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 This single arm, open-label trial was designed to evaluate the activity of apitolisib (GDC-0980), a dual PI3K/mTOR inhibitor, in patients with advanced endometrial cancer (EC). METHODS Patients with recurrent or persistent EC treated with 1–2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral apitolisib 40 mg daily during 28-day cycles until progression or intolerable toxicity. Type I/II diabetic patients requiring insulin were excluded. The primary endpoints were progression-free survival (PFS) at 6 months and objective response rate (ORR). RESULTS A total of 56 women were enrolled including 13 (23%) with well-controlled diabetes. Discontinuation reasons were disease progression (24, 43%), adverse events (13, 23%), and withdrawal by subject (12, 21%). Grade 3/4 apitolisib-related adverse events were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%). PFS at 6 months was 20% (KM estimate 95% CI: 7%–33%). ORR was 6% (confirmed). Median PFS was 3.5 months (95% CI: 2.7–3.7 months); median OS was 15.7 months (95% CI: 9.2–17.0 months). Nineteen patients discontinued prior to first tumor assessment. Dose reductions were required for 4 (31%) diabetic and 18 (42%) non-diabetic patients. Comprehensive molecular profiling of 46 evaluable archival tumor samples showed 57% of patients had at least one alteration in PIK3CA, PTEN, or AKT1. All three patients with a confirmed response had at least one alteration in a PI3K pathway gene. CONCLUSION Anti-tumor activity of 40 mg apitolisib daily was limited by tolerability, especially in diabetic patients. Patients with PI3K pathway mutation may have derived enhanced benefit from apitolisib.

Integrated Molecular Characterization of Uterine Carcinosarcoma

“…A current clinical trial (NCT02059265) is testing the multi-target tyrosine kinase inhibitor dasatinib in clear cell ovarian and endometrial carcinomas with ARID1A loss (Miller et al, 2016). PI3K inhibition has been successful in advanced endometrial cancers with responses seen in patients with pathway alterations despite some limitations due to tolerability (Makker et al, 2016). …”

Phase II, 2‐stage, 2‐arm, PIK3CA mutation stratified trial of MK‐2206 in recurrent endometrial cancer

“…Overall, there appears to be a higher level of toxicity among patients with endometrial cancer compared to other solid tumors. This finding has been observed in other studies in recurrent endometrial cancer, where previously identified recommended Phase II doses had to be reduced due to patient tolerance . To date, the etiology of the increased toxicity has not been elucidated.…”

Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

“…Specifically, a recent phase 2 study of BKM‐120, a pan‐class 1 PI3K inhibitor, in advanced endometrial cancer showed an ORR of 0% and excessive toxicity that necessitated a recruitment hold and dose reduction; 21% of patients discontinued BKM120 for toxicity . Similarly, studies of apitolisib (a dual PI3K/mTOR inhibitor) and pilaralisib (a pan‐class 1 PI3K inhibitor) in advanced endometrial cancer both failed to meet their primary efficacy endpoints (6% ORR in both studies) . Although neither of these studies required PI3K pathway alteration for enrollment, it is noteworthy that all responders in the apitolisib study (n = 3) and all responders in the pilaralisib study (n = 4) harbored at least 1 PI3K pathway‐activating alteration.…”

“…Cancer March 15, 2020 inhibitor) in advanced endometrial cancer both failed to meet their primary efficacy endpoints (6% ORR in both studies). 12,13 Although neither of these studies required PI3K pathway alteration for enrollment, it is noteworthy that all responders in the apitolisib study (n = 3) and all responders in the pilaralisib study (n = 4) harbored at least 1 PI3K pathway-activating alteration. Similar to our findings, the responding patients in these studies harbored mixed cell type or serous histology.…”

“…Cancer March 15, 2020 Clinical experience with various PI3K pathway inhibitors in endometrial cancer, including pan-class 1 inhibitors and dual PI3K/mTOR inhibitors, have resulted in overall response rates (ORRs) ranging from 0% to 6% and medication discontinuation secondary to side effects. [11][12][13] AKT and mTOR inhibitors have also led to modest results, and trials with these agents have had limited retrospective biomarker analysis and/or no prospective biomarker selection strategies. 14,15 It is noteworthy that the specific pattern of PI3K pathway activation in endometrial cancer presents a unique drug development challenge.…”