Randomized phase II study of sapanisertib (SAP) + paclitaxel (PAC) versus PAC alone in patients (pts) with advanced, recurrent, or persistent endometrial cancer.
6087 Background: SAP (TAK-228, MLN0128) is a selective dual inhibitor of mammalian target of rapamycin complexes 1 and 2. In endometrial tumor xenograft models, SAP+PAC exhibited stronger antitumor efficacy than PAC alone. Methods: Female pts with histologic/cytologic diagnosis of endometrial cancer were randomized to receive SAP 4 mg by mouth (days [d] 2–4, 9–11, 16–18, 23–25) plus PAC 80 mg/m2 intravenously (d 1, 8, 15), or PAC alone, in 28-day cycles until unacceptable toxicity or disease progression. Randomization was stratified by histologic subtype, lines of prior chemotherapy (1 vs. 2), and prior taxane therapy. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; ORR + stable disease), and safety. Additional treatment arms of SAP alone (weekly dosing) and SAP+TAK-117 were closed after futility analyses. Results: 180 pts were randomized to SAP+PAC (n=90) or PAC (n=90); 86 and 87 pts received SAP+PAC and PAC, respectively; 3 pts from each arm were ongoing on treatment at data cut (30 July 2019). Baseline characteristics were balanced between arms. After a median follow-up of 17.2 vs. 14.4 mos with SAP+PAC vs. PAC, median PFS was 5.6 mos vs. 3.7 mos (hazard ratio [HR] 0.82; 95% CI 0.58–1.15). In pts with endometrioid histology (n=116), median PFS was 5.7 mos with SAP+PAC vs 3.3 mos with PAC (HR 0.66; 95% CI 0.43–1.03). In pts with nonendometrioid histology (n=64), median PFS was 3.6 mos with SAP+PAC vs. 5.4 mos with PAC (HR 1.09; 95% CI 0.62–1.90). Median OS was 13.7 mos with SAP+PAC vs. 14.6 mos with PAC (HR 1.01; 95% CI 0.67–1.53). Confirmed ORR was 24% with SAP+PAC vs. 18% with PAC (endometrioid, 23% vs. 16%; nonendometrioid, 28% vs. 22%); CBR was 80% vs. 58% (endometrioid, 84% vs. 55%; nonendometrioid, 72% vs. 63%). Median number of cycles received was 5 (range 1–23) with SAP+PAC and 4 (range 1–37) with PAC. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) were 90% with SAP+PAC vs. 54% with PAC; the most common included anemia (21% vs.12%), neutropenia (12% vs. 3%), fatigue (12% vs. 5%), hypophosphatemia (12% vs. 1%), and pulmonary embolism (11% vs. 3%). Conclusions: Median PFS was longer with SAP+PAC vs. PAC in pts with endometrial cancer but did not reach statistical significance. PFS was particularly longer in the endometrioid subtype but again was not significant, and further studies are warranted. Incidence of grade ≥3 TEAEs was higher with SAP+PAC vs. PAC, but SAP+PAC toxicity was manageable, with no new safety signals. Clinical trial information: NCT02725268.