The hope that converting immunologically "cold" breast cancers that do not respond to the new immune therapies, such as checkpoint inhibitors, into "hot" tumors that could potentially be cured by them, was supported by early findings from the Neo-CheckRay study reported at the at the European Society for Medical Oncology (ESMO) Breast Cancer 2022 Congress (Ann Oncol 2022; https://doi.org/10.1016/j.annonc.2022.03.114).
"Cold tumors are less infiltrated by lymphocytes, so there is less immune activity and [they] will respond less well to immunotherapy," Alex De Caluwe, MD, Radiation Oncologist at the Institut Jules Bordet in Brussels, told Oncology Times after reporting his group's findings from a safety run-in of the study looking at patients with breast tumors classed as luminal B-which he described as cold. "The challenge in our project is to increase the response to immunotherapy." This was already looking promising in the more immunologically active hot tumors.
The Neo-CheckRay trial aimed to investigate the use of stereotactic body radiation therapy (SBRT) directed to the primary tumor combined with adenosine pathway inhibition using the drug oleclumab to improve response to neoadjuvant immuno-chemotherapy.
De Caluwe noted that the promise of immunotherapy had not yet been realized in luminal B breast cancer, but it could be. "We know now [from] other trials that neoadjuvant immunotherapy is an indication for [immunological] treatment in triple-negative breast cancer. But in luminal cancer, it has not been demonstrated yet because it's colder. So, we look for strategies to make it hot so it will respond to immunotherapy," he said.
Trial Design
The Neo-CheckRay study used a standard-of-care chemotherapy "backbone" treatment for all patients. Added to this was the anti-programmed death ligand-1 (PD-L1) immunotherapy durvalumab. "And then there are two components which we hope will convert a cold tumor into a hot one: stereotactic body radiation therapy (SBRT)-specifically on the cancer, with a very precise technique-and oleclumab [which is a blocker of CD73]," De Caluwe stated.
The safety run-in was an open-label, single-arm trial in which six patients with early-stage luminal B breast cancer received neoadjuvant treatment with paclitaxel, doxorubicin, and cyclophosphamide, as well as durvalumab, oleclumab, and SBRT to the primary tumor. Surgery was performed after primary systemic treatment and adjuvant therapy was given according to local guidelines. To qualify for the study, patients needed to be female, at least 18 years old, have ECOG performance status of 1, be estrogen receptor-positive and HER2-negative, and at high risk-as judged by genomic testing and tumor size.
De Caluwe said oleclumab's mechanism of blocking adenosine was a possible way of restoring immunological sensitivity because it could synergize with radiation therapy. "Adenosine is associated with many immunosuppressive characteristics that make the cancer colder. And when you treat a cancer with radiation, there is immunosuppressive escape through this pathway. So, we believe that the combination of an adenosine blocker, such as oleclumab, and radiation will work well together."
"Radiation always stimulates the creation of new antigens," he added. "So, the immune system has new targets to identify."
The "safety run-in" phase of the study (reported at the breast cancer congress) was to see if the combination was safe before recruiting for a randomized trial to test whether the combination could convert such cold cancers into hot tumors.
"The safety run-in showed that the combination seemed safe enough to go forward to a randomized trial," said De Caluwe.
The patients in the Neo-CheckRay trial had much colder tumors than, for example lung cancers or melanomas, for which immunotherapy had been successfully used. "So, basically, we are attacking more challenging tumors with immunotherapy, and we need the radiation and other components to try to make [them] respond."
Evidence supporting the combination of chemoradiotherapy plus adenosine blockade and PD-L1 inhibition had come from studies in these other cancers, De Caluwe said. "Data in lung cancer showed that durvalumab and oleclumab worked well together in a population of patients treated with radiation and chemotherapy."
The hope of the researchers had been to demonstrate that converting a colder tumor to a hotter one could increase response rates. "That [would] give us the possibility to do more breast-sparing surgeries in large tumors, [and] avoid axillary lymph node dissection in large tumors because we [could] induce much better response in the neoadjuvant phase than we have with chemotherapy alone right now," he explained.
The six patients investigated in the safety run-in had a median age of 53 years. They all received SBRT. Eighty-five percent of the total planned primary systemic therapy was given. Median follow-up time was a year after the subsequent surgery.
There were no Grade 4-5 adverse events reported. A single Grade 3 event occurred: pericarditis that resolved rapidly under corticosteroids. There was some Grade 1 rash, conjunctivitis, hand eczema, hyperthyroidism, diarrhea, and lipase. No Grade 2/3 radiation dermatitis or pneumonitis was reported. And the overall cosmetic breast evaluation after surgery was described as "excellent" in four patients and "good" in the other two.
On the basis of these results, the novel combination treatment was considered to be safe. So, the Neo-CheckRay Phase II randomized trial was activated and currently recruiting patients at French and Belgian sites.
De Caluwe saw immune therapies as potentially broadening the scope for using immunotherapy in breast cancer. "In the start of this new era of immunotherapy, it was only given in selected tumors, like melanoma [and] lung. And now we try to expand this to more challenging cancers," he concluded.
Peter M. Goodwin is a contributing writer.