ICON

PI: JA Kyte

We utilize selected chemotherapy for inducing immunogenic cell death, which represents a personalized in vivo vaccination covering the entire repertoire of antigens expressed in each individual tumor, and harness the immune response with checkpoint blockers. The PD1 blockers have shown activity against metastatic breast cancer, but only in a minority of patients when used as monotherapy. There is a strong preclinical rationale for combining PD1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. Luminal B (Lum B) disease is the most common subgroup among metastatic breast cancer patients, aggressive and usually responds only transiently to any form of therapy. In ICON, we will use the same Nanostring platform to identify the Lum B study patients. We hypothesize that nivolumab/ipilimumab (nivo/ipi) may

1. potentiate the patient´s spontaneous anti-tumor immune response
2. synergize with chemotherapy that counter immune tolerance and induce immunological cell death.

Study design and objectives

This is a randomized phase IIb study evaluating the safety and efficacy of combining nivolumab and ipilimumab with immunogenic chemotherapy in subjects with metastatic luminal B breast cancer. The patients (n=75) will be randomized into two arms:

• Arm A: Chemo only (pegylated liposomal doxorubicin + cyclophosphamide)
• Arm B: Chemo + ipilimumab + nivolumab
• Randomization 2:3 in favour of arm B, stratified according to tumor PD-L1 status.
• Upon progression, patients may continue study treatment until loss of clinical benefit.

Primary objectives:

• Assessment of toxicity of combined treatment with nivo, ipi and chemotherapy
• Assessment of clinical response: Progression-free survival

Secondary objectives:

• Assessment of clinical response: OS, ORR, DRR
• Assessment of toxicity of ipi/nivo (without chemotherapy) in cross-over arm
• ORR, DRR, PFS and OS in cross-over arm receiving ipi/nivo (without chemotherapy)

 Exploratory objectives:

• Assessment of immunological response
• Identification of biomarkers for clinical response, toxicity and immune response
• Characterization of tumor evolution and changes in immunological milieu
• Patient-reported outcomes