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PURPOSE Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician’s choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

6051 Background: Niraparib improves progression-free survival (PFS) in pts with newly diagnosed AOC after complete or partial response to first-line, platinum-based chemotherapy. In the PRIMA/ENGOT-OV26/GOG-3012 (PRIMA) trial, pts were treated with a fixed starting dose (FSD) of 300 mg QD until a protocol amendment introduced the individualized starting dose (ISD) regimen: 200 mg QD for pts with baseline bodyweight (BW) < 77 kg and/or platelet count (PC) < 150,000/µL, or 300 mg QD for pts with baseline BW ≥77 kg and PC ≥150,000/µL. Here, we developed a population pharmacokinetic (PopPK) model for niraparib and evaluated exposure-response relationships for pts receiving niraparib using safety and efficacy data from PRIMA. Methods: The PopPK model for niraparib was developed based on 7418 plasma samples from 1442 pts from 4 studies: PN001, NOVA, QUADRA, and PRIMA. PRIMA PK samples were collected on cycle 1, day 1 (C1D1), C2D1 pre-dose and 2 h post-dose, C4D1, and C8D1 pre-dose (or EOT if patient discontinued before C8D1). The relationship between PopPK model-based prospective exposure (average concentration [ Cave] until progression/death) and efficacy (PFS) were evaluated in pts receiving niraparib in both the homologous-recombination deficient (HRd) and overall population. The relationship between model-predicted exposure metrics and incidence of clinically relevant adverse events (AEs) was analyzed using univariate logistic regression in pts receiving niraparib. Results: Of 484 pts receiving niraparib in PRIMA, 480 had PK data and were included in the efficacy and safety analysis. The safety exposure-response showed significant associations ( p≤0.0128) between increasing niraparib exposure and increasing probability of experiencing any-grade and grade ≥3 AEs, except grade ≥3 hypertension. The incidence of AEs, including thrombocytopenia, was lower in pts who received a 200-mg ISD. Efficacy was not compromised in these pts. Conclusions: Niraparib exposure was associated with increased risk of select AEs. However, the ISD regimen decreased AE risk without compromising efficacy. Clinical trial information: NCT02655016.

5543 Background: The extent of tumor infiltrating lymphocytes (TILs) has emerged as a potential clinical useful biomarker in epithelial ovarian cancer (OC); however differences in TILs among OC histological types have not been extensively analysed. Methods: From a prospective early stage (I-II) GEICO registry of 1151 cases, 573 were sent for central pathology review. Complete analysis for classification of OC correctly identified 488 cases. Histological typing was performed according to morphological features and the expression of WT1, p53, p16, estrogen receptor (ER), progesterone receptor, and napsin A. The expression of mismatch repair (MMR) proteins MLH1, PMS2, MSH2 and MSH6 was performed in all tumors. The absolute number of stromal and intraepithelial CD8+ TILs per 0.6 mm2 TMA core was quantified and correlated with pathological features. Results: The series included 127 high-grade serous carcinomas (HGSC) (26%), 22 low-grade serous carcinomas (LGSOC) (4.5%), 165 endometrioid carcinomas (EC) (33.8%), 124 clear cell carcinomas (CCC) (2.4%), and 50 mucinous carcinomas (MC) (10.2%). The mean of intraepithelial CD8+ TILs was higher in HGSG (48.7) than in all other histological types (LGSG: 16.3; EC: 27.1; MC: 7.0; and CCC 10.3; p+TILs was also higher in HGSG (31.1) than in EC, MC and CCC (15.8, 8.0 and 12.7, respectively; p+ TILs was significantly higher in RE-positive (71.9) than in RE-negative (34.8) HGSC ( p=0.002). In the complete series, 33 (6.6%) OCs showed absent expression of at least 1 MMR protein, and the mean of intraepithelial CD8+ TILs was significantly higher in these OCs (57.0) than in those with preserved expression of all MMR proteins (23.6; p=0.0035). MMR protein deficiency was observed in 27 (16%) ECs, and these tumours had significantly higher mean of both intraepithelial (60.4 vs. 20.7 p=0.003) and stromal CD8+ TILs (26.6 vs. 13.8, p= 0.046). No significant differences in TILs were observed among EC of different histological grades. Conclusions: The extent of CD8+TILs significantly correlates with the histological type and MMR status in OCs, being HGSCs and EC with MMR deficiency those OCs with higher CD8+TILs.

5554 Background: Early stage ovarian cancer (ESOC) represents 10-15% of all Ovarian Cancer (OC) cases and most frequent ESOC substage (IC) has undergone major changes in FIGO 2014 staging. Methods:...

5582 Background: Early stage ovarian cancer (ESOC) represents 10-15% of all Ovarian Cancer (OC) cases and the reported experience is limited. Methods: A centralized prospective register of ESOC (I-...

e15590 Background: To evaluate the safety and efficacy of bevacizumab (BEV) alone or combined with chemotherapy (CT) in a compassive use program sponsored by the Spanish Ovarian Cancer Research Gro...

5101 Background: Preclinical and clinical evidence suggests that a prolonged infusion may be more effective than the standard 30-minute infusion of gemcitabine. To investigate the activity and toxi...