Pembrolizumab Combo Enhances Response Rate in ER+/HER2– Breast Cancer

The safety profile of pembrolizumab plus neoadjuvant chemotherapy was consistent with the known profiles for each treatment.

Adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy elicited a statistically significant improvement in pathological complete response (pCR) vs placebo in patients with previously untreated estrogen receptor (ER)–positive/HER2-negative grade 3 high-risk invasive breast cancer, according to results from the phase 3 KEYNOTE-756 trial (NCT03725059) published in Nature Medicine.¹

Findings from the first interim analysis of the trial revealed that a pCR benefit was seen in the pembrolizumab/chemotherapy arm at a rate of 24.3% (95% CI, 21.0%-27.8%). The placebo/chemotherapy arm had a pCR rate of 15.6% (95% CI, 12.8%-18.6%), yielding an estimated difference of 8.5% (95% CI, 4.2%-12.9%; P = .00005). Additionally, an absence of invasive and in situ cancer was observed in 21.3% (95% CI, 18.1%-24.7%) and 12.8% (95% CI, 10.3%-15.6%) of the respective groups, an estimated difference of 8.3% (95% CI, 4.2%-12.4%). Furthermore, an absence of invasive cancer in the breast was observed in 29.4% (95% CI, 25.9%-33.2%) and 18.2% (95% CI, 15.3%-21.4%), respectively, a difference of 11.0% (95% CI, 6.5%-15.7%).

“In this randomized phase 3 trial involving patients with previously untreated, high-risk, early-stage, [ER-positive/HER2-negative breast cancer], a significantly higher percentage of patients in the pembrolizumab/chemotherapy arm than in the placebo/chemotherapy arm had a pCR at the time of surgery,” Fatima Cardoso, MD, director of the Breast Unit of the Champalimaud Clinical Centre in Lisbon, Portugal, wrote in the publication with study coinvestigators.¹ “The between-group difference in pCR favored pembrolizumab/chemotherapy across all prespecified subgroups, albeit with a differing magnitude of benefit and wide 95% CIs in some subgroups.”

Investigators in the phase 3 KEYNOTE-756 trial enrolled patients 18 years or older with centrally confirmed ER-positive/HER2-negative grade 3 invasive ductal breast carcinoma, who were randomly assigned 1:1 to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy.

Treatment in the neoadjuvant phase consisted of 200 mg of intravenous pembrolizumab or placebo once every 3 weeks for 4 cycles plus 80 mg m^-2 of paclitaxel once weekly for the first treatment. The second treatment was 4 cycles of pembrolizumab or placebo with either 60 mg m^-2 of doxorubicin (Adriamycin) or 100 mg m^-2 of epirubicin (Ellence) plus 600 mg m^-2 of cyclophosphamide once every 2 or 3 weeks. Patients who completed or discontinued the first treatment could either start the second treatment or undergo surgery. Those who completed or discontinued the second neoadjuvant treatment could undergo surgery.

Surgery consisted of breast conservation or mastectomy with or without sentinel lymph node biopsy or axillary dissection at no more than 6 weeks after the last dose of neoadjuvant treatment. In the adjuvant phase, beginning 60 or fewer days after surgery, patients received pembrolizumab or placebo every 3 weeks for a maximum of 9 cycles plus investigator’s choice of endocrine therapy.

For patients in the pembrolizumab and placebo arms, the median age was 49 (range, 24-82), and 49 years (range, 19-78), most patients had a PD-L1 combined positive score (CPS) of 1 or greater (75.9% vs 76.0%), and most had an ECOG performance status score of 0 (89.8% vs 91.4%). Additionally, in the respective arms, most patients had anthracycline scheduled every 3 weeks (65.4% vs 66.1%), had a T1-T2 tumor classification (63.3% vs 64.2%), had positive nodal involvement (89.8% vs 90.5%), and stage II disease (62.8% vs 63.5%).

The coprimary end points were pCR and event-free survival (EFS), which will be presented during a subsequent analysis.² Secondary objectives included overall survival (OS), pCR rate by residual invasive or in situ cancer, EFS and OS in patients with a PD-L1 CPS of 1 or greater, and safety.

Any-grade adverse events (AEs) occurred in 100% of the pembrolizumab arm and 99.4% of the chemotherapy arm, with grade 3 or higher occurrence rates of 60.1% and 54.5%, respectively. Treatment-related AEs (TRAEs) occurred in 98.4% and 98.6% of the respective arms, with grade 3 or higher occurrence rates of 52.5% and 46.4%. The most common grade 3 or higher TRAEs in the respective arms included neutrophil count decreases (14.0% vs 16.0%), neutropenia (13.4% vs 15.7%), and alanine aminotransferase increases (3.8% vs 2.8%).

References

1. 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. Nat Med. Published online January 21, 2025. doi:10.1038/s41591-024-03415-7
2. Study of pembrolizumab (MK-3475) versus placebo in combination with neoadjuvant chemotherapy & adjuvant endocrine therapy in the treatment of early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/​HER2-) breast cancer (MK-3475-756/​KEYNOTE-756). ClinicalTrials.gov. Updated November 19, 2024. Accessed January 29, 2025. https://tinyurl.com/3u4ymdr4