A phase II study of the AKT inhibitor TAS-117 in patients with advanced solid tumors and germline PTEN mutations

Abstract

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.

Highlights

• •TAS-117 was evaluated in advanced solid tumors with germline PTEN-inactivating mutations in this phase II study.
• •Three patients experienced a DLT (n = 1 at 20 mg o.d. and n = 2 at 28 mg ID); no DLTs occurred at 16 mg o.d. (RP2D).
• •The most common treatment-related AEs were rash, fatigue, pruritus, hyperglycemia, and decreased appetite.
• •DCR was 41.2% (n = 7 with stable disease); response is ongoing in one patient with a germline PTEN mutation.
• •TAS-117 at 16 mg o.d. was tolerable and durable clinical benefit was observed in one patient with a germline PTEN mutation.

Introduction

Phosphatase and tensin homolog (PTEN) is a key enzyme in the regulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, where it acts as a potent tumor suppressor by inhibiting PI3K signaling.¹

Somatic PTEN alterations or epigenetic down-regulation is common in a variety of cancers; in particular, endometrial carcinomas and glioblastomas are frequently associated with somatic PTEN mutations.^2,3 Tumor suppression activity of the PTEN protein varies with the specific mutation.²

Germline mutations in PTEN can cause a spectrum of rare phenotypes, collectively known as PTEN hamartoma tumor syndrome (PHTS), which include benign overgrowths, malignant tumors, and metabolic and neurodevelopmental disorders.⁴ PHTS is a rare condition with an estimated incidence ranging from 1 : 200 000 to 1 : 250 000.^5,6 Of the clinically distinct allelic disorders encompassed by PHTS, the most common and best described is Cowden syndrome, an autosomal dominant disorder characterized by multiple hamartomas and increased lifetime risks of breast, thyroid, endometrial, and other cancers.^3,7,8 Other phenotypes include Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome.⁹

Therapies targeting carcinogenetic mechanisms associated with various germline mutations have been investigated with treatments shown to be efficacious in treating the related disorders, including poly(adenosine diphosphate-ribose) polymerase inhibitors for germline BRCA mutations, the MEK inhibitor selumetinib for neurofibromatosis type 1, and anti-programmed death 1 immune checkpoint inhibitors for Lynch syndrome.10, 11, 12 In a phase III trial, the combination of capivasertib, a tyrosine kinase inhibitor of AKT, and fulvestrant, an antiestrogenic therapy, demonstrated improved progression-free survival versus placebo for metastatic breast cancer, including patients harboring somatic PTEN alterations, leading to United States Food and Drug Administration approval in 2023.13, 14, 15 AKT-directed therapy has been proposed as an effective approach to treat tumors harboring germline PTEN mutations, based on preclinical evidence and sporadic patient cases showing durable responses to AKT inhibitors in germline PTEN carriers.¹⁶ The European Society for Medical Oncology (ESMO) Precision Medicine Working Group classified PTEN mutations or deletions in a high tier on the ESMO Scale of Clinical Actionability for molecular targets in advanced breast cancer (level I/II) and advanced prostate cancer (level IIA) for AKT inhibitors.¹⁴

The prognoses of certain cancers with PTEN-inactivating mutations, depending on tumor type, have been shown to be worse compared with PTEN wild-type tumors.17, 18, 19 However, there are currently no approved targeted therapies for patients with germline PTEN-mutant tumors or many other tumors with PTEN-inactivating mutations. Therefore, this orphan patient population continues to represent an area of high unmet medical need.

TAS-117 is a highly potent and selective oral, non-adenosine triphosphate-competitive inhibitor of all three isoforms of AKT (distinct AKT1, AKT2, and AKT3 genes), with no observed off-target inhibition of kinases.²⁰ TAS-117 has shown antitumor activity in preclinical models of human cancers and has demonstrated preliminary antitumor activity and a manageable safety profile in a Japanese phase I study in patients with advanced solid tumors.²¹ Additionally, a phase II study investigating TAS-117 in patients with refractory gastrointestinal cancers [part of the Korea biomarker-driven multiarm drug screening, knowledge-, and evidence-generating targeted study (K-BASKET)] showed TAS-117 had limited antitumor activity and manageable toxicity.²² In both of these studies, efficacy signals were observed in patients with tumors harboring genomic alterations of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA)/AKT signaling pathway.^21,22

Given the rarity of PHTS conditions, including Cowden syndrome, and the significant clinical need for effective treatments, the current phase II study was designed as tumor agnostic to target any type of cancer harboring germline PTEN-inactivating mutations. The objective of the study was to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of TAS-117 in Western patients with advanced or metastatic solid tumors harboring germline PTEN-inactivating mutations (EudraCT: 2020-004770-22).

Materials and methods

Study design and treatment

Full details of the study design and methods have been published previously.²³ Briefly, this study was designed as an open-label, multicenter, single-arm phase II study conducted in two parts (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.105932). Part A was a safety phase I-like lead-in [dose-escalation and dose and regimen confirmation (DRC)] phase, conducted to investigate the safety and tolerability and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) and regimen of TAS-117 in patients with advanced solid tumors. Part B was designed to be a phase II study to evaluate the antitumor activity of TAS-117 in patients with solid tumors harboring germline PTEN-inactivating mutations.

Part A followed a 3 + 3 design using once daily (o.d.) and intermittent dosing regimens (4 days on/3 days off), with a starting dose of 16 mg/day (o.d.) or 24 mg/day (intermittent dosing) in 21-day cycles. Enrollment into the o.d. and intermittent dosing cohorts occurred in parallel, with patients assigned to treatment via an interactive voice/web response system. Following selection of the recommended dose and regimen, additional patients with advanced solid tumors harboring germline PTEN-inactivating mutations were to be enrolled into part A to further assess safety and tolerability.

In part B, only patients with advanced solid tumors harboring germline PTEN-inactivating mutations were to be enrolled and treated at the RP2D and dosing schedule for TAS-117 identified in part A. Treatment with TAS-117 was to be continued until disease progression, unacceptable toxicity, study termination, or other withdrawal criterion.

The study was carried out in accordance with the principles of the Declaration of Helsinki, good clinical practice, and applicable regulatory requirements.²⁴ The study protocol was approved by the institutional review board(s) and/or independent ethics committee(s) at each participating center and all patients provided written informed consent.

Patients

Eligible patients were aged ≥12 years (≥18 years for part A, dose escalation only) with histologically or cytologically confirmed advanced or metastatic solid tumors (excluding primary brain tumors) that had progressed after all standard treatment or were intolerant to or ineligible for standard therapies. All patients were required to have at least one measurable or nonmeasurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients enrolled in the DRC portion in part A and all patients in part B were required to have locally confirmed germline PTEN-inactivating mutations determined from a blood sample. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1 (patients aged ≥18 years) or Karnofsky performance status of ≥70% (patients aged ≥12 years and <18 years), and adequate organ function. Availability of archival tumor tissue or newly obtained core or excisional biopsy samples was mandatory.

Exclusion criteria included prior treatment with any PI3K/AKT/mTOR pathway inhibitor, unresolved clinically relevant grade ≥2 toxicity from previous anticancer therapy, unstable brain metastases, and current receipt of chronic corticosteroid therapy (prednisone ≥10 mg/day or equivalent).

Endpoints and assessments

The primary endpoints in part A were safety, tolerability, and dose-limiting toxicities (DLTs). In part B, the primary endpoint was objective response rate per RECIST v1.1 based on independent central review. Secondary endpoints in both parts included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival, PK (part A only), biomarkers (part A only), and safety (part B only).

All toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v5.0. DLTs were evaluated in cycle 1 and defined as selected laboratory abnormalities and/or adverse events (AEs; Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105932) that were considered by the investigator to be at least possibly related to the administration of study medication. In the DRC phase, the dose and schedule were confirmed if <33% of assessable patients experienced a DLT during cycle 1.

PK sampling (part A)

Blood samples for PK assessment in part A were collected before the dose and at prespecified time points after the dose (0.5, 1, 2, 3, 4, 6, and 24 h) on cycle 1 day 1 and cycle 1 day 8 (o.d. dosing only). PK parameters were calculated using noncompartmental analysis methods.

Statistical analysis

DLTs were assessed in the DLT-assessable population, which included all patients in the dose-escalation phase who either experienced a DLT during the first cycle or completed the first cycle without DLT and with ≥80% of planned study treatments administered. Safety and efficacy analyses were conducted in the full analysis set, comprising all patients who received at least one dose of study drug. The PK-assessable set included all patients who received TAS-117 and had plasma concentration data available unless significant protocol deviations may have affected the data or if key dosing information was missing.

The target sample size in part A was up to 42 patients, including a minimum of six patients who received TAS-117 at the RP2D and regimen.

Results

Patient disposition and baseline characteristics

Between 2 April 2021 and 9 May 2023, a total of 17 patients were enrolled in part A and received at least one dose of TAS-117, including 10 patients administered o.d. dosing and seven patients administered intermittent dosing of TAS-117. In the dose-escalation part, patients received TAS-117 at two dose levels for both the o.d. dosing (n = 3, 16 mg o.d.; n = 6, 20 mg o.d.) and intermittent dosing (n = 4, 24 mg; n = 3, 28 mg) regimens. In addition, one patient was treated with TAS-117 16 mg o.d. in the DRC part. Overall, two patients enrolled in part A had a germline PTEN mutation, including one patient enrolled in the DRC cohort who had a locally confirmed germline PTEN-inactivating mutation determined from a blood sample. Due to the challenges of enrolling patients with germline PTEN mutations in the DRC part, the study was closed before initiation of part B.

Baseline characteristics of the 17 patients enrolled are summarized in Table 1. The majority (82.4%) of patients were female, with a median age of 52 years (range 23-82 years). Patients enrolled had all received previous standard-of-care treatment, with a median number of five prior lines of systemic therapies (range 1-11). The most frequent cancer types for enrolled patients were breast (n = 8), colon (n = 2), and ovarian (n = 2; Table 1).

Table 1.

Baseline characteristics

	Dose escalation—o.d.			Dose escalation—intermittent			DRC	All patients (N = 17)
	16 mg (n = 3)	20 mg (n = 6)	Total (n = 9)	24 mg (n = 4)	28 mg (n = 3)	Total (n = 7)	16 mg o.d. (n = 1)
Age, median (min, max), years	61.0 (56, 82)	48 (38, 65)	56 (38, 82)	57 (49, 70)	46 (23, 62)	52 (23, 70)	43 (43, 43)	52 (23, 82)
Female, n (%)	3 (100)	6 (100)	9 (100)	1 (25.0)	3 (100)	4 (57.1)	1 (100)	14 (82.4)
Ethnicity, n (%)
Hispanic or Latino	1 (33.3)	0	1 (11.1)	0	0	0	0	1 (5.9)
Not Hispanic or Latino	2 (66.7)	2 (33.3)	4 (44.4)	2 (50.0)	1 (33.3)	3 (42.9)	1 (100)	8 (47.1)
Unknown	0	4 (66.7)	4 (44.4)	2 (50.0)	2 (66.7)	4 (57.1)	0	8 (47.1)
Race, n (%)
White	3 (100)	1 (16.7)	4 (44.4)	1 (25.0)	1 (33.3)	2 (28.6)	0	6 (35.8)
Black or African American	0	1 (16.7)	1 (11.1)	1 (25.0)	0	1 (14.3)	0	2 (11.8)
Asian	0	0	0	0	0	0	1 (100)	1 (5.9)
Unknown	0	4 (66.7)	4 (44.4)	2 (50.0)	2 (66.7)	4 (57.1)	0	8 (47.1)
ECOG PS, n (%)
0	0	3 (50.0)	3 (33.3)	1 (25.0)	2 (66.7)	3 (42.9)	0	6 (35.3)
1	3 (100)	3 (50.0)	6 (66.7)	3 (75.0)	1 (33.3)	4 (57.1)	1 (100)	11 (64.7)
Primary cancer type, n (%)
Breast	1 (33.3)	3 (50.0)	4 (44.4)	1 (25.0)	2 (66.7)	3 (42.9)	1 (100)	8 (47.1)
Colon	1 (33.3)	1 (16.7)	2 (22.2)	0	0	0	0	2 (11.8)
Ovary	0	1 (16.7)	1 (11.1)	0	1 (33.3)	1 (14.3)	0	2 (11.8)
Cervix	0	1 (16.7)	1 (11.1)	0	0	0	0	1 (5.9)
Head and neck	0	0	0	1 (25.0)	0	1 (14.3)	0	1 (5.9)
Thyroid	0	0	0	1 (25.0)	0	1 (14.3)	0	1 (5.9)
Lung	0	0	0	1 (25.0)	0	1 (14.3)	0	1 (5.9)
Other	1 (33.0)	0	1 (11.1)	0	0	0	0	1 (5.9)

DRC, dose and regimen confirmation; ECOG PS, Eastern Cooperative Oncology Group performance status; max, maximum; min, minimum; o.d., once daily.

Safety and exposure

Among assessable patients in the dose-escalation part (n = 16), three patients experienced a DLT, including one patient receiving o.d. dosing and two patients receiving intermittent dosing of TAS-117. The patient receiving o.d. dosing who experienced a DLT was in the 20-mg o.d. cohort and experienced a treatment-related grade 3 neutropenic infection that resolved within 6 days, and the TAS-117 dose was not modified. This patient with stage IV breast adenocarcinoma had previously received five lines of therapy, including chemotherapy and targeted therapy. No DLTs were observed at the 16-mg o.d. dose level.

Within the o.d. dosing regimen, the most common treatment-related AEs (TRAEs; ≥20% of patients) were rash (66.7%), fatigue (22.2%), hyperglycemia (22.2%), and diarrhea (22.2%; Table 2). TRAEs (100% versus 66.7%) and grade ≥3 TRAEs (66.7% versus 33.3%) were more common in the 20-mg o.d. dose cohort than the 16-mg dose o.d. cohort. The only TRAEs reported for patients enrolled at the 16-mg o.d. dose level were rash (grade 3) and hyperglycemia (grade 2). At the 20-mg dose level, four out of six patients experienced grade ≥3 TRAEs, including rash, fatigue, anemia, and maculopapular rash (one each). Treatment-related serious AEs (SAEs) were reported in three patients in the four o.d. dosing groups, all at the 20-mg o.d. dose level (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.105932). The median duration of treatment within the o.d. dosing regimen was 42.0 days (range 14-580 days) and median relative dose intensity was 100.0%. Overall, within the o.d. dosing regimen, AEs leading to dose interruptions and reductions were experienced by six (66.7%) and no (0%) patients, respectively, of which one was grade ≥3. Treatment was discontinued in three (50.0%) patients due to a TRAE (one grade 2 drug reaction with eosinophilia and systemic symptoms; and one grade 1 and one grade 3 rash), all in the 20-mg o.d. dose group.

Table 2.

Most common TRAEs (occurring in >2 patients overall) and corresponding grade ≥3 TRAEs in total cohorts

TRAEs, n (%)	Dose escalation—o.d.				Dose escalation—intermittent				DRC	All patients (N = 17)
	16 mg (n = 3)	20 mg (n = 6)	Total (n = 9)		24 mg (n = 4)	28 mg (n = 3)	Total (n = 7)		16 mg o.d. (n = 1)
			Any grade	Grade ≥3			Any grade	Grade ≥3		Any grade	Grade ≥3
Patients with any TRAE	2 (66.7)	6 (100)	8 (88.9)	5 (55.6)	2 (50.0)	3 (100)	5 (71.4)	3 (42.9)	0	13 (76.5)	8 (47.1)
Rash	2 (66.7)	4 (66.7)	6 (66.7)	2 (22.2)	2 (50.0)	2 (66.7)	4 (57.1)	1 (14.3)	—	10 (58.8)	3 (17.6)
Fatigue	—	2 (33.3)	2 (22.2)	1 (11.1)	2 (50.0)	2 (66.7)	4 (57.1)	—	—	6 (35.3)	1 (5.9)
Pruritus	—	1 (16.7)	1 (11.1)	—	2 (50.0)	2 (66.7)	4 (57.1)	—	—	5 (29.4)	—
Decreased appetite	—	1 (16.7)	1 (11.1)	—	—	2 (66.7)	2 (28.6)	—	—	3 (17.6)	—
Hyperglycemia	1 (33.3)	1 (16.7)	2 (22.2)	—	1 (25.0)	2 (66.7)	3 (42.9)	1 (14.3)	—	5 (29.4)	1 (5.9)
Diarrhea	—	2 (33.3)	2 (22.2)	—	—	1 (33.0)	1 (14.3)	—	—	3 (17.6)	—
Nausea	—	1 (16.7)	1 (11.1)	—	—	1 (33.0)	1 (14.3)	—	—	2 (11.8)	—
Stomatitis	—	—	—	—	—	3 (100)	3 (42.9)	2 (28.6)	—	3 (17.6)	2 (11.8)
Rash maculopapular	—	1 (16.7)	1 (11.1)	1 (11.1)	—	1 (33.3)	1 (14.3)	1 (14.3)	—	2 (11.8)	2 (11.8)

DRC, dose and regimen confirmation; o.d., once daily; TRAE, treatment-related adverse event.

Because all patients treated at the 24-mg o.d. dose level had intolerable skin toxicities in the previous Japanese study,²¹ further dose escalation was not evaluated for the o.d. regimen, and based on tolerability and rates of treatment discontinuations, the 16-mg o.d. dose level was considered the RP2D for the o.d. dosing regimen.

Within the intermittent dosing groups (4 days on/3 days off), two out of three patients at the 28-mg dose level experienced a DLT of grade 3 stomatitis. In both these patients with ductal breast carcinoma, TAS-117 was paused, and stomatitis was resolved within 6 days in one patient and 7 days in the other. There was a similar trend for dose dependency of TRAEs among the patients in the intermittent dosing groups as observed in the o.d. dosing groups. This included a numerically higher incidence of any-grade and grade ≥3 TRAEs in the 28-mg dose group compared with the 24-mg dose group (any grade, 100.0% versus 50.0%; grade ≥3, 66.7% versus 25.0%). For the two intermittent dosing groups, the most common TRAEs (≥20% of patients) were rash, fatigue, and pruritus (all 57.1%); hyperglycemia and stomatitis (both 42.9%); and decreased appetite (28.6%; Table 2). Grade ≥3 TRAEs were reported for 42.9% of patients; stomatitis was the only TRAE that occurred in more than one patient (n = 2; 28.6%; Table 2). The other grade ≥3 TRAEs were rash, hyperglycemia, and maculopapular rash. The median duration of treatment in the intermittent dosing cohort was 60.0 days (range 15-106 days) and median relative dose intensity was 59.0%. For the intermittent dosing groups, four (57.1%) and three (42.9%) patients experienced dose interruption and dose reductions due to an AE (three and three grade ≥3 AEs), respectively; dose interruptions or reductions occurred more frequently in patients at the 28-mg dose level compared with the 24-mg dose level (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.105932). Treatment was discontinued in one (14.3%) patient due to a grade 3 TRAE of skin exfoliation at the 28-mg dose level.

Based on the 3 + 3 design, dose escalation was stopped for the intermittent regimen due to DLTs in two out of three patients at the 28-mg dose level, and the MTD was determined to be 24 mg in this patient population.

Details of the most common treatment-emergent AEs (TEAEs; regardless of causality) across both dosing schedules are provided in Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.105932. No TEAEs leading to death for either dosing regimen were reported in this study.

Pharmacokinetics

TAS-117 PK parameters on cycle 1 day 1 and cycle 1 day 8 in the dose-escalation phase are summarized in Table 3. TAS-117 exposures generally increased with increasing doses within the dose range of 16-28 mg, and the maximum plasma concentration (C_max) was reached at ∼2 h after oral administration on cycle 1 day 1. Geometric mean coefficient of variation values of C_max and areas under the concentration–time curves (AUCs) ranged from 29.2% to 180.7% on cycle 1 day 1 and from 34.3% to 157.2% on cycle 1 day 8. Time to C_max on cycle 1 day 8 was similar to cycle 1 day 1 at ∼2-4 h. Following multiple o.d. dosing, twofold to threefold accumulation of C_max and AUC from time 0 to 24 h after dose (AUC_0-24) was observed. There was no formal analysis of TAS-117 pharmacodynamic markers in this study given the limited tumor samples available for analysis.

Table 3.

PK parameters of TAS-117 on cycle 1 day 1 and cycle 1 day 8 in the dose-escalation phase

Dose	N	Tmax, h	Cmax, ng/ml	AUC0-last, ng·h/ml	AUC0-24, ng·h/ml	R (Cmax)	R (AUC0-24)
Cycle 1 day 1
16 mg o.d.	2	(3.05, 20.88)	(12.8, 14.5)	(180.7, 244.3)	(180.7, 244.3)	—	—
20 mg o.d.	6	2.06 (1.15-6.42)	21.5 (29.2)	333 (34.7)	333 (34.7)	—	—
24 mg intermittent	4	2 (1.98-3.65)	23.2 (33.9)	290.5 (86)	412.8 (30.6)	—	—
28 mg intermittent	3	2 (0.92-5.65)	48.1 (35.9)	426.3 (180.7)	754.4, 961.1a	—	—
Cycle 1 day 8
16 mg o.d.	3	4.08 (2-5.5)	33.3 (34.3)	231.7 (157.2)	811.3b	1.57, 2.95	—c
20 mg o.d.	6	2.33 (1.02-5.58)	60.1 (58.8)	924 (54.5)	924 (54.5)	2.8 (31.6)	2.8 (24.3)

Values are geometric mean (CV%), except for T_max, which is shown as median (range). For PK parameters where n ≤ 2 in a dose level, the individual PK parameter value(s) are reported.

AUC_0-24, area under the plasma concentration–time curve from time 0 to 24 h; AUC_0-last, area under the plasma concentration–time curve from time 0 to the time of the last measurable plasma concentration; C_max, maximum plasma concentration; CV%, geometric mean coefficient of variation; PK, pharmacokinetics; o.d., once daily; T_max, time to reach maximum plasma concentration.

^an = 2.

^bn = 1.

^cn = 0.

Antitumor activity

None of the patients assessed [n = 15, dose escalation (all-comers)] had an objective response according to RECIST v1.1 per investigator assessment (see Figure 1). An unconfirmed partial response with ∼60% tumor reduction was reported in one patient at the 20-mg o.d. dose level, but this patient experienced disease progression at the next tumor scan. In total, seven patients had stable disease as best response (Figure 1), for a DCR of 41.2% [95% confidence interval (CI) 18.4% to 67.1%]; this included three patients receiving TAS-117 o.d. dosing (all at 20 mg) and four patients treated with intermittent dosing of TAS-117 (two patients at 24 mg and two patients at 28 mg). Duration of treatment in all patients ranged from 0.5 to 19.1 months (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.105932). The median PFS was 2.7 months (95% CI 1.3-3.5 months) across all cohorts, with no noticeable difference between patients receiving o.d. or intermittent TAS-117 dosing.

Figure 1.

Best overall response. NE, not evaluable; PD, progressive disease; o.d., once daily; SD, stable disease.

Anecdotally, a patient with a germline PTEN mutation and metaplastic breast cancer received TAS-117 20 mg o.d. for 19.1 months and was still receiving treatment as of the data cut-off, with a best overall response of stable disease. This patient has advanced breast cancer disease with thyroid and kidney metastases and has received multiple lines of prior therapy (including but not limited to, paclitaxel, carboplatin, and capecitabine). Before enrollment, the patient progressed on an advanced metastatic treatment regimen while being treated with eribulin for a short period; the patient also received other chemotherapies, including dose-dense doxorubicin-cyclophosphamide, carboplatin, paclitaxel, and capecitabine. Following study completion, the patient continues treatment with TAS-117 under single-patient investigational new drug access and is still ongoing on TAS-117 for >3 years as of the drafting this manuscript.

Discussion

This phase II study aimed to evaluate the safety, tolerability, PK, pharmacodynamics, and antitumor activity of the novel allosteric AKT inhibitor TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations. TAS-117 at the RP2D of 16 mg/kg o.d. was tolerable, with a manageable AE profile in this Western population with advanced cancer. However, due to enrollment issues, only anecdotal antitumor activity in a single patient with an inactivating germline PTEN mutation was observed before closure of this trial.

The type and nature of AEs observed for TAS-117 in this study were consistent with data published for other PI3K/AKT/mTOR pathway inhibitors, which have demonstrated a generally acceptable safety profile, and typically include on-target and off-target effects such as rash, hyperglycemia, stomatitis, diarrhea, nausea, and fatigue.^21,25,26 In particular, rash, gastrointestinal disorders, myelosuppression, and hyperglycemia reported with TAS-117 treatment during this study were similar to those reported in the TAS-117 phase I study conducted in Japan.²¹

Consistent with the Japanese phase I study,²¹ the MTD for intermittent dosing was determined to be 24 mg due to DLTs in two out of three patients enrolled at the 28-mg intermittent dose level. Overall, there was a trend toward an increase in TRAEs (including skin toxicities) and dose reductions and interruptions for patients receiving TAS-117 at the 28-mg compared with the 24-mg dose level.

For TAS-117 o.d. dosing, the current study confirmed the 16-mg o.d. dose level to be tolerable in a Western cancer patient population demonstrating a manageable safety profile, with no DLTs observed. In addition, this study evaluated an intermediate 20-mg o.d. dose level compared with the 24-mg o.d. dose in the Japanese phase I study, which was considered intolerable. The TAS-117 20-mg dose did not meet the MTD criteria (DLT ≥33%), with one DLT observed among six patients. However, because the rates of TRAEs (including grade ≥3 TRAEs and SAEs) and treatment discontinuation due to AEs were higher for the 20-mg dose compared with the 16-mg dose, TAS-117 16 mg o.d. was selected as the RP2D following data review and discussions with the investigators. In addition, the TAS-117 16-mg o.d. dose demonstrated a higher total exposure per week compared with 24-mg intermittent dosing and subsequently a higher potential for antitumor activity.

TAS-117 exposures showed dose-dependent increases on cycle 1 day 1 and cycle 1 day 8 (16-28 mg). Following multiple days of o.d. dosing, a twofold to threefold accumulation of C_max and AUC_0-24 was observed in this study, lower than the threefold to fourfold accumulation reported in the Japanese phase I study.²¹

A tentative assessment indicates that TAS-117 antitumor activity was limited in the unselected tumor population enrolled in this study at this preplanned interim analysis, with no patients having a confirmed response. Objective responses have been observed previously for TAS-117 in patients with advanced solid tumors, including 1 out of 16 (6.3%) patients with PIK3CA-mutant endometrial cancer and 3 out of 20 (15%) patients with ovarian clear cell carcinoma in the Japanese phase I study,²¹ and 1 patient with PIK3CA-mutant ovarian cancer who achieved a partial response in the phase II basket study²²; the latter study also included two patients with breast cancer harboring PIK3CA and AKT1 mutations, respectively, who achieved stable disease with a decrease in tumor burden.²² Based on the clinical observations and its mechanism of action, TAS-117 is expected to exert antitumor activity only in patients with genomic alterations associated with activation of the PI3K/AKT/mTOR signaling pathway; as a monotherapy, antitumor activity may be further restricted to certain tumor types with an oncogene addiction to the PI3K/AKT/mTOR pathway.^22,27

The intent of the current study was to focus on patients with germline PTEN-inactivating mutations. This patient population reflects a group that is both rare and has an unmet medical need, with preclinical and clinical data suggesting AKT-directed therapy as an effective approach.^16,28 Despite careful selection of study sites focused on the treatment of these patients, only one patient with a germline PTEN mutation was identified and enrolled into the DRC part of this study before its closure. However, the patient enrolled in the dose-escalation part had metaplastic breast cancer and a germline PTEN mutation and achieved a best overall response of stable disease that lasted for >3 years and was ongoing on TAS-117 treatment (treatment duration was 19.1 months at the data cut-off). She had received multiple lines of prior therapy (including, but not limited to paclitaxel, carboplatin, and capecitabine) before being enrolled in this study.

Limitations of this study include the small number of treated patients, including only two patients with a germline PTEN-inactivating mutation, being enrolled across five participating centers in three countries before the closure of the study. The trial does not include a comprehensive efficacy assessment in the target population, which limits the interpretability of the findings and renders them exploratory in nature. Notably, one patient with a germline PTEN mutation experienced a sustained period of stable disease—a finding of interest, though anecdotal. Nevertheless, given the relevance of PTEN within the PI3K/AKT/mTOR pathway, this trial represents an important step toward advancing precision medicine for rare molecular subgroups and several insights have been gained during its conduct. Recruitment of study patients with germline PTEN-inactivating mutations was challenging due to the low prevalence of this situation (estimated incidence of 1 : 200 000²⁹), logistical issues (e.g. access to a cancer center and to germline genetic testing), and patient ineligibility due to previous off-label treatment with drugs targeting the same pathway. More widespread use of next-generation genomic screening and germline genetic testing, collaboration with companies specialized in genetic screening for rare patient populations, and involvement of patient advocacy groups may help to overcome similar enrollment challenges in future studies targeting this patient population. Following review of ongoing clinical studies, and in light of the experienced enrollment challenges, the study was closed before initiation of part B. This decision was not based on safety or efficacy concerns.

In summary, this study established the RP2D of TAS-117 to be 16 mg o.d. in Western patients with advanced cancer. In this unselected patient population, TAS-117 demonstrated a tolerable and clinically manageable safety profile consistent with known AKT inhibitor class side-effects and clinical benefit was observed in one patient with germline PTEN-mutant breast cancer. If enrollment challenges could be overcome, further studies are warranted to evaluate the efficacy of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations or even earlier in the treatment course before resistance mechanisms are embedded.