A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study)

Abstract

Background: The current single-arm, open-label trial was designed to evaluate the activity of apitolisib (GDC-0980), a dual phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC).

Methods: Patients with recurrent or persistent EC who were treated with 1 to 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral apitolisib at a dose of 40 mg daily during 28-day cycles until disease progression or intolerable toxicity occurred. Patients with type I/II diabetes who required insulin were excluded. The primary endpoints were progression-free survival (PFS) at 6 months and objective response rate.

Results: A total of 56 women were enrolled, including 13 (23%) with well-controlled diabetes. Reasons for discontinuation were disease progression (24 patients; 43%), adverse events (13 patients; 23%), and withdrawal by subject (12 patients; 21%). Grade 3/4 apitolisib-related adverse events were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The PFS rate at 6 months was 20% (Kaplan-Meier estimate; 95% confidence interval [95% CI], 7%-33%). The objective response rate was 6% (confirmed). The median PFS was 3.5 months (95% CI, 2.7-3.7 months) and the median overall survival was 15.7 months (95% CI, 9.2-17.0 months). Nineteen patients discontinued the study before the first tumor assessment. Dose reductions were required for 4 diabetic (31%) and 18 nondiabetic (42%) patients. Comprehensive molecular profiling of 46 evaluable archival tumor samples demonstrated that 57% of patients had at least 1 alteration in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), or AKT1. All 3 patients with a confirmed response had at least 1 alteration in a PI3K pathway gene.

Conclusions: The antitumor activity noted with the use of a dose of 40 mg of apitolisib daily was limited by tolerability, especially in diabetic patients. Patients with PI3K pathway mutations may have derived enhanced benefit from apitolisib. Cancer 2016;122:3519-28. © 2016 American Cancer Society.

Keywords: GDC-0980; MAGGIE; apitolisib; endometrial cancer.

Figure 1

Consort diagram.

Figure 2

RECIST response and correlative biomarker data. (A) Best percent change from baseline. (B) Distribution of PI3K pathway alterations and other commonly altered genes across 46 endometrial cancer tumor samples sorted by histology. Clear cell and mixed histology tumor samples were categorized as “other.” PTEN mutations include frameshift and nonsense alterations only. PIK3CA mutations include missense alterations only.

Figure 3

Kaplan-Meier graphs for progression-free survival and overall survival.

Figure 4

Correlation of PTEN protein expression and alteration type in MAGGIE study endometrial cancer tumor samples. (A) Scatter plot of PTEN H-scores grouped by alteration type. Each point represents the H-score from a single tumor sample. The horizontal line for each group represents the mean H-score +/− the standard error. Wilcoxon rank sum test P value shown for frameshift or nonsense vs wildtype. (B) Examples of PTEN IHC staining from representative endometrial cancer samples, ranging from total absence of PTEN in the tumor compartment (H-score 0), to PTEN expression in tumor cells equivalent to surrounding normal and stromal cells (H-score 300).

Figure 4

Correlation of PTEN protein expression and alteration type in MAGGIE study endometrial cancer tumor samples. (A) Scatter plot of PTEN H-scores grouped by alteration type. Each point represents the H-score from a single tumor sample. The horizontal line for each group represents the mean H-score +/− the standard error. Wilcoxon rank sum test P value shown for frameshift or nonsense vs wildtype. (B) Examples of PTEN IHC staining from representative endometrial cancer samples, ranging from total absence of PTEN in the tumor compartment (H-score 0), to PTEN expression in tumor cells equivalent to surrounding normal and stromal cells (H-score 300).

Figure 5

Apitolisib exposure and patient response. Scatter plot showing AUC levels (ng*hr/mL) as a measure of drug exposure for (A) patients with tumors harboring a PIK3CA, PTEN, AKT1, or ERBB2 alteration, or (B) patients without these alterations. Patients are grouped according to tumor response. Partial/complete response includes 3 confirmed and 2 unconfirmed patients.