A randomised, multicentre, double-blind, placebo-controlled phase III CheckMate 7FL study investigated whether the addition of nivolumab to anthracycline and taxane neoadjuvant chemotherapy could significantly increase pathological complete response (pCR) rates in patients with newly diagnosed early-stage, high-risk, high-grade ER-positive, HER2-negative breast cancer. The study met its primary endpoint, with a significantly higher rate of pCR in the nivolumab arm versus placebo. The median follow-up is too short in this analysis to make conclusions about event-free survival (EFS). The findings were published by Dr. Sherene Loi of the Peter MacCallum Cancer Centre in Melbourne and University of Melbourne in Parkville, Australia and colleagues on 21 January 2025 in the Nature Medicine.
A randomised, multicentre, double-blind, placebo-controlled phase III KEYNOTE-756 study evaluated the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab plus endocrine therapy versus neoadjuvant placebo plus chemotherapy followed by adjuvant placebo plus endocrine therapy in patients with previously untreated high-risk, early-stage, ER-positive, HER2-negative breast cancer. The addition of pembrolizumab to neoadjuvant chemotherapy significantly improved the pCR rate. Evaluation of EFS is ongoing. The findings were reported by Dr. Fatima Cardoso of the Breast Unit, Champalimaud Clinical Centre/Champalimaud Foundation in Lisbon, Portugal and colleagues on 21 January 2025 in the Nature Medicine too.
The CheckMate 7FL study
The authors wrote in the background that heterogeneity in responses to treatment and clinical outcomes may be caused by distinct differences in the molecular subtypes of ER-positive, HER2-negative breast cancer, including subtypes with varying ER and PgR expression, and those that are immunogenic, proliferative and receptor tyrosine kinase-driven, which require specific treatments.
Systemic treatment for patients with high-risk, early-stage ER-positive, HER2-negative breast cancer include neoadjuvant or adjuvant chemotherapy, prolonged adjuvant endocrine therapy with or without adjuvant targeted therapies, including CDK4/6 inhibitors, and PARP inhibitors for patients whose tumours carry germline pathogenic BRCA alterations.
Anti-PD-L1 agents significantly improve clinical outcomes in early-stage triple negative breast cancer (TNBC) and PD-L1-positive metastatic TNBC. A subset of ER-positive, HER2-negaitve breast cancers contains a dense lymphocytic infiltration, similar to that seen in TNBC; however, it is unclear how this relates to the response to immune checkpoint inhibitors in ER-positive, HER2-negative breast cancer.
Findings from the adaptively randomised I-SPY2 study suggest that anti-PD-(L)1 agents have the potential to increase the proportion of patients with high-risk ER-positive, HER2-negative breast cancer who achieve pCR or minimal residual disease with residual cancer burden (RCB) score of 0 or 1 following neoadjuvant treatment.
The CheckMate 7FL study aimed to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy followed by adjuvant endocrine therapy in patients with newly diagnosed early-stage high-risk ER-positive, HER2-negative breast cancer. The study investigators also sought to define patient subpopulations most likely to respond to nivolumab in combination with neoadjuvant chemotherapy.
In total, 510 patients were randomised to receive anthracycline and taxane-based chemotherapy with either intravenous nivolumab or placebo. The primary endpoint of pCR was significantly higher in the nivolumab arm compared with placebo, 24.5% versus 13.8% (p = 0.0021), with greater benefit observed in patients with PD-L1-positive tumours, 44.3% versus 20.2%, respectively. RCB 0 or 1 rates were also improved in the nivolumab versus placebo arm. The median follow-up is too short in this analysis to make conclusions about EFS.
Analyses of pCR rates by ER and PgR levels confirm that patients with ER and/or PgR levels <10% have greater benefit with the addition of nivolumab than patients with ER and/or PgR levels ≥10%. Notably, the study investigators observed this effect also in the setting of ER ≤50%. Although this remains to be further validated, it suggests that patients with lower ER and PgR levels may be treated similarly to patients with early TNBC.
Safety was consistent with the known safety profiles, with no change in the feasibility of surgery following the addition of nivolumab to chemotherapy. There were no new safety signals identified. Of the five deaths that occurred in the nivolumab arm, two were related to study drug toxicity; no deaths occurred in the placebo arm.
The results from CheckMate 7FL consolidate the benefit of adding an immune checkpoint inhibitor to neoadjuvant chemotherapy in this breast cancer subtype and context, and longer follow-up will indicate whether pCR translate into greater EFS benefit for all or just for patients with PD-L1-positive tumours. Notably, whereas previous studies have shown that addition of PD1 inhibitor in TNBC led to small increases in pCR rates, including in patients with low PD-L1 expression, significant EFS benefit was observed.
Overall, the results represent a new milestone in the neoadjuvant treatment of ER-positive, HER2-negative breast cancer, because there have been intensive but thus far unsuccessful efforts to improve pCR rates in this patient population. The findings reshape understanding in the context of T cell immunosurveillance and immunotherapy response in luminal disease. Patients with higher levels of stromal tumour infiltrating lymphocytes or PD-L1 expression experienced higher pCR rates, potentially setting a new standard for future neoadjuvant studies in this subset.
The KEYNOTE-756 study
The authors wrote in the background that pembrolizumab combined with neoadjuvant chemotherapy in the phase II, I-SPY2 study more than doubled the estimated pCR rates for patients with high-risk, defined by MammaPrint score, ER-positive, HER2-negative tumours compared with patients receiving neoadjuvant chemotherapy alone. Additionally, pembrolizumab combined with neoadjuvant chemotherapy has been shown to improve pCR and EFS in patients with early-stage TNBC.
KEYNOTE-756 investigators built on previous findings and conducted a double-blind, placebo-controlled phase III study in which patients with previously untreated ER-positive, HER2-negative grade 3 high-risk invasive breast cancer were randomly assigned 1:1 to neoadjuvant pembrolizumab or placebo every 3 weeks given with paclitaxel weekly for 12 weeks, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide every 2 or 3 weeks. After surgery with or without adjuvant radiotherapy, patients received adjuvant pembrolizumab or placebo for 9 cycles plus adjuvant endocrine therapy. Dual primary endpoints were pCR and EFS in the intention-to-treat population.
In total, 635 patients were assigned to the pembrolizumab/chemotherapy arm and 643 to the placebo/chemotherapy arm. At the study’s prespecified first interim analysis, the pCR rate was 24.3% in the pembrolizumab/chemotherapy arm and 15.6% in the placebo/chemotherapy arm (p = 0.00005). EFS was not mature in this analysis.
A numerically higher rate of pCR difference was observed with higher tumour PD-L1 expression and in the subgroup of patients with ER positivity <10%. The estimated treatment differences in the prespecified subgroups based on PD-L1 combined positive score (CPS) of <1, ≥1 and ≥10 were 4.5, 9.8 and 13.2 percentage points, respectively. The estimated treatment difference was 17.4 percentage points in the post hoc subgroup analysis of pCR based on PD-L1 CPS of ≥20. The addition of pembrolizumab to neoadjuvant chemotherapy also shifted more patients to lower RCB categories, demonstrating the ability of the combination to reduce tumour tissue remaining after surgery among those without pCR.
During the neoadjuvant phase, treatment-related adverse events of grade ≥3 were reported in 52.5% and 46.4% of patients in the pembrolizumab/chemotherapy and placebo/chemotherapy arms. Adverse events in the pembrolizumab/chemotherapy arm were consistent with the known safety profiles of the individual agents.
The authors commented that the results are consistent with those from the phase II, I-SPY2 study in which the addition of pembrolizumab to chemotherapy improved pCR in patients with previously untreated, high-risk, early-stage, HER2-negative breast cancer. In the phase III, CheckMate 7FL study, a similar improvement in pCR outcomes was reported among patients with high-risk, early-stage, grade 2 or grade 3 ER-positive, HER2-negative breast cancer who received nivolumab plus neoadjuvant chemotherapy compared to those who received placebo plus neoadjuvant chemotherapy. Data for other primary endpoint of EFS in both, CheckMate 7FL and KEYNOTE-756 studies, are not mature and continue to be evaluated.
References
- Loi S, Salgado R, Curigliano G, et al. Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial. Nature Medicine; Published online 21 January 2025. DOI: https://doi.org/10.1038/s41591-024-03414-8
- Cardoso F, O’Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2− breast cancer: a randomized phase 3 trial. Nature Medicine; Published online 21 January 2025. DOI: https://doi.org/10.1038/s41591-024-03415-7