ESMO open · 2025
A phase II study of the AKT inhibitor TAS-117 in patients with advanced solid tumors and germline PTEN mutations.
СтатьяКлиническое исследование II фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Ródon J, Arkenau H-T, Funchain P, Hervieu A, Anthony K, Chawla S P, Laetsch T W, Murciano-Goroff Y R, Singer C F, He Y, Mina M, Wacheck V, Delaloge S
Аннотация
BACKGROUND: Protein kinase B (AKT)-directed therapies offer promise for patients with cancers harboring germline and somatic phosphatase and tensin homolog (PTEN) mutations. TAS-117 is an oral, selective, non-adenosine triphosphate-competitive allosteric AKT inhibitor that showed encouraging antitumor activity in a phase I study. This phase II study aimed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAS-117 in patients with advanced/metastatic solid tumors, including those harboring germline PTEN-inactivating mutations (EudraCT: 2020-004770-22).
MATERIALS AND METHODS: In this open-label, multicenter, single-arm phase II study, the 3 + 3 phase I-like dose escalation lead-in part A enrolled patients with advanced/metastatic solid tumors irrespective of gene alterations (all-comers). Patients received TAS-117 once daily (o.d.) or intermittent dosing (ID) regimens (4 days on/3 days off), with a 16-mg/day o.d. or 24-mg/day ID starting dose. The primary objective was safety and to define maximum tolerated dose/recommended phase II dose (RP2D). The dose/regimen confirmation part B was to further assess RP2D in patients harboring germline PTEN mutations.
RESULTS: Overall, 17 patients were enrolled in part A (all-comers n = 16, dose and regimen confirmation, n = 1). Dose-limiting toxicities were observed in three patients [febrile neutropenia at 20 mg o.d. (n = 1); grade 3 oral mucositis at 28 mg ID (n = 2)]. Most common treatment-related adverse events (AEs) (all grade/grade ≥3) were rash (58.8%/17.6%), fatigue (35.3%/1%), pruritus (29.4%/0%), hyperglycemia (29.4%/1%), and decreased appetite (17.6%/0%). RP2D was determined to be 16 mg/kg o.d. Seven patients had stable disease. One of two patients with a germline PTEN mutation (metaplastic breast cancer) had stable disease ongoing for 19.1 months as of the data cut-off. The study was closed due to enrollment challenges in the germline PTEN mutation carrier population.
CONCLUSIONS: TAS-117 at the RP2D of 16 mg o.d. was tolerable, with a manageable safety profile. Clinical benefit, although durable, was only observed in a single patient with a germline PTEN mutation.
MATERIALS AND METHODS: In this open-label, multicenter, single-arm phase II study, the 3 + 3 phase I-like dose escalation lead-in part A enrolled patients with advanced/metastatic solid tumors irrespective of gene alterations (all-comers). Patients received TAS-117 once daily (o.d.) or intermittent dosing (ID) regimens (4 days on/3 days off), with a 16-mg/day o.d. or 24-mg/day ID starting dose. The primary objective was safety and to define maximum tolerated dose/recommended phase II dose (RP2D). The dose/regimen confirmation part B was to further assess RP2D in patients harboring germline PTEN mutations.
RESULTS: Overall, 17 patients were enrolled in part A (all-comers n = 16, dose and regimen confirmation, n = 1). Dose-limiting toxicities were observed in three patients [febrile neutropenia at 20 mg o.d. (n = 1); grade 3 oral mucositis at 28 mg ID (n = 2)]. Most common treatment-related adverse events (AEs) (all grade/grade ≥3) were rash (58.8%/17.6%), fatigue (35.3%/1%), pruritus (29.4%/0%), hyperglycemia (29.4%/1%), and decreased appetite (17.6%/0%). RP2D was determined to be 16 mg/kg o.d. Seven patients had stable disease. One of two patients with a germline PTEN mutation (metaplastic breast cancer) had stable disease ongoing for 19.1 months as of the data cut-off. The study was closed due to enrollment challenges in the germline PTEN mutation carrier population.
CONCLUSIONS: TAS-117 at the RP2D of 16 mg o.d. was tolerable, with a manageable safety profile. Clinical benefit, although durable, was only observed in a single patient with a germline PTEN mutation.