Adding the immune checkpoint inhibitor durvalumab, with or without the monoclonal antibody oleclumab, to neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) significantly improved pathologic complete response rates in patients with high-risk hormone receptor (HR)-positive breast cancer, according to data presented at the European Society for Medical Oncology (ESMO) Congress 2024.¹

Results of the phase II Neo-CheckRay trial, which focused on the luminal B subtype of HR-positive breast cancer, showed a doubling of pathologic complete response rates from 16.7% with standard care to 33.3% with durvalumab (anti–PD-L1) and 31.1% with durvalumab plus oleclumab (anti-CD73). Authors of the study reported particularly encouraging results with the addition of immunotherapy in PD-L1–negative and node-positive subgroups.

Alex De Caluwé, MD

“Neo-CheckRay is the first phase II trial to examine the addition of immune checkpoint inhibitors and the anti-CD73 oleclumab to neoadjuvant chemotherapy and SBRT in luminal B breast cancer,” said lead study author Alex De Caluwé, MD, a radiation oncologist at Institut Jules Bordet in Belgium. “The trial demonstrated promising activity at surgery, and we are especially intrigued by the activity in the PD-L1–negative subgroup.”

Background

As Dr. De Caluwé explained, high-risk luminal B breast cancer represents a subgroup that benefits from chemotherapy, with pathologic complete response rates of about 15% when chemotherapy is given in the neoadjuvant setting. Although luminal breast cancers are generally considered “immune colder” than triple-negative breast cancers, he noted, previous studies have shown that adding PD-L1 immune checkpoint inhibitors to neoadjuvant chemotherapy may increase pathologic complete response rates by 9% overall and by 4% in patients with PD-L1–negative tumors.

Radiation therapy has emerged as a potential synergistic partner for immunotherapy. It is capable of priming the immune response through various mechanisms, including stimulation of the cGAS-STING pathway and release of tumor-associated neoantigens.

Study Design

The Neo-CheckRay trial enrolled 135 patients with high-risk luminal B breast cancer, as determined by MammaPrint testing. The study design included three arms, all receiving a backbone of neoadjuvant chemotherapy (paclitaxel followed by dose-dense epirubicin/cyclophosphamide) and SBRT (3 × 8 Gy):

1. Standard arm: Chemotherapy + SBRT alone
2. Durvalumab arm: Chemotherapy + SBRT + durvalumab
3. Combination arm: Chemotherapy + SBRT + durvalumab + oleclumab.

SBRT was administered to all arms before the second cycle of durvalumab. The SBRT dose was an immune-stimulating dose of three daily fractions of 8 Gy; this dose is not an ablative dose as in regular SBRT. The radiation therapy was solely administered to the primary tumor, not to the lymph nodes, also in case of involved nodes. The primary endpoint was residual cancer burden (RCB) 0 to 1, with pathologic complete response as a secondary endpoint. The trial was stratified for PD-L1 status, nodal stage, and tumor stage.

Benefit in PD-L1–Negative and Node-Positive Patients

Although the trial did not meet its primary endpoint of increasing the RCB 0 to 1 rate from 15% to 45%, it demonstrated significant improvements in pathologic complete response rates. The standard arm, which received chemotherapy and SBRT alone, showed a pathologic complete response rate of 16.7%. In contrast, the durvalumab arm, which added the immune checkpoint inhibitor to the standard regimen, achieved a pathologic complete response rate of 33.3%. The combination arm, which included both durvalumab and oleclumab with chemotherapy and SBRT, showed a similar improvement, with a pathologic complete response rate of 31.1%.

Of note, in the PD-L1–negative subgroup, the difference between the standard arm and the experimental arms was more pronounced, said Dr. De Caluwé. The benefit of immunotherapy was particularly evident in node-positive patients, with the effect persisting when combining PD-L1 negativity and node positivity.

Safety Profile

As expected, Dr. De Caluwé indicated, there was an increase in grade 3 and 4 adverse events in the immunotherapy arms. This translated to a 7% increase in serious adverse events, with no deaths reported. The most frequent immune-mediated adverse event was hyperthyroidism. Of note, the SBRT component was well tolerated, he added, with no grade 3 or 4 adverse events reported.

“The novel treatment combination is overall safe and feasible,” Dr. De Caluwé concluded. “We’re conducting extensive translational research, including biopsies 1 week after SBRT, to better understand the mechanisms of response and to see what role oleclumab plays in enhancing the effects of durvalumab and radiation.” Future studies may explore optimizing the combination therapy, investigating its potential in other breast cancer subtypes, and evaluating long-term survival outcomes.

EXPERT POINT OF VIEW

Elgene Lim, MBBS, FRACP, PhD

Invited discussant of Neo-CheckRay, Elgene Lim, MBBS, FRACP, PhD, emphasized the trial’s innovative approach to enhancing immune-tumor antigen interaction through two mechanisms: the addition of stereotactic body radiation therapy (SBRT) to stimulate the immune response, and the use of oleclumab (anti-CD73) to inhibit immunosuppressive adenosine effects. Dr. Lim is a medical oncologist at St Vincent’s Hospital Sydney; Lab Head at Garvan Institute of Medical Research; and Professor of Medicine at the University of New South Wales, Australia.

“The results show a benefit of adding immunotherapy over chemotherapy plus SBRT alone, particularly in terms of pathologic complete response rates,” commented Dr. Lim. “Interestingly, there was little difference between the two immunotherapy-containing arms.”

Dr. Lim highlighted the trial’s stratification by PD-L1 status, pointing out the combination therapy showed significant improvement in pathologic complete response rates for patients with PD-L1 expression less than 1%. This finding contrasts with other recent trials, such as KEYNOTE-756 and CheckMate 7FL, he said, where patients with low PD-L1 expression did not see significant pathologic complete response improvements with immunotherapy.

“The Neo-CheckRay trial achieved relatively high pathologic complete response rates in the subgroup with PD-L1 expression less than 1% compared with the other two trials,” Dr. Lim observed. “However, it’s important to consider the grade 3 toxicity was notably higher in this combination than in the other trials.”

While acknowledging the promising nature of the trial, Dr. Lim pointed out some limitations. The lack of a non-SBRT arm makes it difficult to compare across trials, but SBRT does not appear to add to neoadjuvant chemotherapy pathologic complete response rates based on these results, he said.

Dr. Lim also emphasized the need for long-term follow-up to see whether these results will translate into improved event-free survival. “We eagerly wait to see the biological insights from the proposed translational studies, particularly given the intriguing differences in the exploratory analysis of different PD-L1 subgroups,” he concluded. “There is an urgent need for predictive biomarker selection strategies for neoadjuvant immunotherapy in estrogen receptor–positive breast cancer.”

DISCLOSURE: Dr. De Caluwé reported financial relationships with AstraZeneca, the European Organisation for Research and Treatment of Cancer, the Belgian Society of Medical Oncology, and the European Society for Radiotherapy and Oncology. Dr. Lim reported financial relationships with Novartis, Lilly, Roche, AstraZeneca, Gilead Sciences, MSD, Pfizer, and Ellipses Pharma.

REFERENCE

1. De Caluwé A, Desmoulins I, Cao K, et al: Primary endpoint results of the Neo-CheckRay phase II trial evaluating stereotactic body radiation therapy ± durvalumab ± oleclumab combined with neoadjuvant chemotherapy for early-stage, high risk ER+/HER2– breast cancer. ESMO Congress 2024. Abstract LBA10. Presented September 16, 2024.