2732 - A phase 2 study of pembrolizumab in combination with doxorubicin in advanced, recurrent or metastatic endometrial cancer

Background

New approaches are needed for patients with advanced endometrial cancer (EC) since there is no standard second-line therapy after failure to platinum-based chemotherapy. The TCGA subtypes, POLE and MSI, show high tumour mutation burden (TMB) that correlates with PD-L1 expression. Pembrolizumab (anti-PD-1 antibody) conferred a 13% objective response rate (ORR) in patients with advanced EC whose tumors expressed PD-L1. However, the majority of patients with advanced disease belong to the serous-like or CN-low subtypes, with fewer potential neoantigens and may experience less benefit from immunotherapy. We hypothesize that combining pembrolizumab with an inducer of immunogenic cell death such as doxorubicin could improve clinical responses in all EC subtypes. The purpose of this trial is to determine the efficacy/safety of the combination and to identify predictive biomarkers of response.

Trial design

This investigator-initiated, single-arm, multicenter, phase 2 study aims to enroll 41 to 51 patients with relapsed/metastatic EC (endometrioid, serous, squamous, clear-cell, and an exploratory cohort of carcinosarcoma). Patients must have received one prior line of platinum-based chemotherapy, have an ECOG PS ≤ 1, and tumor specimen available for biomarker analysis. Patients will receive IV doxorubicin (60 mg/m²) plus IV pembrolizumab (200 mg) every 3 weeks up to 9 cycles; treatment with pembrolizumab will continue in 3-week cycles until disease progression, unacceptable toxicity, or 35 administrations (approximately 2 years). The primary endpoint is investigator assessed progression-free survival (PFS) rate by RECIST v1.1 at 6 months. Key secondary endpoints include duration of response, PFS, ORR, overall survival, and the association with TCGA subtypes. An exploratory translational analysis will be also performed on tumour samples to investigate genetic predictors of response, such as distribution of PD-L1, tumour-stroma immune-regulatory gene expression, and TMB.The study is actively recruiting. At the time of submission, the safety run-in part with 6 patients had been completed with no safety concerns and 30 patients enrolled. Clinical trial information: NCT03276013.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Vall d’Hebron Institute of Oncology (VHIO).

Funding

MSD.

Disclosure

A. Oaknin: Full / Part-time employment: Vall d’Hebron Univeristy Hospital; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Immunogen; Advisory / Consultancy: Genmab. L. Fariñas Madrid: Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Roche. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai. A. González Martín: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Speaker Bureau / Expert testimony: PharmaMar; Advisory / Consultancy: GenMab. I. Romero: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Tesaro; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar. J. Garcia-Donas: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: GammaMabs; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol Meiers; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Squibb; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BioClin. A. Gallego Martínez: Advisory / Consultancy: PharmaMar; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Tesaro. M.D. Fenor de la Maza Lopez Olmedo: Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (institution): Pierre Fabre; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Janssen. V. Rodriguez Freixinos: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar. J.M. Piulats Rodriguez: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy: Roche; Advisory / Consultancy: BeiGene; Advisory / Consultancy: VCN Biosciences; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.