Abstract
PurposeNRG Oncology conducted a phase II trial to assess the antitumor activity and tolerability of copanlisib, a selective inhibitor of PIK3CA, in persistent or recurrent endometrial carcinoma harboring hotspot PIK3CA mutations. Patients and methodsEligible patients had endometrial cancer with endometrioid, serous or mixed histology, a somatic PIK3CA gene mutation, measurable disease, and GOG performance status ≤2. Treatment consisted of IV copanlisib (60 mg weekly, day 1, 8 and 15 of 28-day cycle) until disease progression or prohibitive toxicity. The primary endpoints of the study were objective tumor response as assessed by RECIST 1.1 and to determine the nature and degree of toxicity of copanlisib as assessed by CTCAE version 4. The study used a 2-stage group sequential design. ResultsEleven patients were enrolled onto stage I of the treatment trial. Five patients had endometrioid, four serous and two had a tumor of mixed histology. The most common PIK3CA mutation was Q546X (n = 3) in exon 9. The most common grade 3 or 4 AE was hyperglycemia. No grade 5 adverse events were reported. No clinical responses were detected. Six patients had a best overall response of stable disease. Of 11 who initiated treatment, 10 progressed on treatment. One patient with stable disease on copanlisib withdrew from treatment secondary to relocation. The median progression-free survival (PFS) was 2.8 months; at 6 months 27% were alive, progression-free. The median overall survival (OS) was 15.2 months. Due to the lack of CR/PR continuation of accrual to the second stage of accrual was not warranted. ConclusionCopanlisib is well tolerated but has limited activity as a single agent in this population.
Highlights
Endometrial cancer (EC) is the most common gynecologic malignancy with 63,230 new cases and 11,350 estimated deaths related to the disease in the United States in 2018 (Siegel et al, 2018)
Screening for PIK3CA mutations by the cobas® PIK3CA mutation test performed by Q2 Solutions was initiated on January 23, 2017
Ten patients enrolled with a performance status of no worse than 1
Summary
Endometrial cancer (EC) is the most common gynecologic malignancy with 63,230 new cases and 11,350 estimated deaths related to the disease in the United States in 2018 (Siegel et al, 2018). Type I endometrial cancer accounts for 65–70% of cases and is associated with grade 1–2 endometrioid histology, younger age of onset, retention of estrogen receptor (ER) and progesterone receptor (PR) status, a history of unopposed estrogen, and deletions in k-Ras, PTEN, or mismatch repair mechanisms (Bokhman, 1983; Matthews et al, 1997). Type II endometrial cancer is associated with serous, clear cell or grade 3 endometrioid histology, loss of ER/PR, black race, absence of unopposed estrogen, presentation at later stage, reduced E-cadherin expression, aneuploidy, mutations in p53 and HER2/Neu overexpression (Bokhman, 1983; Matthews et al, 1997; Kandoth et al, 2013; Zhao et al, 2013). The genetic aberrations of endometrial carcinomas may represent a novel tool to classify these tumors and guide adjuvant treatment in women with recurrent chemotherapy-resistant disease
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