Immunotherapy in early HR⁺ breast cancer: lessons from KN-756 and CM-7FL

Female breast cancer (BC) ranked as the second most common cancer worldwide in 2022, with an estimated 2.3 million new cases diagnosed (1). The classification of intrinsic BC subtypes was established through genomic analysis. However, this method is not feasible in clinical practice and has instead been implemented using immunohistochemical surrogates (2). Hormone receptor (HR)-positive BC accounts for approximately 70% of all BC cases and represents a heterogeneous group concerning genomic features and clinical outcomes, typically characterized by low immunogenicity (3,4). The treatment of high-risk disease includes surgery, chemotherapy, endocrine therapy, and, more recently, cyclin inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA mutations (3). While these approaches have improved outcomes, the potential role of immunotherapy in this population remains under investigation.

Immunotherapy has been incorporated into the neoadjuvant treatment of triple-negative BC (TNBC), demonstrating a benefit in overall survival (OS) (5). In luminal tumors, this strategy has been studied, as a subset may present a more immunogenic tumor microenvironment. The use of a gene expression signature of total tumor-infiltrating lymphocytes (TILs) may help identify patients with immune-rich, estrogen receptor-positive (ER⁺) tumors who could potentially benefit from checkpoint inhibitors (6). In the phase 2 I-SPY2 trial, incorporating pembrolizumab into the standard neoadjuvant chemotherapy (NACT) regimen resulted in a more than two-fold increase in complete pathological response rates compared to chemotherapy alone in HR-positive and HER2-negative BC (7). The phase II GIADA trial also evaluated immunotherapy with NACT in luminal B tumors, demonstrating that patients with PAM50 basal BC had a higher pathological complete response (pCR) rate (8). Building on this, two phase 3 studies have recently evaluated the role of immunotherapy in this setting.

KEYNOTE-756 (KN-756) is a phase 3 trial that assessed the use of pembrolizumab in combination with NACT in high-risk, early-stage ER⁺/HER2⁻ BC. Inclusion criteria included grade 3 tumors greater than 2 cm with axillary involvement or T3–T4 tumors, regardless of axillary status. Notably, 90% of the enrolled population had positive axillary lymph nodes. The study involved 1,278 patients who were randomly assigned to receive either neoadjuvant pembrolizumab or placebo, combined with paclitaxel, followed by doxorubicin/epirubicin plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for nine cycles, along with adjuvant endocrine therapy. At the first interim analysis, the pCR rate was significantly higher in the pembrolizumab group (24.3%) compared to the placebo group (15.6%), with an estimated treatment difference of 8.5 percentage points [95% confidence interval (CI): 4.2–12.8, P=0.00005]. Event-free survival (EFS) data was not yet mature. Patients were stratified according to their programmed death-ligand 1 (PD-L1) expression and the percentage of ER⁺ cells. A numerically higher rate of pCR was observed in patients with higher tumor PD-L1 expression. The estimated treatment differences in prespecified subgroups based on the PD-L1 combined positive score (CPS) were as follows: for CPS <1, the difference was 4.5 percentage points; for CPS ≥1, it was 9.8 percentage points; and for CPS ≥10, it was 13.2 percentage. Additionally, in a post hoc subgroup analysis, the estimated treatment difference for pCR in patients with a PD-L1 CPS of ≥20 was 17.4 percentage points. Although the group of patients with ER positivity <10% was small, there was a notable difference in the magnitude of the benefit in terms of pCR. Among these patients, the pCR rate was 55.9% in the pembrolizumab arm compared to 30.2% in the placebo arm, with an estimated treatment difference of 25.6 percentage points (9).

Similarly, the CheckMate 7FL (CM-7L) is a phase 3 randomized, multicenter, double-blind trial that assessed the addition of nivolumab to NACT in patients with high-risk, early-stage luminal BC. Eligible patients included those with grade 3 or grade 2 tumors (ER 1% to ≤10%), with a total of 510 participants randomized to receive anthracycline and taxane-based chemotherapy combined with either nivolumab or placebo. pCR was significantly higher in the nivolumab arm compared to the placebo arm (24.5% vs. 13.8%; P=0.0021). The benefit was more pronounced in patients with PD-L1-positive tumors, where pCR rates were 44.3% for nivolumab compared to 20.2% for placebo. Patients were further stratified based on TILs. Among patients with TILs greater than 1%, the pCR rate was 44.4% in the nivolumab arm versus 21.1% in the placebo arm. However, in patients with TILs less than 1%, the pCR rate was 9.2% with nivolumab compared to 10% with placebo. The subgroup analysis also stratified patients based on ER expression, showing that in patients with ER <10%, the pCR rate with nivolumab was 55.6% vs. 28.6% with placebo (10).

Regarding safety, both studies reported no unexpected adverse events associated with the use of checkpoint inhibitors. Immune-mediated thyroid disorders were the most common immune adverse events. In the pembrolizumab study, pneumonitis occurred in 2.8% of patients, while in the nivolumab study, adrenal insufficiency was observed in 5.7% of cases (9,10).

The populations of both studies were comparable, with nearly all patients presenting grade 3 tumors and the majority having axillary positive lymph nodes (Table 1). However, a notable difference was observed in the proportion of patients with PD-L1 >1%, which was 76% in the KN-756 trial versus 34% in the CM-7FL trial. In both studies, the benefit in terms of pCR was more pronounced in PD-L1-positive patients, suggesting its potential as a biomarker for guiding immunotherapy in this context. The variation in PD-L1 expression underscores the heterogeneity of the disease. Both studies evaluated PD-L1 using the CPS method, which quantifies PD-L1 expression in tumor cells and the tumor microenvironment, with the VENTANA SP142 assay used in the CM-7FL trial. This variability raises concerns about whether PD-L1 expression is the most suitable biomarker for this selected population.

The role of TILs as a predictor of response is also complex. The presence of TILs has been associated with a higher likelihood of achieving a pCR and improved survival in TNBC. Despite the better prognosis, the role of TILs as a predictor of response to immunotherapy remains uncertain (11,12). In CM-7FL, patients with TILs <1% achieved a 9% pCR rate with nivolumab compared to 10% with chemotherapy, suggesting that the strategy may not be effective in the absence of TILs.

The ImPrint signature was derived from the I-SPY2 trial as a tool to predict responses to immunotherapy. This biomarker integrates gene expression data related to the immune-tumor microenvironment and signaling pathways. Patients with elevated ImPrint scores were frequently found to have high MammaPrint H2 scores and a Basal-like profile on BluePrint. In the pembrolizumab treatment arm, pCR rates were notably higher in ImPrint-positive patients compared to those who were ImPrint-negative (77% vs. 7%) (13). Another prognostic model was developed by combining a proliferation-related gene signature score with the estrogen-related gene expression module of the Oncotype DX recurrence score. Gene expression data from trials involving NACT, neoadjuvant immunotherapy (I-SPY2), and adjuvant endocrine therapy were analyzed. Tumors characterized by high proliferation gene expression and low ER levels showed significantly higher rates of pCR when pembrolizumab was added to NACT (42% vs. 21%, P=0.07) (14). These genomic analysis data suggest that selecting patients based on high proliferation and low ER signaling may offer a more effective strategy for identifying responders. A phase III trial is further assessing this topic (NCT06058377), as patient selection for immunotherapy is being based on the results of MammaPrint Ultrahigh.

Interestingly, patients with ER expression <10% appeared to benefit more from immunotherapy. This finding aligns with literature data showing distinct behavior and poorer survival for the low ER group (15). A real-world French cohort of estrogen and/or progesterone receptor-low (1–9%) BC patients demonstrated a 75% rate of pCR with pembrolizumab, following the KEYNOTE-522 regimen, further supporting the similarity of their behavior to TNBC (16). On the other hand, the spectrum of patients with high ER⁺ expression shows low pCR rates regardless of the treatment received, as shown in the CM-7FL (ER >50%, pCR 19.8% vs. 12.4%) (10).

Despite these positive results, caution is warranted when using pCR as a surrogate endpoint in HR-positive BC. The association between pCR and EFS and OS exists in luminal tumors but with a lesser magnitude compared to HER2-positive and triple-negative tumors (17). The studies planned an analysis of invasive disease-free survival; however, CM-7L had to discontinue enrollment early due to the rapidly evolving treatment landscape, and long-term data will not be available. Therefore, the only trial that will provide long-term invasive-disease-free survival (iDFS) data is KN-756.

Current standard treatment for high-risk HR⁺ BC involves the use of CDK4/6 inhibitors. Abemaciclib demonstrated a benefit in terms of iDFS in the monarchE study, which included patients with positive lymph nodes and other risk factors, while ribociclib also showed a gain in this outcome in the NATALEE study, which included patients with lower risk, including those with negative lymph nodes (18,19). In both immunotherapy studies mentioned here, the adjuvant phase included maintenance with anti-programmed cell death 1 (PD-1) and endocrine therapy but did not include the use of CDK4/6 inhibitors. Therefore, endocrine therapy will be used without CDK4/6 inhibitors, which are drugs with robust benefits in a higher-expression endpoint, in the choice of neoadjuvant immunotherapy. It is worth noting that the population of the KN-756 and CM-7L trials is represented in the monarchE study, as 38% of the patients have grade 3 tumors and would likely derive benefit from this class of drugs. The sequential use of iCDK4 after immunotherapy can be discussed on an individual basis, although this strategy is not currently supported by the existing literature.

Understanding molecular biology, along with the genomic and clinical heterogeneity of HR⁺ BC is crucial. Emerging evidence has identified a subset of luminal tumors with behavior more closely resembling TNBC. In summary, the heterogeneity of HR⁺ BC presents both opportunities and challenges in tailoring immunotherapy. There is a growing body of evidence suggesting that genomic analysis may aid in the selection of patients for this strategy. While subsets of patients, such as those with TIL-rich, PD-L1⁺, or low-ER tumors, may derive benefit, the lack of mature data on iDFS and OS limits its integration into standard practice. Future data should aim to validate these findings while refining biomarkers to better identify responders.

Acknowledgments

None.

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