Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I–type II study from the GINECO group

Abstract

Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma.Methods:This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety.Results:A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8–6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ⩾3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity.Conclusions:The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.

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

“…Despite the overall disappointing results, the CBR of 24% achieved in this study compares somewhat favorably to recent studies of the other PI3K pathway inhibitors in endometrial cancer. 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) .…”

“…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. 11 Similarly, studies of apitolisib (a dual PI3K/ mTOR inhibitor) and pilaralisib (a pan-class 1 PI3K…”

“…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.…”

Liposomal Curcumin Targeting Endometrial Cancer Through the NF-κB Pathway

“…A more serious problem for clinicians is that either commonly used first-line, or emerging chemotherapeutic drugs cause severe side effects and toxicity [21], which largely limits their clinical use and efficiency. To find safer therapeutic drugs for EC, especially for long-term use, researchers have recently turned to natural anti-tumor drugs containing active plant ingredients.…”

Evaluation of toxicities related to novel therapy in clinical trials for women with gynecologic cancer

“…An example would be the phase 2 study investigating BKM120, a PI3K inhibitor, for endometrial cancer, which was prematurely discontinued because of an unfavorable toxicity profile observed in this specific population. 6 Although BKM120 was established as tolerable with an acceptable safety profile at the estimated maximal tolerated dose of 100 mg/d, 7,8 the same dose resulted in toxicities for women with recurrent endometrial cancer that were not reported in the initial phase 1 trial. Depending on the primary tumor sites and even histological subtypes, the safety profile of BKM120 was found to vary significantly.…”