Highlight
Adding dual immune checkpoint inhibitors targeting PD-1 and LAG-3 to standard neoadjuvant chemotherapy significantly improves pathologic complete response (pCR) rates in early-stage high-risk ERBB2-negative breast cancer subtypes. The combination of cemiplimab and fianlimab yielded superior pCR results across triple-negative and HR-positive ERBB2-negative tumors, particularly in patients with a positive immune gene signature (ImPrint+). However, treatment was associated with immune-related adverse events such as adrenal insufficiency. These encouraging findings from the adaptive, multi-arm I-SPY2 platform trial support further phase 3 validation.
Study Background
Early-stage HER2 (ERBB2)-negative breast cancer, particularly triple-negative breast cancer (TNBC) and high-risk hormone receptor (HR)-positive subtypes, has an unmet clinical need for improved neoadjuvant therapy efficacy to reduce relapse risk. While immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) pathway have improved outcomes in high-risk early breast cancer when combined with chemotherapy, resistance and incomplete responses persist. Lymphocyte activation gene 3 (LAG-3), an emerging immune checkpoint receptor, contributes to immune suppression in tumors. Dual blockade of PD-1 and LAG-3 hypothesizes to further enhance antitumor immunity and improve response rates when added to standard neoadjuvant chemotherapy regimens.
Study Design
The I-SPY2 trial is a multicenter, phase 2 adaptive platform study designed to evaluate multiple experimental neoadjuvant regimens in women with early-stage (stage II or III) breast cancer. The present randomized comparison enrolled participants between February 2, 2020, and December 9, 2021, focusing on patients with ERBB2-negative, high-risk disease. Adaptive randomization allocated 78 patients to receive the investigational combination and 350 patients formed the historical control group receiving standard chemotherapy.
All patients underwent a backbone neoadjuvant chemotherapy schedule consisting of weekly paclitaxel for 12 weeks followed by doxorubicin and cyclophosphamide. The intervention arm received four doses of the PD-1 inhibitor cemiplimab and the anti-LAG-3 antibody fianlimab every three weeks concomitant with paclitaxel. Patients proceeded to surgery following chemotherapy completion. Molecular risk assessment was performed using the MammaPrint assay to categorize high (MP1) or ultrahigh (MP2) risk profiles. Subgroups included triple-negative breast cancer (TNBC) and HR-positive/ERBB2-negative disease.
The primary endpoint was pathologic complete response (pCR), defined as no residual invasive cancer detected in breast and lymph nodes at surgery. The study applied Bayesian adaptive randomization and graduation criteria, requiring 85% posterior probability of success in subtype-specific phase 3 trials to declare regimen efficacy. Immunologic biomarker ImPrint status, indicating a robust tumor immune infiltration signature, was evaluated to predict response.
Key Findings
The addition of cemiplimab and fianlimab (PCF) to chemotherapy significantly improved pCR rates relative to historical controls across all evaluated ERBB2-negative high-risk subtypes:
- Overall ERBB2-negative group: 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) pCR rates
- Triple-negative breast cancer: 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%)
- HR-positive, ERBB2-negative disease: 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%)
These results met the pre-specified Bayesian criteria for graduation in all clinical signatures examined, validating the regimen’s effectiveness. Notably, patients with a positive ImPrint immune gene signature demonstrated markedly higher efficacy, highlighting immune activation as a predictive biomarker.
While the PCF combination was generally tolerable, immune-related adverse events were clinically significant. Adrenal insufficiency, including hypophysitis, affected 21% of patients, with 11% experiencing grade 3 or 4 severity, primarily after immunotherapy completion. This underscores the need for vigilant endocrine monitoring and management strategies during and after treatment.
Expert Commentary
The I-SPY2 trial’s adaptive design facilitated efficient evaluation of novel immunotherapy combinations in a high-risk breast cancer population where improving early pathological response correlates with clinical outcomes. The dual checkpoint inhibition approach leverages complementary immune pathways—PD-1 to reinvigorate exhausted T cells and LAG-3 to relieve additional immune suppression—providing a biologically plausible rationale for augmented antitumor activity observed.
Importantly, these results corroborate and extend data from other studies demonstrating the benefit of adding ICIs to neoadjuvant chemotherapy, especially in TNBC where immunogenicity tends to be higher. The identification of ImPrint as a predictive biomarker offers a potential clinical tool to personalize immunotherapy integration based on tumor immune profiles.
Limitations include the relatively small intervention cohort and use of a historical control group rather than concurrent control, which may introduce biases despite adaptive randomization. The higher incidence of immune-related endocrinopathies also emphasizes the trade-off between therapeutic benefit and toxicity, warranting optimized patient selection and monitoring. Further phase 3 trials are needed to confirm these findings and to better define long-term outcomes such as event-free and overall survival.
Conclusion
The combination of the PD-1 inhibitor cemiplimab and the LAG-3 inhibitor fianlimab with standard neoadjuvant chemotherapy significantly improves pathologic complete response rates in early-stage high-risk ERBB2-negative breast cancer, especially in patients with a positive immune gene signature. These findings provide a compelling rationale for advancing dual immune checkpoint blockade strategies into larger, definitive phase 3 studies that can establish their role in standard breast cancer neoadjuvant regimens. Clinicians should be aware of potential immune-related adverse events, including adrenal insufficiency, as immunotherapy gains wider adoption in this setting.
Funding and Clinical Trial Registration
The I-SPY2 trial is funded by multiple collaborators and conducted at multiple US clinical sites. This trial is registered at ClinicalTrials.gov under identifier NCT01042379.
References
- Isaacs C, Nanda R, Yau 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 Jul 30. PMID: 42530945.
- Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-821.
- Solomon BJ, McCoach CE, Kowanetz M, et al. LAG-3 inhibition and immune checkpoint combinations in cancer immunotherapy: Clinical rationale and current development. J Immunother Cancer. 2022;10(1):e004997.
