COMBINING two immune checkpoint inhibitors with chemotherapy could improve treatment response in patients with a high-risk form of breast cancer, new research shows.
According to results from a phase II trial, adding the PD-1 inhibitor cemiplimab and LAG-3 inhibitor fianlimab to neoadjuvant chemotherapy more than doubled estimated pathologic complete response (pCR) rates in patients with early-stage ERBB2-negative breast cancer, compared with chemotherapy alone.
The study included 76 evaluable patients with stage II or III, high-risk ERBB2-negative breast cancer who received cemiplimab and fianlimab alongside paclitaxel, followed by doxorubicin and cyclophosphamide before surgery. Outcomes were compared with 350 patients from the I-SPY2 control population who received standard chemotherapy.
Cemiplimab targets PD-1, while fianlimab targets LAG-3, two immune checkpoints that can restrict the immune system’s ability to attack cancer cells. Blocking both pathways simultaneously could therefore produce a stronger antitumour immune response.
The primary endpoint of the research was pCR, defined as the absence of residual invasive cancer in the breast and lymph nodes at surgery.
Researchers found that across patients with ERBB2-negative breast cancer, estimated pCR increased from 21% with standard chemotherapy to 44% with the combination treatment.
Improvements were observed in both triple-negative breast cancer (TNBC), where pCR increased from 29% for those who received the standard treatment to 53% in the combined treatment group.
Hormone receptor (HR)-positive/ERBB2-negative disease has similarly promising results, with rates of pCR increasing from 14% in the control group to 36% in the treatment group.
Researchers also investigated whether ImPrint, a 53-gene expression signature associated with immune activity, could identify patients particularly likely to respond to treatment.
Among patients with TNBC receiving cemiplimab and fianlimab, pCR was achieved in 83% of those with ImPrint-positive tumours, compared with 28% of those who were ImPrint-negative.
An even higher response was observed in the HR-positive/ERBB2-negative breast cancer cohort. Ten out of 11 patients with ImPrint-positive tumours achieved pCR, giving an estimated response rate of 91%, compared with 28% among ImPrint-negative patients.
These findings suggest ImPrint could potentially identify a subgroup of patients with particularly immunotherapy-sensitive disease, including within HR-positive breast cancer, where immune checkpoint inhibitors have historically shown more limited activity.
However, researchers found that improved response was accompanied by increased immune-related adverse events.
Adrenal insufficiency occurred in 21% of patients receiving the combination therapy, while 11% had grade or 4 events. Hypothyroidism was also reported, while 4% of patients involved developed diabetes.
Notably, 69% of adrenal insufficiency cases developed after immunotherapy had already been completed, highlighting the potential for delayed immune-related toxicity as a result of the treatment.
Exploratory analysis showed similar event-free and distant recurrence-free survival between the experimental and control groups to date. For this reason, researchers say that longer follow-up and larger trials will be required to establish whether higher pCR rates translate into improved long-term outcomes.
However, the findings still demonstrate substantial activity from combined PD-1 and LAG-3 inhibition and suggest that immune signatures such as ImPrint could help identify patients most likely to benefit from it, while limiting unnecessary exposure to treatment-related toxicity.
Reference
Isaacs C et al. Cemiplimab and fianlimab with neoadjuvant chemotherapy in early-stage high-risk ERBB2-negative breast cancer: The I-SPY2 randomized clinical trial. JAMA Oncol. 2026. doi:10.1001/jamaoncol.2026.2576.
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