Impact of Dual Immunotherapies Before Surgery in HR+/HER2-negative Breast Cancer

In this new study, researchers assessed the feasibility of treating HR+/HER2-negative breast cancer patients with the immunotherapies durvalumab and tremelimumab before standard neoadjuvant chemotherapy and surgery.

Breast cancer immunotherapy has shown promise, but its clinical efficacy remains limited, especially for hormone receptor positive (HR+)/HER2-negative breast cancer. While immune checkpoint inhibitors combined with chemotherapy have benefitted some early-stage and metastatic triple-negative breast cancer patients, HR+/HER2-negative cases have seen fewer improvements.

Recent neoadjuvant trials indicate that early-stage HR+/HER2-negative breast cancers might respond better to immunotherapy strategies that amplify tumor-infiltrating lymphocytes (TILs) through dual PD-(L)1/CTLA-4 checkpoint inhibition before surgery and chemotherapy. This approach could enhance the immune response in the tumor microenvironment and improve outcomes for this challenging breast cancer subtype.

The Study

Increased TILs are associated with improved neoadjuvant chemotherapy (NACT) responses across breast cancer subtypes. Recently, researchers Haven R. Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, Elizabeth A. Mittendorf, and Jennifer K. Litton from the University of Texas MD Anderson Cancer Center, Brigham and Women’s Hospital, Dana-Farber Brigham Cancer Center, and Harvard Medical School hypothesized that amplifying TILs via dual checkpoint blockade would enhance the response to subsequent NACT in breast tumors. 

Their new study aimed to assess the feasibility of enrolling untreated patients with stage II or III HR+/HER2-negative breast cancer for upfront treatment with combined PD-L1/CTLA-4 checkpoint inhibition before standard NACT and surgery. The research paper, published in Oncotarget’s Volume 15 on March 19, 2024, was entitled, “Durvalumab and tremelimumab before surgery in patients with hormone receptor positive, HER2-negative stage II–III breast cancer.”

“This feasibility study was conducted to begin testing the hypothesis that dual checkpoint blockade would increase TIL and enhance the response to subsequent NACT in patients with stage II or III HR+/HER2-negative breast cancer.”

Patient Screening, Recruitment, & Assessment

The study aimed to accrue 16 patients to evaluate the feasibility of enrolling patients with clinical stage II or III HR+/HER2-negative breast cancer onto a trial evaluating investigational immunotherapy agents before standard NACT. Patient tumor samples were collected to assess immunologic and molecular responses to combination checkpoint blockade.

Eligible patients had to have HR+/HER2-negative breast cancer, defined as estrogen receptor (ER) and/or progesterone receptor (PR) expression >10% by immunohistochemistry (IHC), and HER2-negative defined as 0/1+ by IHC or if 2+, negative by fluorescence in situ hybridization. Other inclusion criteria included an ECOG performance status of 0 or 1, planned NACT, and adequate blood counts and organ function.

Patients were excluded if they had received prior PD-1, PD-L1, or CTLA-4 inhibitors or any prior treatment for the primary breast cancer. Other exclusions included current or prior use of immunosuppressive medications within 28 days, active or previous autoimmune disease within 2 years, inflammatory bowel disease, or receipt of a live attenuated vaccination within 30 days before study entry or treatment.

Durvalumab was administered at 1500 mg IV, and tremelimumab at 75 mg IV for 2 cycles on days 1 and 28. Patients then proceeded to standard NACT followed by breast surgery. Baseline breast ultrasounds were performed within 21 days before the first immunotherapy cycle and again between 1 and 7 days after the second cycle. Research biopsies were collected at baseline and after 2 cycles of immunotherapy.

Results & Discussion

The trial’s target accrual of 16 patients was not met, as it was stopped early after three of the first eight enrolled patients experienced immunotherapy-related toxicity or suspected disease progression, indicating that this strategy is not clinically feasible.

Among the eight patients who did receive the study-specified combination immunotherapy, seven had pre- and post-immunotherapy ultrasounds performed, showing mixed responses. Three experienced an increase in tumor volume, three a decrease, and one showed stable disease. The impact of combination immunotherapy on TILs was also mixed. Though limited by the number of patients with available serial biopsies, there did not appear to be a significant increase in the immune response within the tumor microenvironment (TME).

The Phase II NIMBUS trial also assessed dual checkpoint blockade in breast cancer, though in a population of metastatic breast cancer patients with tumors harboring a high tumor mutation burden (TMB ≥9 mutations per megabase). Of the 30 patients enrolled, 20 had ER+/HER2-negative breast cancer. The overall response rate (ORR) was 16.7%, with four durable responses lasting at least 15 months. Three of the five responders had a TMB ≥14 mutations per megabase. The ORR among patients with TMB <14 mutations per megabase was 6.7%. Three patients (10%) experienced grade 3 immune toxicity.

The TAPUR basket trial similarly included patients with TMB-high metastatic breast cancer but utilized single-agent anti-PD-1 checkpoint blockade (pembrolizumab) rather than combination immunotherapy. Half of the 28 enrolled patients had ER+ breast cancer, and the majority had received multiple prior lines of systemic therapy. The ORR was 21% with a median progression-free survival (PFS) of 10.6 weeks. Five patients (17.9%) experienced one or more grade 3 adverse events possibly attributed to pembrolizumab, and six patients discontinued treatment due to side effects.

In summary, while a minority of patients with ER+ metastatic breast cancer may benefit from anti-PD-(L)1/anti-CTLA-4 checkpoint blockade, the majority risk exposure to immune-related adverse events without additional benefit.

Conclusion & Future Directions

The present study did not demonstrate a clear benefit for dual checkpoint blockade administered prior to NACT in patients with stage II or III HR+/HER2-negative breast cancer. Only one out of eight patients (12.5%) achieved a pathologic complete response (pCR) at the time of breast surgery after immune therapy and NACT. Two patients experienced grade 3 immunotherapy-related toxicity.

While the KEYNOTE-756 and CheckMate 7FL trials have demonstrated improved pCR rates with the addition of single-agent anti-PD-1 checkpoint blockade to NACT for patients with high-risk HR+/HER2-negative, stage II/III breast cancer, the risk/benefit calculus of adding immunotherapy for this subtype is different from metastatic triple-negative breast cancer (TNBC) or even stage II/III TNBC, where the risks of morbidity and mortality from disease are higher.

Hopefully, biomarkers such as PD-L1 expression and tumor mutation burden (TMB) will guide the use of single or dual-agent immunotherapy towards those patients most likely to benefit, sparing others from significant toxicity. Notably, immune-mediated adverse events of grade 3 or higher were reported in 12.9% of breast cancer patients receiving pembrolizumab in the KEYNOTE-522 trial and in 38% of patients receiving dual ipilimumab/nivolumab in a trial of patients with metastatic melanoma.

For immunotherapy to play a meaningful role in HR+/HER2-negative early breast cancer, a breast cancer subtype where most patients are cured with standard therapy, it will need to significantly increase the fraction of cured patients without disproportionately causing serious and/or long-term immune toxicity. Future research should focus on identifying predictive biomarkers and optimizing combination strategies to enhance the efficacy of immunotherapy in this challenging breast cancer subtype.

Click here to read the full research paper in Oncotarget.

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