Clinical trials are now demonstrating the value of immune checkpoint inhibitors as neoadjuvant therapy in certain subsets of patients with hormone receptor–positive, HER2-negative breast cancer. Hope S. Rugo, MD, FASCO, described this newer approach—specifically, which subsets of patients may benefit—at the 2024 Miami Breast Cancer Conference.1 Dr. Rugo is Professor of Medicine and Winterhof Family Distinguished Professor of Breast Oncology and Director of Breast Oncology and Clinical Trials Education, University of California San Francisco Comprehensive Cancer Center.
Hope Rugo, MD, FASCO
As Dr. Rugo noted, hormone receptor–positive breast cancer is a heterogeneous disease in which most tumors are luminal by intrinsic subtyping. However, there is a clear separation between luminal A, luminal B, and basal-like tumors in terms of response to neoadjuvant chemotherapy. The pathologic complete response rate is about 5% for luminal tumors altogether, but it rises to 15% or so among the “more proliferative” luminal B tumors and is more similar to that of triple-negative disease for basal-like tumors, she explained.
The value of achieving a pathologic complete response is also heterogeneous, being less prognostic in luminal A tumors than in luminal B and basal tumors. “Patients with luminal A tumors who do not have a pathologic complete response can still have a very good outcome…. This contrasts with luminal B HER2-negative disease, where there is a clear differential in patients who achieve a pathologic complete response and those who do not…. The differential benefit is greatest in patients with grade 3 disease (hazard ratio [HR] = 0.27), vs grade 1 disease,”2 Dr. Rugo said.
“The selection of patients for immunotherapy using clinicopathologic characteristics means treating a large number of patients for the small number who will benefit,” she continued, adding that gene-expression tests are not the complete answer. Although these assays have been quite useful in predicting chemotherapy benefit, their value is less clear in evaluating those who will benefit from immunotherapy.
Dr. Rugo continued: “The big question is whether or not we can improve our understanding of which hormone receptor–positive tumors benefit from neoadjuvant chemotherapy and how to more accurately predict the subset who will benefit from immunotherapy, where we’ve clearly seen an improved outcome in triple-negative disease.”
Chemotherapy is the standard of care for peri- and premenopausal women with one to three positive axillary nodes, regardless of disease biology. However, a strong response to neoadjuvant therapy may warrant modification/personalization of both neoadjuvant and adjuvant therapies, with this approach benefiting subsets whose response impacts prognosis, she explained.
Guidance From MammaPrint and Immune Signature
It seems likely that candidates for neoadjuvant checkpoint inhibitors can be identified within the hormone receptor–positive, HER2-negative population. I-SPY2 investigators determined that molecular subtypes capturing luminal, basal, and immune biology could predict response to immunotherapy.3 In particular, MammaPrint (MP) high 2 scores and tumors with an immune-positive signature by the Responsive Predictive Subtype-5 (RPS-5) classification identified patients most likely to respond to neoadjuvant pembrolizumab.
MP high 1 scores were mostly seen (90%) in luminal tumors, whereas MP high 2 scores were typically (80%) of the basal subtype. Rates of pathologic complete response to pembrolizumab plus chemotherapy were 21% in patients with MP high 1 scores and 19% in patients with luminal tumors, but they were 54% in patients with MP high 2 scores and 67% in patients with basal tumors. Similarly, patients with “immune-positive” tumors by the RPS-5 classification (two-thirds of which were basal) had a pathologic complete response rate of 69% with neoadjuvant pembrolizumab plus chemotherapy, compared with 4% for immune-negative tumors.
Phase III KEYNOTE-756
The concept of immunotherapy in hormone receptor–positive, HER2-negative disease has moved into the clinic. The randomized KEYNOTE-756 trial evaluated the addition of pembrolizumab to standard neoadjuvant chemotherapy; pembrolizumab was continued in the adjuvant setting in combination with endocrine therapy, in patients with T1c to T2 (≥ 2 cm) clinically node-positive tumors (90%) or T3 or T4 node-negative tumors (10%).4 Three-quarters of the population expressed PD-L1, and approximately 5% of patients had estrogen receptor–low tumors (< 10% positivity). Eligibility for this trial required centrally confirmed grade 3 histology and estrogen receptor positivity.
Overall, pathologic complete rate was seen in 24.3% of those given pembrolizumab plus chemotherapy vs 15.6% of those given chemotherapy alone—an 8.5% improvement with checkpoint inhibition (P = .00005). The benefit was seen across those with stage 2 and 3 disease, with a larger magnitude of benefit obtained among patients who had higher PD-L1 levels, estrogen receptor–low tumors, and full exposure to chemotherapy. Given that 90% of patients had node-positive disease, it is impossible to assess the impact of pembrolizumab separately in the node-negative population.
Elaborating on the effect of PD-L1 expression in this estrogen receptor–positive, HER2-negative population, Dr. Rugo noted that pathologic complete response rates improved by level of expression, reaching 53.6% (a 17.4% increase over chemotherapy alone) in patients with a combined positive score (CPS) ≥ 20, with a 13.2% increase in pathologic complete response in patients with a CPS ≥ 10. All subsets of PD-L1 positivity including CPS < 1 had higher pathologic complete response rates with pembrolizumab than with placebo, although some subsets are small, limiting interpretation. Similar to that seen in patients with triple-negative breast cancer, PD-L1 positivity predicted higher pathologic complete response rates with chemotherapy alone. Level of estrogen receptor expression was also important in PD-L1–positive tumors. In the 72 patients with estrogen receptor expression of less than 10%, the pathologic complete response rate was 57.6% (a 24.2% increase). Higher expression of the estrogen receptor was associated with far less benefit from immunotherapy (9.2% increase), although this analysis was limited to all patients with estrogen receptor expression of > 10% (n = 889).
Phase III Checkmate 7FL
The phase III Checkmate 7FL trial5 essentially validated the findings of KEYNOTE-756 and provided a basis for correlative studies. With a primary endpoint of pathologic complete response rate, the study enrolled 521 patients with high-risk, estrogen receptor–positive, HER2-negative disease; 80% had positive nodes, and 33% had PD-L1 expression ≥ 1%. Although grade 2 histology with low estrogen receptor expression was allowed, essentially all enrolled patients had grade 3 disease. Patients were randomly assigned to receive neoadjuvant chemotherapy with or without nivolumab, followed by adjuvant endocrine therapy with or without nivolumab.
“There was a significant improvement in pathologic complete response rate, regardless of how it was defined, with nivolumab,” Dr. Rugo reported. The primary endpoint, pathologic complete response rate in the modified intent-to-treat population, was 24.5% with nivolumab plus chemotherapy and 13.8% with paclitaxel alone—an increase of 10.5% (P = .0021). “Benefit appeared to be greatest in patients with PD-L1–positive disease (44.3% vs 20.2%—a 24.1% increase), a greater variation by PD-L1 expression than that seen in triple-negative breast cancer.... Having any percent tumor-infiltrating lymphocytes also improved the rates, as did estrogen expression ≤ 50%.” The interaction between PD-L1 and estrogen receptor expression is of great interest for future analyses, as are, of course, other predictive markers for response to immunotherapy.
Words of Caution
Despite such exciting results, Dr. Rugo shared these cautionary comments. “Given the toxicity and cost of immunotherapy,” it is still too early to incorporate checkpoint inhibitors into the care of patients with hormone receptor–positive, HER2-negative breast cancer. “We need the event-free survival data to understand how to incorporate pembrolizumab into the neoadjuvant/adjuvant setting for patients with estrogen receptor–positive disease with one important exception: patients with estrogen receptor expression < 10%, where 80% have basal-like disease. These patients benefit from treatment that is targeted to triple-negative disease, so for those patients, I would argue we should routinely be giving a checkpoint inhibitor in combination with neoadjuvant chemotherapy,” she added.
The next challenge will be to determine the optimal use in early disease of the CDK4/6 inhibitors abemaciclib and ribociclib in patients who qualify for neoadjuvant followed by adjuvant immunotherapy, as these agents should not be combined with checkpoint inhibitors because of increased toxicity. “That will be a question for the future,” Dr. Rugo concluded.
DISCLOSURE: Dr. Rugo has received honoraria from Napo Pharmaceuticals, Chugai, Puma, and Mylan.
REFERENCES
1. Rugo H: Neoadjuvant immunotherapy for estrogen receptor-positive disease. Invited lecture. 2024 Miami Breast Cancer Conference. Presented March 9, 2024.
2. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384:164-172, 2014.
3. Huppert LA, Rugo H, Pusztai L, et al: Pathologic complete response rates for HR+/HER2– breast cancer by molecular subtype in the I-SPY2 trial. 2022 ASCO Annual Meeting. Abstract 504. Presented June 7, 2022.
4. 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.
5. Loi S, Curigliano G, Salgado R, et al: Biomarker results in high-risk estrogen receptor positive, human epidermal growth factor receptor 2 negative primary breast cancer following neoadjuvant chemotherapy ± nivolumab: An exploratory analysis of CheckMate 7FL. 2023 San Antonio Breast Cancer Symposium. Abstract GS01-01. Presented December 6, 2023.
