Background Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FRα) is overexpressed in the majority of OCs and presents an attractive target for a combination immunotherapy to potentially overcome resistance to ICI in OCs. The current study sought to examine clinical and immunologic responses to TPIV200, a multiepitope FRα vaccine administered with programmed death ligand 1 (PD-L1) inhibitor durvalumab in patients with advanced platinum-resistant OC. Methods Following Simon two-stage phase II trial design, 27 patients were enrolled. Treatment was administered in 28-day cycles (intradermal TPIV200 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 cycles and intravenous durvalumab for 12 cycles). Primary endpoints included overall response rate and progression-free survival at 24 weeks. Translational parameters focused on tumor microenvironment, PD-L1 and FRα expression, and peripheral vaccine-specific immune responses. Results Treatment was well tolerated, with related grade 3 toxicity rate of 18.5%. Increased T cell responses to the majority of peptides were observed in all patients at 6 weeks (p<0.0001). There was one unconfirmed partial response (3.7%) and nine patients had stable disease (33.3%). Clinical benefit was not associated with baseline FRα or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FRα expression and upregulation of PD-L1 in a progressing lesion. Despite the low overall response rate, the median overall survival was 21 months (13.5–∞), with evidence of benefit from postimmunotherapy regimens. Conclusions Combination of TPIV200 and durvalumab was safe and elicited robust FRα-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FRα vaccination on the OC biology post-treatment.
To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC).
5572 Background: The reported risk of HSR during carboplatin retreatment is 18-44% and increases with repeated carboplatin exposure. We aimed to prospectively study the effect of an extended incremental infusion of carboplatin on the rate of HSR. Methods: Eligible patients (pts) with recurrent ovarian cancer were consented to an IRB-approved phase II randomized study from 01/2011-01/2015. Pts were randomly assigned 1:1 to standard 30-minute or an incremental 3-hour (1% in 1st hour, 9% in 2nd hour and 90% in 3rd hour) carboplatin infusion. Pts were stratified for concomitant taxane. Based on historical estimates the study was powered to detect a reduction in HSR from 20% to 5% with the extended infusion. All pts were prescribed premedication with montelukast 10 mg nocte x 3 days, dexamethasone 20 mg the night before and morning of, as well as famotidine 20 mg (or ranitidine) and diphenhydramine 50 mg (or hydroxyzine) prior to carboplatin. Pts were deemed evaluable for the study endpoint if they completed ≥ 5 cycles of carboplatin-based treatment or had carboplatin HSR. CTCAE criteria were used. Results: A total of 143 pts with recurrent ovarian cancer were enrolled. Median age was 62 years (35-82). 104 pts (52 in each arm) were evaluable for the study endpoint. Among these pts, 72 (69%), 27 (26%), 2 (1.9%) and 3 (2.9%) pts had 1, 2, 3 and 4 prior platinum-based regimens, respectively. 27 pts (26%) received carboplatin single agent and the remainder a platinum-doublet (46 liposomal doxorubicin, 24 gemcitabine, 7 paclitaxel). There were 15 HSR (14% of pts); 9 HSR in standard arm (9/52, 17%) and 6 HSR in the extended arm (6/52, 12%). There was 1 grade 3 HSR in the extended arm. No pt required hospitalization or epinephrine for HSR. The other 14 HSR were grade 1 or 2. HSR occurred on cycle #1 (1 pt); #2 (5 pts); #3 (4 pts); #4 (2 pts); #5 (2 pts) and #6 (1 pt). 2/9 HSR pts in standard arm were able to complete therapy with an extended infusion without further HSR. Conclusions: We did not demonstrate a statistically significant reduction in carboplatin HSR with use of an extended carboplatin infusion. However, the relatively low frequency of severe HSR in both arms suggests there may be a role for prophylactic premedication prior to carboplatin retreatment. Clinical trial information: NCT01248962.
The treatment of women with advanced-stage epithelial ovarian cancer (EOC) is aggressive surgical cytoreduction and a combination of platinum plus taxane chemotherapy. The timing and extent of surgery has direct implications on the selection of subsequent treatment as well as the prognosis of patients with EOC. Frontline chemotherapeutic regimens have evolved through a series of large multi-institutional randomized clinical trials that focused on targeted agents as maintenance therapy. On June 13, 2018, the U.S. Food and Drug Administration (FDA) approved adding bevacizumab to adjuvant intravenous chemotherapy followed by maintenance based on the results of Gynecologic Oncology Group protocol 218. Maintenance olaparib was FDA-approved on December 19, 2018, for frontline maintenance among those with advanced EOC who respond to frontline chemotherapy and harbor a germline or somatic BRCA1 or BRCA2 mutation. This was based on the results of SOLO-1. Despite a strong rationale and extensive study, intraperitoneal chemotherapy has not been adopted in clinical practice. Alternatively, heated intraperitoneal chemotherapy has shown promise as a more tolerable and technically feasible method of regional therapy, but widespread application will require more evidence. Significant strides have also been made in understanding the biology of EOC, resulting in a personalized approach to first-line therapy. One approach calls for recognizing differences in histologic subtypes and molecular alterations, which may open up alternative therapeutic interventions.
e16535 Background: Epithelial ovarian, primary peritoneal, and fallopian tube cancers (EOC) express the AR in 67-90% of cases. Epidemiological studies have shown a correlation between hyperandrogenic states, including polycystic ovary syndrome, hirsutism, and truncal obesity, and a higher incidence of EOC. Enza is a well-tolerated, oral, AR inhibitor that is FDA-approved for treatment of advanced prostate cancer post-docetaxel. We performed in vitro and in vivo experiments to determine the activity of enza in AR+ EOC. Methods: Immunoblotting confirmed that OVCAR3 and OVCA432 were AR-expressing ovarian cancer cell lines while OVCA429 was not. OVCAR3 and OVCA429 cells were treated with increasing concentrations of enza to define the IC50. Eighteen NOD SCID gamma (NSG) female mice were subcutaneously implanted with 10 million OVCAR3 cells. Three cohorts were examined: OVCAR3 xenografts treated with PO vehicle (n=6); PO vehicle plus dihydrotestosterone (DHT) pellet implantation to simulate excess androgen exposure (n=6); or PO enza 30mg/kg plus DHT pellet implantation (n=6). Enza was administered by oral gavage when mean tumor size reached 100mm3. The experiment was duplicated in an additional 45 NSG mice, 15 per cohort, using an enza dose of 50mg/kg. Mice were sacrificed after 56 days of treatment. Statistical analysis was performed using the tumor volume area under the curve (AUC) until day 56. The Wilcoxon Rank Sum Test was used to compare the median tumor volumes between groups. Results: The IC50 of OVCAR3 cells in vitro was determined to be 25 nM of enza, the IC50 of OVCA429 was not reached (max concentration 50 nM). The median size of tumors on day 56 in the 30mg/kg cohort was 1031 mm3 (mean 1108.7, range 502-2838) and 424 mm3 (mean 416.3, range 49-829) in the 50mg/kg cohort. Androgen exposure led to a significant increase in tumor growth in both cohorts (p=0.025 [30mg] and p=0.009 [50mg]) while treatment with enza led to a significant decrease in median tumor volume in androgen exposed mice in both cohorts (p=0.045 [30 mg]; p=0.004 [50mg]. Conclusions: Treatment with enza led to a significant decrease in AR+ EOC tumor growth both in vitro and in vivo. A prospective clinical trial of enza for treatment of human AR+ EOC is warranted.
