SAN ANTONIO — Preoperative radiotherapy (RT) plus PD-1 inhibitor pembrolizumab (Keytruda) significantly increased immune activation and tumor response in node-positive hormone receptor-positive (HR+)/HER2-negative breast cancer versus pembrolizumab alone, a small randomized trial showed.
The higher of two tumor-directed RT doses led to greater T-cell invasion (TCI) from baseline, whereas pembrolizumab alone or combined with a lower dose of RT did not significantly increase T-cell invasion (P=0.023). TCI response was associated with increased PD-L1 expression. Surgical outcomes also improved with the addition of RT, including node negativity (ypN0), pathologic complete response (pCR), and residual cancer burden (RCB).
An exploratory analysis showed that almost all responses occurred in non-luminal A breast tumors, which account for about 50% of HR+/HER- breast cancers, reported Gaorav Gupta, MD, PhD, of the University of North Carolina at Chapel Hill, at the San Antonio Breast Cancer Symposium (SABCS).
“Despite a high burden of disease and inclusion of non-grade 3 tumors, we observed encouraging rates of pathologic complete response in the radiation-plus-pembrolizumab arms,” said Gupta. “Exploratory analyses suggest the greatest benefit of this radiation-immunotherapy combination is in non-luminal A tumors that induce the highest PD-L1 expression at 2 weeks. Future trials examining preoperative radiation plus pembrolizumab, or other immune checkpoint inhibitors in HR-positive, HER2-negative breast cancer are needed to clarify potential benefits and disease control.”
With regard to “next steps,” Gupta said the future of a radio-immunotherapy approach depends heavily on whether neoadjuvant checkpoint inhibition becomes standard of care for early HR+/HER2- breast cancer.
“Going forward, if we want to increase the number of patients that are responding to immuno-chemotherapy for HR-positive, HER2-negative breast cancer that’s at higher risk, I think we should do future trials that look at this immuno-radiation priming prior to immuno-chemotherapy to see if we can get even more responders,” he added.
Results of the so-called P-RAD trial are within the range of other recent studies of neoadjuvant chemo-immunotherapy for high-risk HR+/HER2- breast cancer, said SABCS discussant Stephen Shiao, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles. Several factors could have limited the immune response and outcomes.
“P-RAD showed that in ER-positive tumors, RT and PD-1 directed therapy can induce activated T-cell responses that may synergize with chemo-immunotherapy,” said Shiao. “Absolute pCR rates in P-RAD may be lower than expected from the positive correlative data due to baseline inclusion of more luminal A tumors and tumors with lower TIL [tumor-infiltrating lymphocyte] and PD-L1 levels. RT-mediate compensatory immunosuppression may prevent some resistant tumors from responding to the triple combination [including chemotherapy].”
Future studies should evaluate post-treatment PD-L1 expression as a way to identify a subset of patients that are responding to neoadjuvant radio-immunotherapy and might receive less aggressive chemotherapy regimens while maintaining high response, Shiao continued. Another potential avenue for future research would target radiation-specific immunosuppressive pathways with neoadjuvant radio-immunotherapy combinations “to effectively harness immune response triggered by radiation.”
The recently reported CheckMate 7FL and KEYNOTE-756 trials showed that adding an immune checkpoint inhibitor to chemotherapy improved pCR versus neoadjuvant chemotherapy in early HR+/HER2- breast cancer.
“But the effect was not uniform,” Gupta said of the two trials. “It seemed that the benefit of immune checkpoint inhibitors was limited or specific to those tumors that already had high stromal TILs or high PD-L1 at baseline. That suggested that if we could perhaps improve the immune infiltration of these tumors before we start the immuno-chemotherapy, we may get better response.”
Investigators in the P-RAD research program are evaluating preoperative RT, in addition to neoadjuvant chemo-immunotherapy, in node-positive HR+/HER2- and triple-negative breast cancer. Gupta reported findings from the HR+/HER2- cohort.
All patients received pembrolizumab alone or with concurrent RT targeting the tumor (9 Gy or 24 Gy in three fractions), followed by neoadjuvant chemotherapy and surgery. The primary endpoint was breast tumor TCI at the 2-week biopsy. The co-primary endpoint was the rate of ypN0, with statistical power to detect an increase in the upper quartile of TCI versus pembrolizumab alone. Secondary endpoints were composite pCR and RCB 0/1 rate and evaluation of PD-L1 expression. With 51 randomized patients, the trial lacked statistical power to compare outcomes for secondary endpoints.
The patients had a median age of 51. Most patients had T2 (37%) or T3 (47%) disease, N1 (51%) or N2 (25%) nodal status, grade 3 (63%) tumors. ER positivity was 90% and progesterone 69%.
The cohort randomized to the higher dose of RT met the primary endpoint, whereas TCI levels did not increase significantly from baseline in the lower RT and pembrolizumab-only cohorts. Patients whose TCI levels met “response” criteria also had significantly higher PD-L1 expression versus the other two cohorts.
Rates of the co-primary endpoint and secondary endpoints for pembrolizumab alone, 9-Gy RT, and 24-Gy RT, respectively, were:
- ypN0: 23.5%, 29.4%, 33.3%
- pCR: 5.9%, 29.4%, 20.0%
- RCB 0/1: 17.7%, 29.4%, 33.3%
Predictors of pCR in the RT plus pembrolizumab groups were non-luminal A (46.7% vs 6.25%, P=0.016), fourth quartile PD-L1 expression at 2 weeks (50% vs 0%, P=0.0024), and non-luminal A plus fourth quartile PD-L1 expression (70% vs 4.8%, P=0.0003).
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