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Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial.

ABSTRACT: BACKGROUND:Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FR?) 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 FR? 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 FR? 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 FR? or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FR? 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 FR?-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FR? vaccination on the OC biology post-treatment.

SUBMITTER: Zamarin D

PROVIDER: S-EPMC7279674 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial.

Zamarin Dmitriy D Walderich Sven S Holland Aliya A Zhou Qin Q Iasonos Alexia E AE Torrisi Jean M JM Merghoub Taha T Chesebrough Lewis F LF Mcdonnell Autumn S AS Gallagher Jacqueline M JM Li Yanyun Y Hollmann Travis J TJ Grisham Rachel N RN Erskine Courtney L CL Block Mathew S MS Knutson Keith L KL O'Cearbhaill Roisin E RE Aghajanian Carol C Konner Jason A JA

Journal for immunotherapy of cancer 20200601 1

<h4>Background</h4>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 ...[more]

PMID: 32503949

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Project description:PurposePreclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.Patients and methodsIn a single-center, proof-of-concept phase II study, we enrolled women aged ?18 with recurrent ovarian cancer. All patients were immune checkpoint inhibitor-naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300 mg twice daily and durvalumab 1,500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment.ResultsThirty-five patients with ovarian cancer [median, four prior therapies (IQR, 2-5.5), predominantly platinum-resistant (86%), BRCA wild-type (77%)] received at least one full cycle of treatment. ORR was 14% [5/35; 95% confidence interval (CI), 4.8%-30.3%]. Disease control rate (PR+SD) was 71% (25/35; 95% CI, 53.7%-85.4%). Treatment enhanced IFN? and CXCL9/CXCL10 expression, systemic IFN?/TNF? production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFN? production was associated with improved PFS [HR, 0.37 (95% CI, 0.16-0.87), P = 0.023], while elevated VEGFR3 levels were associated with worse PFS (HR, 3.22 (95% CI, 1.23-8.40), P = 0.017].ConclusionsThe PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.

Dataset Information

Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial.

Publications

Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial.

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