Patients
Between November 21, 2017 and June 27, 2019, 13 patients with advanced solid tumors harboring PI3K/Akt gene aberrations were screened and enrolled. The baseline characteristics are listed in Table 1. The median age was 53 years (range, 34–71), and 12 patients (92%) were female. The ECOG performance status was 0 for eight patients (62%).
Table 1
Baseline characteristics of patients
Median age (range)
|
53 (34–71)
|
Sex
|
|
Female
|
12 (92%)
|
Male
|
1 (8%)
|
ECOG*
|
|
0
|
8 (62%)
|
1
|
5 (39%)
|
Cancer
|
|
Breast cancer
|
4 (31%)
|
Ovarian cancer
|
2 (15%)
|
Endometrial cancer
|
1 (8%)
|
Colon cancer
|
2 (15%)
|
Rectal cancer
|
1 (8%)
|
Gastric cancer
|
1 (8%)
|
Gallbladder cancer
|
1 (8%)
|
NSCLC
|
1 (8%)
|
Line of treatment for TAS-117
|
|
2
|
1 (8%)
|
3
|
2 (15%)
|
4
|
6 (46%)
|
5
|
2 (15%)
|
6
|
1 (8%)
|
9
|
1 (8%)
|
Royal Marsden Score
|
|
0
|
1 (8%)
|
1
|
5 (38%)
|
2
|
6 (46%)
|
3
|
1 (8%)
|
GRIm-Score
|
|
0
|
6 (46%)
|
1
|
5 (38%)
|
2
|
1 (8%)
|
3
|
1 (8%)
|
Number of metastatic organs
|
|
1
|
1 (8%)
|
2
|
6 (46%)
|
3
|
4 (31%)
|
5
|
2 (15%)
|
Abbreviations: ECOG, Eastern Cooperative Oncology Group; GRIm-Score, Gustave Roussy Immune Score |
*An ECOG performance status score 0 means that the patient is fully active, and 1 means that the patient is restricted in physically strenuous activity but ambulatory. |
Eight patients from non-GI cancers were enrolled, including breast (n = 4, 31%), ovarian (n = 2, 15%), endometrial (n = 1, 8%), and non-small cell lung cancer (NSCLC; n = 1, 8%). In addition, five patients with GI cancers, including colon (n = 2, 15%), rectal (n = 1, 8%), gastric (n = 1, 8%), and gallbladder cancer (n = 1, 8%), were enrolled. With the exception of three patients who received TAS-117 as second- or third-line treatment, most of the patients (n = 10, 77%) treated with TAS-117 had already received more than three lines of treatment. In addition, 46% (n = 6) and 84% (n = 11) of patients had Royal Marsden Scores (RMS) and Gustave Roussy Immune Scores (GRIm-Scores) of 0 and 1, respectively. Most patients had two or more metastatic organs (n = 12, 92%). Twelve patients showed mutations in PIK3CA: E542K (n = 2, 15%), E545A (n = 1, 8%), E545K (n = 4, 31%), H1047R (n = 4, 31%), and Q546K (n = 1, 8%), and one patient harbored Akt1E17K mutations (Supplementary Table S1).
Antitumor Activity
At the end of the data collection period on February 19, 2020, the median follow-up duration was 6.6 months (range, 1–18.1 months). The median duration of treatment was 1.4 months (range, 0.4–3.2 months), and the median number of treatment cycles was 2 (range, 1–5; Supplementary Table S2). Of the 13 patients, none showed a complete response, one patient with ovarian cancer showed a confirmed partial response, and two patients with breast cancer had stable disease (Fig. 1, Supplementary Table S3). Eleven patients were assessed via radiology, but two patients did not have radiological assessments because of rapid clinical deterioration.
The ORR and DCR of TAS-117 were 8% (n = 1) and 23% (n = 3), respectively (Table 2). All responses were achieved in patients with non-GI tumors and the median time to response was 6 weeks (Fig. 2A). One patient with metastatic ovarian cancer harboring PI3Kα E545K mutations showed a 39% tumor reduction at 6 weeks (data not shown). However, this decrease in tumor burden was not maintained over subsequent assessments, and the patient showed progression in non-target lesions and an increase in tumor markers at 12 and 18 weeks (Fig. 2B). The two patients with breast cancer who achieved stable disease condition (n = 2, 15%) and harbored Akt1E17K and PI3Kα H1047R mutations showed disease progression at 12 weeks, associated with an increase in non-target lesions (Figs. 2 and 3). Other patients with breast cancer (n = 2, 15%), ovarian cancer (n = 1, 8%), GI cancer (n = 5, 38%), and NSCLC (n = 1, 8%) showed progression at the first response evaluation, as depicted in both the spider and swimmer plot (Figs. 2 and 3, respectively). In eight patients expressing tumor markers, there was an increase in the percentage of tumor markers at 6 weeks in six patients, which did not correlate with radiological responses (Fig. 2B). A summary of the best responses according to PI3K/Akt aberrations is shown in Supplementary Table S4.
Table 2
Summary of best response to TAS-117
CR
|
0 (0%)
|
PR
|
1 (8%)
|
SD
|
2 (15%)
|
PD
|
10 (77%)
|
Overall response rate (CR + PR)
|
1 (8%)
|
Disease control rate (CR + PR + SD)
|
3 (23%)
|
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease
The median PFS was 1.4 months (95% CI: 1.2–1.6 months) for TAS-117 treatment (Fig. 4A, Supplementary Figure S1). PFS values prior to (PFS 1) and after (PFS 3) TAS-117 treatment were 2.6 (95% CI: 1.7–3.5 months) and 1.2 months (95% CI: 0–4.7 months), respectively. PFS2/1 ratio > 1.3 and PFS3/2 ratio > 1.3 were both 0%, and PFS2/1 ≥ 1.2 ratio and PFS3/2 ≥ 1.2 ratio were 8% and 23%, respectively[17]. The median OS was 4.8 months (95% CI: 2.6–11.2 months; Fig. 4B). A univariate analysis of treatment line (< 4 vs ≥ 4), RMS (0 or 1 vs ≥ 2), GRIm-Score (0 or 1 vs ≥ 2), and number of metastatic lesions (< 2 vs ≥ 2) showed that there was no statistical significance in either PFS or OS (Supplementary Table S5).
Nine patients had disease progression, two experienced adverse events, one withdrew from the study, and one discontinued treatment owing to the physician’s decision. Of the 11 evaluable patients, most showed progression in previous target lesions (n = 9, 69%), such as the lungs (n = 6, 55%), peritoneal carcinomatosis (n = 5, 46%), and liver (n = 4, 36%; Supplementary Table S6). One patient developed a new site of metastasis in the liver (n = 1), and one patient developed new lesions in both the common bile duct and pancreas. The two patients without radiological assessments also showed clinical progression. A one-way analysis of variance (ANOVA) showed no statistical difference in progression between organs (p = 0.076; Supplementary Figure S2).
At progression, six patients (46%) received subsequent treatment, including cytotoxic chemotherapy (n = 3, 23%), immunotherapy (n = 2, 15%), and targeted agents (n = 1, 8%; Supplementary Table S2). At the time of analysis, 11 patients had died, one patient was receiving best supportive care, and one patient was receiving subsequent chemotherapy (Fig. 3).
Co-existing Mutations
Co-existing mutations
In this study, patients with PI3K/Akt aberrations also harbored diverse co-existing mutations (n = 22; Supplementary Fig. 3). The most common mutations identified were tumor protein 53 (TP53) mutations (n = 7), including missense mutations (n = 5), frameshift deletion (n = 1), and frameshift insertion (n = 1). There were no statistically significant correlations with regard to the site of biopsy (primary vs metastatic), biopsy time period (initial cancer diagnosis vs prior to TAS-117 treatment), response evaluation according RECIST criteria (PR, SD, or PD), or tumor type (Supplementary Fig. 4).
Safety
AEs were evaluated in all 13 patients (Supplementary Table S7). Treatment-related AEs are listed in Table 3. Overall, 11 patients (85%) experienced ≥ 1 treatment-related AE, including hyperglycemia (all grades, n = 4, 36%), skin rash (all grades, n = 4, 36%), anorexia (all grades, n = 4, 36%), nausea (all grades, n = 2, 15%), and diarrhea (all grades, n = 2, 15%). Notably, two patients (15%) experienced grade 3 (n = 1, 8%) and grade 4 hyperglycemia (n = 1, 8%; Supplementary Table S8). Patients who were scheduled to receive dose reductions progressed radiologically and discontinued treatment. One patient experienced grade 3 anorexia (n = 1, 8%), which was well managed with supportive care. The median dose intensity for TAS-117 was 100% for both cohorts 1 and 2 (Supplementary Table S2, Figure S5). No patient death occurred as a result of treatment-related AEs.
Table 3
Incidence of treatment-related adverse events
Treatment-related adverse events
|
Grade 1
|
Grade 2
|
Grade 3
|
Grade 4
|
All grades
|
Any event
|
7 (54%)
|
17 (100%)
|
2 (15%)
|
1 (8%)
|
27 (100%)
|
Anorexia
|
1 (8%)
|
2 (15%)
|
1 (8%)
|
0 (0%)
|
4 (36%)
|
Constipation
|
0 (%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Diarrhea
|
1 (8%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
2 (15%)
|
Nausea
|
1 (8%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
2 (15%)
|
Mucositis
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Skin rash
|
2 (15%)
|
2 (15%)
|
0 (0%)
|
0 (0%)
|
4 (36%)
|
Itching
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Fatigue
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Headache
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Back pain
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Shoulder pain
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Dyspnea
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Pneumonia
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Pulmonary thromboembolism
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
Hyperglycemia
|
1 (8%)
|
1 (8%)
|
1 (8%)
|
1 (8%)
|
4 (36%)
|
Neutropenia
|
0 (0%)
|
1 (8%)
|
0 (0%)
|
0 (0%)
|
1 (8%)
|
NOTE. Adverse events were those with onset after enrolment to last follow-up after disease progression. |
Some of the percentages are rounded up or down and may not equal in sums.