regimen. Plus, there’s been a theory that giving a checkpoint inhibitor early before surgery—when the immune system is more robust and the tumors intact—may lead to better outcomes, Green noted.On a key secondary endpoint, Keytruda recorded a 9.4% major pathological response rate—defined as 10% or lower residual invasive cancer cells in resected tissues—versus 0% in the standard-of-care arm.Green acknowledged that 9.4% is a fairly small number. But it could indicate that adjuvant Keytruda provided some contribution to the EFS benefit.Neoadjuvant treatment with Keytruda appeared to have led to fewer uses of chemo in the adjuvant setting because more patients were deemed to have lower risk post-surgery.Green called that element out because removing the need for chemo could mean better tolerability. In Keynote-689, the Keytruda arm recorded numerically fewer chemo-related side effect incidents such as severe skin reactions.Finally, data on whether Keytruda could extend patients’ lives remained immature. Keytruda showed a favorable 28% reduction in the risk of death in the CPS 10 or above population. Because the statistical significance bar was not met, testing of this endpoint in the rest of the study population was not formally performed, and additional follow-up is ongoing. Merck’s application based on Keynote-689 is under FDA priority review with a target decision date of June 23, 2025.

BRISBANE, Calif., April 28, 2025 (GLOBE NEWSWIRE) -- Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage biotechnology company developing first-in-classi targeted and immune-mediated therapeutics to fight cancer, today announced that a presentation of new data supporting the immune component of amezalpat’s purported dual mechanism of action that reinforces its potential as a novel cancer treatment at the 2025 American Association for Cancer Research (AACR) Annual Meeting. “The data presented at the AACR Annual Meeting show that amezalpat reduced tumor promoting immunosuppression by M2 macrophages and T regulatory cells resulting in immune activation. These data support the immune-mediated anti-cancer activity of the proposed dual MOA of amezalpat,” said Sam Whiting, M.D., Ph.D., chief medical officer and head of R&D at Tempest, “and are consistent with clinical data showing promising results in patients with HCC, RCC and CCA including in combination with approved immunotherapy. The results reinforce amezalpat’s novel and potentially first-in-class profile as a cancer therapy.” Amezalpat is an inhibitor of PPAR-alpha, the key regulator of fatty acid oxidation (FAO), which is a key metabolic pathway used by immunosuppressive macrophages and regulatory T cells (Tregs). Both cell populations are associated with poor prognosis in multiple cancer indications. Data presented demonstrated that amezalpat inhibits the development of these cells from precursor populations and is associated with reduced mitochondrial mass, the site of FAO, in immunosuppressive macrophages. Additionally, treatment of Tregs or immunosuppressive macrophages with amezalpat in the presence of tumor and cytotoxic T cells decreases anti-inflammatory cytokine production, indicating blockade of immune suppression that likely contributes to the efficacy of amezalpat observed in clinical trials. About Amezalpat Amezalpat is an oral, small molecule, selective PPAR⍺ antagonist. Data suggests that amezalpat treats cancer by targeting tumor cells directly and by modulating immune suppressive cells and angiogenesis in the tumor microenvironment. In a global randomized phase 1b/2 study of amezalpat in combination with atezolizumab and bevacizumab in first-line patients with advanced HCC, the amezalpat arm showed clinical superiority across multiple study endpoints, including overall survival in both the entire population and key subpopulations, when compared to atezolizumab and bevacizumab alone, the standard of care. These randomized data were supported by additional positive results observed in the Phase 1 clinical trial in patients with heavily pretreated advanced solid tumors, including renal cell carcinoma and cholangiocarcinoma. About Tempest Therapeutics Tempest Therapeutics is a clinical-stage biotechnology company advancing a diverse portfolio of small molecule product candidates containing tumor-targeted and/or immune-mediated mechanisms with the potential to treat a wide range of tumors. The company’s novel programs range from early research to later-stage investigation in a randomized global study in first-line cancer patients. Tempest is headquartered in Brisbane, California. More information about Tempest can be found on the company’s website at www.tempesttx.com. Forward-Looking Statements This press release contains forward-looking statements, as that term is defined under the federal securities laws, that are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking terminology such as “may,” “will,” “should,” “would,” “could”, “expect,” “anticipate,” “plan,” “likely,” “believe,” “estimate,” “project,” “intend,” and other similar expressions. Forward-looking statements contained in this press release include but are not limited to statements relating to: the initiation, timing and results of the Phase 2 study for TPST-1495; and the ability of TPST-1495 to benefit from the ODD designation, including potential tax credits and market exclusivity. Any forward-looking statements in this press release are based on Tempest Therapeutics’ current expectations, estimates and projections about its industry as well as management’s current beliefs and expectations of future events only as of today and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, risks relating to: changes in the regulatory environment resulting in potentials delays in the clinical development and regulatory approval of our product candidates, including TPST-1495; the volatility and uncertainty in the capital markets for biotechnology companies; and our ability to raise additional capital or other pursue our plan to identify and complete a strategic transaction on attractive terms or at all. These and other factors that may cause actual results to differ from those expressed or implied are discussed in greater detail in the “Risk Factors” section of the company’s Annual Report on Form 10-K for the year ended December 31, 2024, filed with the Securities and Exchange Commission (SEC) on March 27, 2025, as well as in other filings the company may make with the SEC in the future. Except as required by applicable law, Tempest Therapeutics undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. These forward-looking statements should not be relied upon as representing Tempest Therapeutics’ views as of any date subsequent to the date of this press release and should not be relied upon as prediction of future events. In light of the foregoing, investors are urged not to rely on any forward-looking statement in reaching any conclusion or making any investment decision about any securities of Tempest Therapeutics. Investor & Media Contacts: Sylvia Wheeler Wheelhouse Life Science Advisors swheeler@wheelhouselsa.com Aljanae Reynolds Wheelhouse Life Science Advisors areynolds@wheelhouselsa.com _______________________ i If approved by the FDA