Treatment with TAS-117, a highly potent and selective oral allosteric pan-v-akt murine thymoma viral oncogene homolog inhibitor, demonstrated some clinical efficacy in patients with ovarian cancer harboring PIK3CA E545K mutations and in those with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.
Treatment with TAS-117, a highly potent and selective oral allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor, demonstrated some clinical efficacy in patients with ovarian cancer harboring PIK3CA E545K mutations and in those with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.
Findings from the single-center, phase 2 K-BASKET trial (NCT03017521) conducted at Yonsei Cancer Center in Seoul, South Korea, were presented in a poster during the 2021 AACR Annual Meeting. These data were also published online in Investigational New Drugs in March 2021.1,2
“TAS-117 had limited antitumor activity and a manageable safety profile,” said lead author Jii Bum Lee, MD, a physician in the Division of Medical Oncology at Yonsei Cancer Center.
She added that combination treatments with chemotherapy, targeted therapy, and immunotherapy may overcome de novo resistance to TAS-117.
Lee and her colleagues enrolled 13 patients with advanced solid tumors harboring PI3K/Akt gene aberrations from November 2017 to June 2019. Four (31%) patients had breast cancer, 2 (15%) had ovarian, and 1 each had endometrial (8%) or non‒small-cell lung cancer. Five other patients had gastrointestinal (GI) cancers, including colon (n = 2, 15 %), rectal (n = 1, 8 %), gastric (n = 1, 8 %), and gallbladder cancer (n = 1, 8 %).
The 5 patients with GI cancers were assigned to 16 mg daily TAS-117. The remaining patients were assigned to 24 mg TAS-117 for 4 days followed by a 3-day rest. The study was conducted over 21-day treatment cycles.
Twelve patients (92%) had 2 or more metastatic organs. Twelve harbored PIK3CA mutations while 1 harbored Akt1E17K mutations.
“Most of the patients were heavily treated,” Lee said. “Ten patients were treated during fourth or subsequent treatment.”
The median duration of follow-up was 6.6 months (range, 1.0-18.1 months) and the median duration of treatment was 1.4 months (range, 0.4-3.2 months). Patients received a median of 2 treatment cycles (range, 1-5).
There were no complete responses at the February 19, 2020, data cutoff. At the time of data cutoff, 9 patients had disease progression, 2 experienced adverse events, 1 withdrew, and 1 patient discontinued treatment due to physician’s decision.
One patient with ovarian cancer showed a confirmed partial response for an overall response rate of 8%. Two patients with breast cancer had stable disease, for a disease control rate (DCR) of 23%.
The median progression-free survival was 1.4 months (95% CI, 1.2-1.6) and the median overall survival was 4.8 months (95% CI, 2.6-11.2).
Overall, 85% of patients experienced treatment-related adverse events. Three (27%) experienced 3/4 events—1 grade 3 anorexia, 1 grade 3 hyperglycemia, and 1 grade 4 hyperglycemia.
In previous studies, investigators found that TAS-117 inhibits the proliferation of human cancer cell lines in vitro including breast, endometrial, lung, and ovarian cancer cells. Tumor cell lines with Akt2 and HER2 gene amplification, PI3K mutations, and PTEN loss were also found to be sensitive to TAS-117.3 In a phase 1 study of patients with advanced solid tumors, TAS-117 induced a DCR of 61.5% in 13 patients with PIK3CA-mutated endometrial cancer, 80.0% in 5 patients with AKT-altered endometrial cancer, and 37.5% in 16 patients with ovarian clear cell carcinoma.4