Pembrolizumab added to neoadjuvant chemotherapy followed by adjuvant pembrolizumab plus endocrine therapy improved pathologic complete responses in patients with early-stage, high-risk, estrogen receptor (ER)-positive, HER2-negative breast cancer, according to updated results of the phase III KEYNOTE-756 trial reported at the 2023 San Antonio Breast Cancer Symposium (SABCS).1 Pathologic complete responses were improved by the addition of pembrolizumab in subgroups assessed according to geographic location, disease stage, baseline clinical lymph node involvement, and PD-L1 expression.
“[The] addition of pembrolizumab to neoadjuvant chemotherapy led to a statistically significant increase in pathologic complete response in the intention-to-treat population,” stated Joyce O’Shaughnessy, MD, Co-Chair of Breast Cancer Research and Chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and for The US Oncology Network. “A larger magnitude of benefit was observed in patients with node-positive disease, higher PD-L1 CPS [combined positive score] thresholds, and ER-low tumors [defined as less than 10% of ER-positive cells].”
Joyce O’Shaughnessy, MD
Event-free survival, the co-primary endpoint, is immature and will be reported at a future time.
Study Details
KEYNOTE-756 enrolled 1,278 patients with invasive ductal breast carcinoma who had T1c to T2 disease and one to two positive lymph nodes or T3 to T4 disease with zero to two positive lymph nodes. Patients had centrally confirmed ER-positive, HER2-negative, grade 3 disease and were treatment-naive.
Participants were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo every 3 weeks for four cycles in combination with paclitaxel weekly for 12 weeks, followed by pembrolizumab at 200 mg or placebo plus either doxorubicin or epirubicin in combination with cyclophosphamide for four cycles. After definitive surgery, patients received adjuvant pembrolizumab at 200 mg every 3 weeks or placebo for 6 months paired with endocrine therapy for up to 10 years and concurrent or sequential radiation therapy if indicated.
The treatment arms were generally well balanced for patient characteristics. The median patient age was 49 years (range = 19–82). About 76% had a PD-L1 CPS of 1 or higher, and about 40% had a CPS of 10 or higher. About 62% had stage II disease, and 38% had stage III disease.
Immune-mediated adverse event rates were consistent with the known toxicity profile of neoadjuvant pembrolizumab and chemotherapy. No new safety concerns were observed. The most common immune-mediated adverse events occurring in at least five patients in either the pembrolizumab or placebo arm included hypothyroidism (17.5% vs 1.7%), hyperthyroidism (9.0% vs 0.5%), and pneumonitis (2.8% vs 1.4%).
Updated Results
Previously, with a median follow-up of 33.2 months, data from KEYNOTE-756 reported at the 2023 European Society for Medical Oncology Congress showed the pathologic complete response rate was significantly improved with the addition of pembrolizumab: 24.3% for patients on pembrolizumab (n = 635) vs 15.6% of those in the placebo arm (n = 643), meeting a primary endpoint of the trial, for a significant 8.5% absolute difference between arms (P = .00005).2
New subgroup analyses presented at the 2023 SABCS showed that patients with stage II disease treated with pembrolizumab (n = 399) achieved a pathologic complete response rate of 25.8% vs 16.7% in the placebo arm (n = 408), for an absolute difference of 9.1% favoring pembrolizumab. Patients with stage III disease treated with pembrolizumab (n = 236) had a pathologic complete response rate of 21.6% vs 13.6% with placebo (n = 235), an absolute difference of 8% favoring pembrolizumab.
The subgroup of patients with positive lymph nodes at baseline (n = 570) also had a higher rate of pathologic complete response compared with placebo: 25.1% vs 15.8%, respectively, for an absolute difference of 9.3%. In patients with baseline node-negative disease, the pathologic complete response rate was 16.9% with pembrolizumab vs 13.1% with placebo, an absolute difference of 3.8%.
Other Subgroup Analyses
Pembrolizumab was superior to placebo in subgroups according to geographic region. In patients from China, those treated with pembrolizumab (n = 88) or placebo (n = 91) achieved pathologic complete response rates of 12.5% and 9.9%, respectively. In patients from Eastern Europe, the pathologic complete response rates were 29% with pembrolizumab (n = 139) and 16.2% with placebo. In patients from all other countries, (n = 408), pathologic complete response rate was 25.0% vs 16.6% (n = 422).
A linear improvement in pathologic complete response rate with pembrolizumab was observed with increasing PD-L1 expression. In patients with a PD-L1 CPS less than 1, pathologic complete response rate was 7.2% vs 2.6% with placebo. In patients with a PD-L1 CPS of 1 to 9, the corresponding pathologic complete response rates were 15.7% and 9.1%, respectively. In those with a PD-L1 CPS of 10 or higher, the rate was 42.3% vs 29.0%. In the group of patients with the highest PD-L1 expression (CPS > 20), the corresponding rates were 53.6% and 36.4%, respectively. When the results were analyzed according to ER status and PD-L1 expression, pembrolizumab was also found to be superior to placebo.
DISCLOSURE: Research funding was provided by Merck Sharp & Dohme. Dr. O’Shaughnessy has received consulting fees from Agendia, Aptitude Health, AstraZeneca, Carrick Therapeutics, Daiichi Sankyo, Eisai, F. Hoffmann–La Roche, G1 Therapeutics, Genentech, Gilead Sciences, Immunomedics, Eli Lilly, Loxo Oncology, Merck, Novartis, Ontada, Pfizer, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Seagen, Stemline Therapeutics, and Synthon.
REFERENCES
1. Cardoso F, O’Shaughnessy J, McArthur H, et al: Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2– breast cancer: KEYNOTE-756. 2023 San Antonio Breast Cancer Symposium. Abstract GS01-02. Presented December 6, 2023.
2. Cardoso F, McArthur HL, Schmid P, et al: LBA21 KEYNOTE-756: Phase III study of neoadjuvant pembrolizumab or placebo + chemotherapy followed by adjuvant pembrolizumab or placebo + endocrine therapy for early-stage high-risk ER+/HER2– breast cancer. Ann Oncol 34(suppl 2):S1260-S1261, 2023.
