75 A combination of two immunotherapy drugs has shown encouraging results when added to standard chemotherapy before surgery for patients with high-risk, early-stage HER2-negative breast cancer, according to phase 2 findings from the ongoing I-SPY2 clinical trial platform. The approach significantly improved the likelihood of eliminating detectable cancer before surgery. However, the specific regimen will not be evaluated in additional patients because of higher-than-expected toxicities. The findings were published in JAMA Oncology on 30th July 2026. “By continuously learning and adding new arms to the I-SPY2 trial, the ultimate goal is to identify which drug regimens are most likely to benefit individual patients, maximising benefit and minimising toxicities rather than defaulting to a one-size-fits-all treatment plan,” said Professor Claudine Isaacs, MD, associate director for clinical research at Georgetown’s Lombardi Comprehensive Cancer Center and lead author of the report. “As part of this individualisation effort, the I-SPY2 team is also developing advanced molecular profiling tests to identify which patients derive the greatest benefit from newer therapies such as immunotherapy.” HER2-negative breast cancer, also known as ERBB2-negative breast cancer, refers to tumours that do not overexpress the HER2 protein. The study focused on patients with high-risk stage II or III disease. This included people with triple-negative breast cancer and those with hormone receptor-positive, HER2-negative disease. The trial evaluated dual immune checkpoint blockade alongside standard chemotherapy, with all treatment given before surgery. Cemiplimab blocks the programmed cell death protein 1 (PD-1) receptor on T cells, helping prevent tumour cells from evading the immune system. Fianlimab blocks the lymphocyte activation gene 3 (LAG-3) receptor on T cells, enhancing the immune response against cancer cells. Both immunotherapy drugs were administered every three weeks alongside weekly paclitaxel, followed by doxorubicin and cyclophosphamide before surgery. This treatment regimen was referred to as PCF. A total of 78 participants were randomly assigned to the PCF group, while 350 received standard therapy in the control group. The dual immunotherapy regimen met the I-SPY2 trial’s prespecified threshold for the probability of success in a future phase 3 trial. The primary endpoint was pathological complete response (pCR), defined as the absence of residual invasive cancer in the breast or lymph nodes at the time of surgery. Achieving pCR is associated with a lower risk of the cancer returning. Estimated pCR rates increased from 21% with standard-of-care therapy to 44% with PCF across all HER2-negative patients. Among those with triple-negative breast cancer, rates rose from 29% to 53%. In patients with hormone receptor-positive, HER2-negative disease, pCR rates increased from 14%–36%. “Ultimately, these results show that this particular regimen was very effective,” said Professor Isaacs. “This establishes a proof of principle for dual targeting, which is promising because new drugs are being developed, such as bispecific antibodies that can target two pathways with a single drug while potentially reducing toxicity and maintaining similar efficacy.” Particularly strong results were seen among patients whose tumours tested positive for ImPrint, a 53-gene immune response signature. ImPrint-positive status indicates a tumour microenvironment that is more likely to respond to immune stimulation. In this subgroup, pCR rates reached 83% in patients with triple-negative breast cancer and 91% in those with hormone receptor-positive, HER2-negative disease treated with PCF. Although the regimen showed encouraging efficacy, it was also associated with higher rates of immune-related adverse events. Reduced hormone production by the adrenal glands affected 21% of patients receiving PCF, with 11% experiencing serious grade 3 or 4 events. Diabetes developed in 4% of patients. Many endocrine complications emerged weeks after immunotherapy had ended, highlighting the need for continued monitoring. Over its 15-year history, the I-SPY2 platform has enrolled more than 2,500 patients with breast cancer and evaluated 25 investigational therapies across multiple phase 2 trials. Its adaptive design enables researchers to test promising treatments more rapidly while continuously refining approaches to personalised care. “Given these trial results, we may look at alternate dosing of the drugs or explore novel ways to target those two immune pathways with different drugs that are better tolerated while maintaining high efficacy,” said Professor Isaacs. “The bottom line is that we want to treat people individually with the drugs they need while avoiding unnecessary toxicities to achieve the best possible outcomes.” The findings reinforce growing interest in immunotherapy combinations for high-risk early-stage breast cancer while underscoring the importance of balancing effectiveness with tolerability. Future research is expected to explore refined approaches to dual immune targeting that aim to improve outcomes while reducing treatment-related toxicity.