study with atezolizumab in combination with trastuzumab and vinorelbine in her2-positive advanced/metastatic breast cancer

Conditions: Breast Cancer

Summary: immune checkpoint inhibitors given in monotherapy in advanced breast cancer have shown modest benefit in first-line, but very limited efficacy in later lines. thus, combination therapies are needed. response following anti-pd1/pd-l1 monotherapy is associated with large survival benefit in the advanced setting. previous studies of the intrinsic subtypes have shown that basal-like and her2-e are associated with higher expression of immune-related genes or higher infiltration of stromal tumor infiltrating lymphocytes compared to the luminal subtypes. immune infiltration in bc is associated with chemo/antiher2 responsiveness and potentially benefit from anti-pd-1/pd-l1 inhibitors. in addition, one emerging biomarker of response to anti-pd-1 therapy is the tumor mutational burden (i.e. the total number of mutations per coding area of a tumor genome). the her2-e and basal-like profiles have been associated with high mutational burden. a range of studies have been initiated including several phase ii/iii studies evaluating atezolizumab in combination with different chemotherapeutic compounds routinely used in breast cancer, but none with predefined biomarker beyond the expression of pd-l1 by ihc


Eligibility criteria:
inclusion criteria: * male or female (premenopausal or postmenopausal women) * ecog 0 to 2 * histologically confirmed adenocarcinoma of the breast, metastatic or unresectable locally advanced. * all patients must have received at least trastuzumab and other anti-her2 adcs (including but not limited to t-dm1). * measurable disease according to recist 1.1 criteria. * adequate organ function * baseline lvef ≥50% * participants with asymptomatic brain metastases are eligible. exclusion criteria: * treatment with any investigational anticancer drug within 14 days of the start of study treatment. * patient has received vinorelbine or any other vinca alkaloids previously immediately prior to initiate study treatment. * history of other malignant tumors in the past 3 years * known or suspected leptomeningeal disease (lmd)/ poorly controlled (\> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases. * symptomatic hypercalcemia requiring treatment with bisphosphonates in the 14 days prior to inclusion * cardiopulmonary dysfunction * any other severe, uncontrolled * major surgery in the 28 days prior to enrolment * infection with hiv or active hepatitis b and/or hepatitis c. * history of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity. * known hypersensitivity or allergy to biopharmaceuticals produced in chinese hamster ovary cells or any component of the atezolizumab formulation * history of autoimmune disease, * prior allogeneic stem cell or solid organ transplantation * history of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest ct scan. (note: history of radiation pneumonitis in the radiation field \[fibrosis\] is permitted.) * active tuberculosis * receipt of a live, attenuated vaccine within 4 weeks prior to enrollment * prior treatment with cd137 agonists, anti-pd-1, or anti-pd-l1 therapeutic antibody or immune checkpoint targeting agents * treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin \[il\]-2) within 4 weeks or five half-lives of the drug prior to enrolment * treatment with systemic immunosuppressive medications within 2 weeks prior to enrolment, or anticipated requirement for systemic immunosuppressive medications during the trial.

Keywords: cancer breast cancer