IntroductionOregovomab, a murine IgGκ1 MAb, binds to the circulating tumor associated antigen CA125, resulting in development of immunogenic complexes with CA125, which are subsequently processed by dendritic cells and macrophages leading to downstream CA125-specific antitumor activity by T and B lymphocytes. In a randomized Phase 2 study in previously untreated EOC patients, immunization with oregovomab with paclitaxel and carboplatin (PC) demonstrated significant improvement in mPFS (months) 41.8 for PCO and 12.2 for PC (p = 0.0027, HR 0.46) and mOS has not yet been reached (NE) for PCO and was 43.2 months for PC (p = 0.043, HR 0.35).MethodsThis Phase 3, double-blind, placebo-controlled, multicenter trial, has enrolled patients from 14 countries. Patients with optimally debulked with FIGO III/IV EOC and serum CA125 ≥ 50 U/ml receiving adjuvant (Cohort 1) or neoadjuvant (Cohort 2) chemotherapy were randomized post-surgery to PCO or PCP. Patients with germline BRCA1/2 mutations were excluded. Chemotherapy will be administered every 3 weeks in both cohorts. In cohort 1, oregovomab/placebo is administered simultaneously at cycles 1, 3, and 5 of chemotherapy with an additional dose at 12 weeks following cycle 5. In cohort 2, oregovomab/placebo is administered post interval debulking surgery at cycles 4 and 6 with an additional dose at 6- and 18-weeks following cycle 6. The primary objective is PFS determined by RECIST 1.1 criteria.Current Trial StatusAt the time of abstract submission, 618 patients were enrolled and target enrolment Cohort 1 (378) and Cohort 2 (240) was achieved.

IntroductionDostarlimab+carboplatin-paclitaxel demonstrated PFS and OS benefits vs carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (pA/rEC). Here, we report on the management of immune-related adverse events (irAEs) in the RUBY (NCT03981796) trial.MethodsPatients with pA/rEC were randomized 1:1 to dostarlimab 500 mg, or placebo, plus carboplatin AUC 5 and paclitaxel 175 mg/m2 Q3W for 6 cycles, followed by dostarlimab 1000 mg, or placebo, Q6W for up to 3 years. AEs were assessed according to CTCAE v4.03. irAEs were defined as CTCAE grade ≥2 from a predefined list.ResultsThe safety population included 487 patients who received ≥1 dose of treatment (241 dostarlimab+carboplatin-paclitaxel; 246 placebo+carboplatin-paclitaxel). irAEs related to dostarlimab or placebo were reported by 38.2% in the dostarlimab+carboplatin-paclitaxel arm and 15.4% in the placebo+carboplatin-paclitaxel arm; grade ≥3 irAEs related to dostarlimab or placebo were reported by 12.4% and 3.3%, respectively (table 1). Only 7.9% and 3.7% of patients discontinued dostarlimab or placebo because of an irAE, respectively; there were no irAE-related deaths. Of those experiencing irAEs in the dostarlimab+carboplatin-paclitaxel arm, 63.5% were treated with steroids, immunosuppressants, and/or thyroid therapy; 73.6% resolved (median resolution 10.0 days). Of the 36.5% patients not receiving steroids, immunosuppressants, and/or thyroid therapy, 80.0% resolved (median resolution 8.0 days). Management and resolution frequency were similar in the placebo+carboplatin-paclitaxel arm (table 1).Conclusion/ImplicationsIn the RUBY trial, most irAEs were mild and resolved. Few patients discontinued dostarlimab because of irAEs. The irAE profile observed in the dostarlimab+carboplatin-paclitaxel arm showed similar trends as that observed with dostarlimab monotherapy. PR038/#248 Table 1

Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

Ovarian cancer (OvCa) has a dismal prognosis because of its late-stage diagnosis and the emergence of chemoresistance. Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase known to regulate cancer cell “stemness”, epithelial-mesenchymal transition (EMT), and drug resistance. Here we show that DCLK1 is a druggable target that promotes chemoresistance and tumor progression of high-grade serous OvCa (HGSOC). Importantly, high DCLK1 expression significantly correlates with poor overall and progression-free survival in OvCa patients treated with platinum chemotherapy. DCLK1 expression was elevated in a subset of HGSOC cell lines in adherent (2D) and spheroid (3D) cultures, and the expression was further increased in cisplatin-resistant (CPR) spheroids relative to their sensitive controls. Using cisplatin-sensitive and resistant isogenic cell lines, pharmacologic inhibition (DCLK1-IN-1), and genetic manipulation, we demonstrate that DCLK1 inhibition was effective at re-sensitizing cells to cisplatin, reducing cell proliferation, migration, and invasion. Using kinase domain mutants, we demonstrate that DCLK1 kinase activity is critical for mediating CPR. The combination of cisplatin and DCLK1-IN-1 showed a synergistic cytotoxic effect against OvCa cells in 3D conditions. Targeted gene expression profiling revealed that DCLK1 inhibition in CPR OvCa spheroids significantly reduced TGFβ signaling, and EMT. We show in vivo efficacy of combined DCLK1 inhibition and cisplatin in significantly reducing tumor metastases. Our study shows that DCLK1 is a relevant target in OvCa and combined targeting of DCLK1 in combination with existing chemotherapy could be a novel therapeutic approach to overcome resistance and prevent OvCa recurrence.

5503 Background: RUBY (NCT03981796) evaluated the efficacy and safety of the anti–programmed death 1 (PD-1) dostarlimab + standard of care (SOC) carboplatin paclitaxel (CP) versus CP alone in A/R EC. The primary endpoint of PFS by investigator assessment (INV) per RECIST v1.1 was significantly longer with dostarlimab+CP than placebo (PBO)+CP in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H; HR 0.28; 95% CI 0.162–0.495) and overall populations (HR 0.64, 95% CI 0.507–0.800). Here we present secondary efficacy endpoints by BICR. Methods: RUBY is a phase 3, global, randomized, double-blind, multicenter, PBO-controlled study. Patients (pts) with primary advanced stage III or IV or first recurrent EC were randomized 1:1 to receive dostarlimab 500 mg, or PBO, plus carboplatin AUC 5 and paclitaxel 175 mg/m2 Q3W (6 cycles), followed by dostarlimab 1000 mg, or PBO, monotherapy Q6W for up to 3 y. Secondary endpoints by BICR assessment per RECIST v1.1 were PFS, ORR, DOR, and DCR in the overall and dMMR/MSI-H populations. Results: 494 pts were randomized (245:dostarlimab+CP; 249:PBO+CP); 47.8% had recurrent disease, 18.6% and 33.6% had primary stage III and IV disease, respectively. PFS by BICR was longer with dostarlimab+CP than PBO+CP in the dMMR/MSI-H (HR 0.29; 95% CI 0.158–0.543) and overall populations (HR 0.66; 95% CI 0.517–0.853; Table). Consistent benefits were seen with dostarlimab+CP for ORR, DCR, and DOR by BICR in the dMMR/MSI-H and overall populations (Table). Safety was previously reported. Conclusions: Dostarlimab+CP showed clinically meaningful improvement in BICR-assessed PFS in the dMMR/MSI-H and overall populations compared with CP alone. The HRs for PFS per BICR and per INV were consistent, which supports the reliability of PFS by INV in EC trials. Benefits were seen in all BICR-assessed endpoints, which were consistent with INV. Dostarlimab+CP represents a new SOC for pts with primary A/R EC. Clinical trial information: NCT03981796 . [Table: see text]

BackgroundDostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer.MethodsWe conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration–time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed.ResultsOf the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair–deficient (dMMR), microsatellite instability–high (MSI-H) tumors. In the dMMR–MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group.ConclusionsDostarlimab plus carboplatin–paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR–MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.)

ObjectiveDetection of lymph node metastases in cervical cancer patients is important for guiding treatment decisions, however accuracies of current detection methods are limited. We evaluated associations of abnormal glycosylation, represented by Tn and STn antigens on mucin (MUC) proteins, in primary tumor specimens with lymph node metastasis or recurrence of cervical cancer patients. MethodsSurgical specimens were prospectively collected from 139 patients with locally-advanced cervical cancer undergoing lymphadenectomy enrolled in a nation-wide clinical trial (NCT00460356). Of these patients, 133 had primary cervix tumor, 67 had pelvic lymph node (PLN) and 28 had para-aortic lymph node (PALN) specimens. Fixed tissue serial sections were immunohistochemically stained for Tn, STn, MUC1 or MUC4. Neuraminidase was used to validate Tn versus STn antibody specificity. Stain scores were compared with clinical characteristics. ResultsPrimary tumor STn expression above the median was associated with negative PLN status (p-value: 0.0387; odds ratio 0.439, 95% CI: 0.206 to 0.935). PLN had higher STn compared to primary tumor, while primary tumor had higher MUC1 compared to PALN, and MUC4 compared to PALN or PLN (p = 0.017, p = 0.011, p = 0.016 and p < 0.001, respectively). Tn and STn expression correlated in primary tumor, PALN, and PLN, Tn and MUC1 expression correlated in primary tumors only (Spearman correlation coefficient [r] = 0.301, r = 0.686, r = 0.603 and r = 0.249, respectively). ConclusionsSTn antigen expression in primary cervical tumors is a candidate biomarker for guiding treatment decisions and for mechanistic involvement in PLN metastases.

ObjectiveThe Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) is a national study of a combined diet and physical activity intervention for stage II-IV ovarian cancer survival, an under-represented cancer in lifestyle behavioral intervention research. Here, we present the data on recruitment, retention, and baseline demographic, clinical and lifestyle behavior characteristics of the LIVES study participants. MethodsThe LIVES study (NRG Oncology/GOG 0225) is a Phase III diet plus physical activity intervention trial testing the hypothesis that ovarian cancer survivors in the lifestyle intervention will demonstrate better progression-free survival than those in the control condition. Study interventions were delivered via centralized telephone-based health coaching. Baseline descriptive statistics were computed for demographic, clinical, and lifestyle behavior characteristics. ResultsThe LIVES study exceeded its recruitment goals, enrolling 1205 ovarian cancer survivors from 195 NRG/NCORP-affiliated oncology practices across 49 states from 2012 to 2018. The mean age of enrollees was 59.6 years; the majority (69.4%) with stage III disease; 89% White, 5.5% Hispanic; 64% overweight/obese. Baseline self-reported diet showed a mean daily intake of 6.6 servings of fruit and vegetables, 62.7 fat grams, and 21.7 g of fiber. Physical activity averaged 13.0 MET-hours/week of moderate to vigorous physical activity; 50.9 h/week of sedentary time. Retention rates exceeded 88%. ConclusionThe LIVES study demonstrates efficiency in recruiting and retaining ovarian cancer survivors in a 24-month study of diet and physical activity intervention with a primary endpoint of progression free survival that will be reported. Trial registrationClinicalTrials.govNCT00719303.