Neo-CheckRay trial

Dr Elisa Agostinetto, a medical oncologist at Institut Jules Bordet in Brussels, discussed with Dr Alex De Caluwé, a radiation oncologist also working at the Institut Jules Bordet, the outcomes of the Neo-CheckRay phase 2 trial that he presented during the Proffered Paper Session on early stage Breast Cancer.

The Neo-CheckRay trial was designed to assess whether radiation therapy could enhance the immune response in luminal breast cancer, a type with low immune infiltration when given before surgery (neoadjuvant setting). The study compared three treatment arms: the standard arm with chemotherapy and radiation therapy (3 doses of 8 Gray to the primary tumour) and two experimental arms adding the immunotherapy drug durvalumab, with one arm also including oleclumab. The patients were stratified by PD-L1 status and tumour stage.

The primary endpoint was the Residual Cancer Burden (RCB) score of 0 or 1, and the secondary endpoint was the pathologic complete response (pCR) at surgery. Results showed high response rates in the experimental arms, with over 50% of patients achieving an RCB score of 0 or 1. However, the standard arm also had a high pCR rate, making the trial statistically neutral for its primary endpoint. A subgroup that drew attention was the group of patients with PD-L1-negative tumours. In this subgroup, patients who received only chemotherapy and radiation had a notably low pCR rate. In contrast, those treated with the addition of immunotherapy demonstrated a substantial improvement, with a 30% absolute increase in pCR. This observation suggests that radiation therapy may synergise with immunotherapy by inducing PD-L1 expression in previously PD-L1-negative tumours, making them more susceptible to the effects of durvalumab. This finding is particularly noteworthy, as it highlights the potential of radiation therapy to convert cold tumours into hot ones, making them more amenable to immunotherapy.

The safety profile was favourable, with no significant grade 3 or 4 side effects from radiation therapy, which targeted only the primary tumour and not the lymph nodes. Surgery was not delayed, and most patients underwent breast-conserving surgery. One of the most critical technical aspects of the trial was that the radiation therapy did not target the entire tumour load. In many patients, particularly those with node-positive disease, the involved lymph nodes were not treated with radiation. Therefore, any pathologic complete response observed in these patients was indicative of a systemic effect of the combination treatment rather than a localised effect of radiation therapy alone. Even within the node-positive subgroup, the experimental treatment showed a high pathologic complete response rate, further supporting the potential of this combined approach.

Looking ahead, the research team has several ongoing translational projects associated with the Neo-CheckRay trial. One of the key investigations involves analysing tissue samples taken one week after the radiation therapy to observe dynamic changes in the tumour microenvironment. Preliminary data suggest an increase in PD-L1 expression in patients who were PD-L1-negative at baseline, which aligns with the hypothesis that radiation can induce an immune response in these cold tumours. Additionally, the team is conducting single-cell analyses of baseline tissue and post-radiation biopsies, as well as lymph node samples, to further understand the immune landscape of these tumours.

In the future, the researchers hope to conduct a larger trial to validate these findings and solidify the concept that combining radiation therapy with immunotherapy can improve outcomes in patients with luminal breast cancer, especially those with PD-L1-negative and node-positive disease. This innovative approach has the potential to significantly alter the treatment landscape for these patients, offering a new avenue for improving long-term outcomes in a challenging subset of breast cancer.