PANACEA is an international phase Ib/II study set up to evaluate the safety and efficacy of using the anti-PD-1 antibody pembrolizumab (KEYTRUDA) in combination with the anti-HER2 trastuzumab, in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer whose cancer has become resistant to trastuzumab.

HER2+ breast cancers are very aggressive, as they grow and spread rapidly. In the metastatic setting, trastuzumab and other anti-HER2 therapies, given with or without chemotherapy, are currently considered to be standard of care. Nevertheless, most patients with metastatic HER2+ breast cancer will ultimately become resistant to these treatments and their disease will progress. It is therefore essential to develop new therapeutic approaches, and both pre-clinical and clinical data suggest that the immune system contributes to the response to trastuzumab.

The PD-1 pathway

The immune system has the ability to differentiate normal cells in the body from “foreign” ones, such as tumour cells, and can attack the foreign cells while leaving the normal ones alone. To launch an immune response, the immune system needs to activate specific molecules, which are present on the immune cells and called “checkpoints”.

PD-1 (programmed death receptor 1) is one of these checkpoints located on the immune T cells. When it binds to its ligand, i.e. the PD-L1 protein present on another normal or cancer cell, it tells the T cells not to attack this specific host. Some tumour cells that have large amounts of PD-L1, use this system to avoid being attacked and destroyed by the immune system.

This suggests that the PD-1/PD-L1 pathway plays an important role in deregulating the immune response, which contributes to the cancer growing and spreading. The fact that tumours with high expression of the PD-L1 are often associated with poor patient outcome further supports this hypothesis.

Some pre-clinical data suggest that the PD-1 pathway is also involved in the resistance to trastuzumab, and that the combination of anti-HER2 and anti-PD-1 therapies (i.e. immunotherapy that inhibits the PD-1 pathway) is synergistic and more effective than either therapy alone in patients with HER2+ tumours.

The objective of PANACEA is to determine if using the anti-PD-1 antibody pembrolizumab, in combination with the anti-HER2 trastuzumab, can reverse resistance to the standard therapy and improve clinical outcomes in these patients.

The study measured the efficacy, tolerability and safety (recommended dose) of pembrolizumab. It will also help us understand the role of the PD-1 pathway in HER2+ breast cancer.

The results of PANACEA were presented publicly at the 2017 San Antonio Breast Cancer Symposium (5-9 December 2017). Read the press release

A tumour biopsy of each patient was tested in a central laboratory to assess the HER2 positivity, PD-L1 status and quantity of tumour-infiltrating lymphocytes (TILs), which are markers of an anti-tumour immune response.

Some of the patients with confirmed HER2+, PD-L1 positive tumours were assigned to the phase Ib part of the study, which aimed to determine the recommended dose of pembrolizumab, in combination with the standard dose of trastuzumab, to be used in the subsequent phase II.

Phase II involved two groups of patients:

1. with HER2+, PD-L1 positive tumours
2. with HER2+, PD-L1 negative tumours

All patients received trastuzumab in combination with the predefined dose of pembrolizumab until progression, lack of tolerability or withdrawal of consent.

The aim of the phase II part of the study was to evaluate the safety and efficacy of this treatment combination, and to observe its correlation with the level of TILs found in the tumour.

In total, 58 patients participated in the study. They are postmenopausal women with locally advanced or metastatic HER2+ breast cancer who experienced disease progression while treated with trastuzumab.  

PANACEA is coordinated by the International Breast Cancer Study Group (IBCSG), which is also the study sponsor, under the BIG umbrella.

PANACEA was launched in 2014. Results were presented publicly at the 2017 San Antonio Breast Cancer Symposium (5-9 December 2017).

11 cancer centers and hospitals from Austria, Australia, France, Belgium and Italy are involved in PANACEA.

 Merck provides drug and funding for this study, which is run according to BIG’s Principles of Research Conduct.

NCT02129556