TOPLINE

Adding dual checkpoint blockade with cemiplimab and fianlimab to standard neoadjuvant chemotherapy more than doubles pathologic complete response (pCR) rates in high-risk ERBB2-negative breast cancer, improving from 21% to 44%. The combination showed particular efficacy in triple-negative breast cancer (TNBC), with pCR rates increasing from 29% to 53%, and in hormone receptor (HR)-positive/ERBB2-negative disease, where rates rose from 14% to 36%.

METHODOLOGY

• The I-SPY2 trial is an ongoing phase 2 clinical platform trial for early-stage breast cancer in which novel agents are tested on a background of standard-of-care neoadjuvant chemotherapy, with the objective of evaluating the combination of anti-PD-1 monoclonal antibody cemiplimab plus the anti-LAG-3 monoclonal antibody fianlimab. R esearchers conducted the trial at multiple US clinical sites, enrolling patients with stage II or III ERBB2-negative, high-risk breast cancer continuously since 2010, with adaptive randomization for this intervention occurring from February 2, 2020, to December 9, 2021.
• A total of 78 participants (mean age, 47 years) were randomized to receive paclitaxel (80 mg/m² intravenous weekly for 12 weeks) plus cemiplimab (350 mg) and fianlimab (1600 mg) on weeks 1, 4, 7, and 10, followed by doxorubicin (60 mg/m²) plus cyclophosphamide (600 mg/m²) every 2-3 weeks for four cycles, then surgery; 350 participants (mean age, 48 years) were randomized to the control group receiving paclitaxel followed by doxorubicin and cyclophosphamide without immunotherapy.
• Participants were classified into eight breast cancer subtypes based on HR status, ERBB2 status, and MammaPrint molecular risk (categorized as high or ultrahigh), with adaptive randomization.
• The primary outcome was pCR at time of surgery, with secondary outcomes including 3-year event-free survival and distant relapse-free survival. Pathway-specific biomarkers, including the 53-gene ImPrint signature, were assessed for response prediction.
• Analysis was performed from January 1, 2022, to August 5, 2025, using a covariate-adjusted Bayesian model based on longitudinal change in magnetic resonance imaging functional tumor volume during treatment and pathologic response after surgery, with treatments graduating when achieving 85% Bayesian probability of success in a hypothetical 300-participant phase 3 trial.

TAKEAWAY

• The combination of paclitaxel, cemiplimab, and fianlimab (PCF) graduated in all clinical signatures with estimated pCR rates of 44% vs 21% (in the control group) in all ERBB2-negative disease, 53% vs 29% in TNBC, and 36% vs 14% in HR-positive/ERBB2-negative disease.
• Among patients with immune-positive ImPrint status, pCR rates were substantially higher at 83% vs 34% in TNBC and 91% vs 31% in HR-positive/ERBB2-negative disease for PCF vs control, while immune-negative patients still showed improvement with pCR rates of 28% vs 21% in TNBC and 28% vs 8% in HR-positive disease.
• Adrenal insufficiency occurred in 16 of 76 patients (21%) in the PCF group, with eight patients (11%) experiencing grade 3 or 4 events, and 11 of 16 cases (69%) occurring after immunotherapy completion; diabetes developed in three patients (4%), all occurring 4-6 months after treatment completion.

IN PRACTICE

“[T]he addition of cemiplimab and fianlimab to standard [neoadjuvant chemotherapy] resulted in impressive pCR rates in all subsets of patients with early-stage high-risk ERBB2-negative breast cancer, most notably in those with the immune-positive signature status. However, this combination was associated with concerning rates of [immune-related adverse effects]…. Given results from collective immunotherapy trials demonstrating the impact of immunotherapy in HR-positive/ERBB2-negative and TNBC, future work should focus on identifying patients who are most likely to derive the greatest benefit and for whom toxic effects may be more acceptable,” the authors of the study wrote. 

SOURCE

This study was led by Claudine Isaacs, MD, Lombardi Comprehensive Cancer Center, Georgetown University in Washington, DC. It was published online on July 30 in JAMA Oncology.

LIMITATIONS

According to the authors, a limitation of the study was the relatively small sample size in the intervention group, which by design in the I-SPY2 adaptive platform can decrease statistical power for some subgroup and biomarker analyses. The control group did not include pembrolizumab or carboplatin, which were not standard of care when this group enrolled, limiting the ability to assess the incremental contribution of fianlimab. Strict eligibility criteria limit generalizability. The exploratory nature of the distant relapse-free survival analyses, along with small sample sizes and methodologic constraints, means these findings should be interpreted with caution.

DISCLOSURES

This research received support from the National Cancer Institute of the National Institutes of Health (NIH; award No. P01CA210961). The study sponsors included the nonprofit organization Quantum Leap Healthcare Collaborative and the Foundation for the NIH. Additional support came from the Safeway Foundation, the William K. Bowes, Jr, Foundation, Give Breast Cancer the Boot, and the Breast Cancer Research Foundation. Drug manufacturers Regeneron and Amgen provided funds and study drugs but had no role in study design, data collection, analysis, or manuscript preparation. Isaacs disclosed receiving collaborative and nonfinancial support from Regeneron during the study, personal fees from multiple pharmaceutical companies including Arvinas, AstraZeneca, Genentech, Gilead, Merck, Novartis, Pfizer, and PUMA outside the submitted work, and institutional research support from several companies including Tesaro/GlaxoSmithKline, Pfizer, AstraZeneca, Bristol Myers Squibb, Genentech, Novartis, Regeneron, and Jazz Pharmaceuticals. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.