The phase 2 study evaluated cemiplimab and fianlimab alongside standard neoadjuvant chemotherapy. Neoadjuvant treatment is delivered before surgery, allowing physicians to measure how effectively a therapy eliminates cancer from the breast and nearby lymph nodes. Patients received weekly paclitaxel followed by doxorubicin and cyclophosphamide, while the immunotherapies were administered every three weeks. Surgery was performed after the drug treatment. The trial included adults with stage II or III disease considered at high risk of recurrence, including people with triple-negative breast cancer and those with hormone receptor–positive, HER2-negative tumors.

HER2-negative breast cancer is also described as ERBB2-negative breast cancer. ERBB2 is the gene that encodes the HER2 protein, a receptor involved in cell-growth signaling. When HER2 is overproduced, tumors can often be treated with HER2-directed drugs; when it is not, treatment generally relies on chemotherapy, endocrine therapy when hormone receptors are present, and increasingly, immunotherapy for selected patients. The I-SPY2 study was designed to identify promising combinations quickly by comparing investigational regimens with standard therapy and using early results to estimate whether a treatment might succeed in a larger phase 3 trial.

In the experimental arm, cemiplimab blocked PD-1, an inhibitory receptor on T cells. Tumors can exploit the PD-1 pathway to weaken immune-cell activity and avoid destruction. Fianlimab targeted LAG-3, another immune checkpoint that can suppress T-cell function when persistently activated. Blocking both pathways was intended to release complementary brakes on the immune response, potentially allowing immune cells to recognize and attack malignant cells more effectively than either approach alone. A total of 78 patients received the combination, while 350 participants were assigned to the control group.

The primary endpoint was pathologic complete response, or pCR, defined as the absence of residual invasive cancer in the breast and lymph nodes at surgery. Although pCR is not identical to long-term cure, it is strongly associated with a lower risk of recurrence in many high-risk breast cancers and is widely used to assess the effectiveness of preoperative treatment. Across all HER2-negative participants, the estimated pCR rate rose from 21% with standard therapy to 44% with the cemiplimab-fianlimab regimen. The result exceeded the I-SPY2 platform’s prespecified threshold for predicted success in a future phase 3 study.

The apparent benefit was observed in both major disease subgroups. Among patients with triple-negative breast cancer, the estimated pCR rate increased from 29% with standard therapy to 53% with the dual-immunotherapy regimen. In hormone receptor–positive, HER2-negative disease, the rate rose from 14% to 36%. These results suggest that combined checkpoint inhibition may have activity beyond tumors traditionally considered most responsive to immunotherapy. However, the study was not designed to establish definitive survival advantages, and the investigators emphasized that the exact regimen should not be adopted as a new standard based on these findings alone.

Tumor biology appeared to influence the magnitude of response. Patients whose tumors were positive for ImPrint, a 53-gene test designed to identify an immune-responsive tumor environment, experienced particularly high pCR rates after receiving the experimental treatment. The estimated rate reached 83% among ImPrint-positive patients with triple-negative disease and 91% among those with hormone receptor–positive, HER2-negative tumors. ImPrint-positive tumors show gene-expression patterns associated with immune-cell activity and a microenvironment that may be more receptive to immune stimulation. The findings support the broader goal of matching immunotherapy to the molecular features of each patient’s tumor.

The safety results nevertheless placed important limits on the treatment’s future development. Decreased adrenal hormone production occurred in 21% of patients receiving the dual-checkpoint combination, including grade 3 or 4 events in 11%. Diabetes developed in 4% of participants. These endocrine toxicities can require long-term hormone replacement or specialist care, and some emerged weeks after immunotherapy had ended. The delayed timing illustrates why patients receiving checkpoint inhibitors need continued monitoring after treatment, even when chemotherapy and surgery have been completed. The investigators concluded that the efficacy signal was compelling but that the toxicity profile was too concerning for the regimen to advance unchanged.

Claudine Isaacs, MD, lead author and associate director for clinical research at Georgetown’s Lombardi Comprehensive Cancer Center, said the results establish a proof of principle for targeting two immune checkpoints at once. Future studies may examine different doses, schedules, or newer drugs designed to hit both pathways with a potentially lower toxicity burden. One possibility is the use of bispecific antibodies, engineered molecules that bind two targets through a single drug. The I-SPY2 platform, which has enrolled more than 2,500 patients and tested 25 therapies over approximately 15 years, will continue evaluating treatment combinations and molecular tests intended to maximize benefit while limiting unnecessary harm.

Subject of Research: People

Article Title: Cemiplimab and Fianlimab With Neoadjuvant Chemotherapy in Early-Stage High-Risk ERBB2-Negative Breast Cancer: The I-SPY2 Randomized Clinical Trial

News Publication Date: 30-Jul-2026

Web References: https://doi.org/10.1001/jamaoncol.2026.2576; ClinicalTrials.gov identifier NCT01042379

References: JAMA Oncology, DOI: 10.1001/jamaoncol.2026.2576

Keywords: breast cancer, HER2-negative breast cancer, ERBB2, immunotherapy, cemiplimab, fianlimab, PD-1, LAG-3, neoadjuvant chemotherapy, pathologic complete response, I-SPY2, precision medicine

This innovative approach centers on transcriptomic profiling of peripheral blood samples, providing a minimally invasive and cost-effective alternative to conventional tissue biopsies. By analyzing RNA sequences from the blood, the researchers could capture the immune system’s evolving reaction to therapy, offering a window into how tumors and immune cells interact over time. This technique not only circumvents the complications of surgical biopsies but also promises real-time insights that could inform personalized treatment regimens.

The study enrolled 160 patients diagnosed with high-risk, stage 2 or 3 breast cancers that were negative for the human epidermal growth factor receptor 2 (HER2). These patients received either chemotherapy alone or in combination with the immunotherapy agent pembrolizumab. From this cohort, 546 peripheral blood samples were collected longitudinally, enabling the team to perform comprehensive RNA sequencing and analyze the gene expression profiles correlated with immune activity.

A key focus of the research was on characterizing the transcriptional signatures of T cells—critical components of the adaptive immune system responsible for targeting and destroying cancer cells. By examining the clonal expansion and activation markers of these T cells in patients’ blood, the investigators could predict responses to pembrolizumab with remarkable accuracy. This approach hints at the possibility of using blood-based transcriptome profiles as predictive biomarkers for immunotherapy outcomes.

The corresponding author of the study, Dr. Justin Balko, emphasized the collaborative nature of this research, which involved multiple investigators from the nationwide I-SPY2 clinical trial network. Patients enrolled in this adaptive trial provided the indispensable blood samples that powered the analyses. The I-SPY2 trial itself is a pioneering initiative designed to tailor breast cancer treatments based on molecular characteristics, enabling precision medicine approaches to improve patient outcomes across diverse subtypes.

What distinguishes this liquid biopsy method is its ability to monitor complex immune responses over the course of treatment. Traditional biopsies provide a static snapshot of tumor biology, whereas serial blood sampling can reveal dynamic immunological changes. This temporal resolution is crucial for understanding mechanisms of resistance or sensitivity to therapy and allows for adaptive treatment modifications that could enhance efficacy.

Current clinical liquid biopsy paradigms primarily focus on cell-free DNA, which has proven valuable for mutation detection and tracking tumor burden across various cancers. However, this study’s focus on RNA sequencing expands the utility of liquid biopsies, offering insights into gene expression patterns that govern immune cell function rather than just genetic alterations in tumor cells.

The research team also highlighted the translational potential of their findings beyond breast cancer. Similar immune transcriptomic profiling could be applied to other solid tumors where immunotherapy is being explored. Such advancements herald a new era of precision oncology, where minimally invasive blood tests guide treatment decisions tailored to each patient’s unique tumor-immune interplay.

While these findings are promising, the authors acknowledge the necessity for further validation in larger clinical cohorts. Confirmatory studies are essential to establish standardized protocols for blood-based RNA sequencing and to integrate these biomarkers into routine clinical workflows. Nonetheless, this research lays a vital foundation for future efforts aiming to harness the immune system’s power more effectively.

The first author, Dr. Xiaopeng Sun, who recently transitioned to Merck, along with co-authors including graduate students Andres Ocampo, Jacey Marshall, and Julia Steele, as well as senior research supervisor Dr. Susan Opalenik, contributed significant expertise. Their combined efforts demonstrate how collaborative scientific inquiry can pave the way for innovative cancer diagnostics.

This study was supported by a robust funding portfolio including grants from the National Institutes of Health, the Department of Defense Era of Hope Award, the Breast Cancer Research Foundation, Stand Up To Cancer, and the California Breast Cancer Research Program. Such financial backing underscores the critical importance of advancing breast cancer research and the high expectations for liquid biopsy technologies in oncology.

The implications of this research are profound, offering a path to more personalized, adaptive immunotherapy regimens. As we move towards an era where treatment is continuously refined based on a patient’s biological responses, liquid biopsies that capture immune transcriptional dynamics will likely become indispensable tools for clinicians. This could dramatically improve survival and quality of life for breast cancer patients facing high-risk diseases.

Subject of Research: Transcriptomic profiling of peripheral blood to predict response to neoadjuvant chemoimmunotherapy in high-risk breast cancer

Article Title: Peripheral blood transcriptional profiling predicts tumor subtype and neoadjuvant chemoimmunotherapy outcomes in human breast cancer

News Publication Date: 22-Apr-2026

Web References:
http://dx.doi.org/10.1126/scitranslmed.aec2358

References:
Study published in Science Translational Medicine, DOI: 10.1126/scitranslmed.aec2358

Keywords: Breast cancer, immunotherapy, liquid biopsy, RNA sequencing, peripheral blood transcriptome, pembrolizumab, T cells, I-SPY2 clinical trial, precision oncology, neoadjuvant therapy, transcriptomic biomarkers