Ho Alice Y, Shiao Stephen, Kobald Samantha A, Chen Jonathan, Duda Dan G, Ly Amy, Bossuyt Veerle, Cho Hae Lin, Arnold Brittany, Knott Simon, Gupta Gaorav P, McAndrew Philomena, Karlan Scott, Tighiouart Mourad, Muzikansky Alona, Basho Reva, McArthur Heather
Department of Radiation Oncology, Duke University Medical Center, Durham, NC.
Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA.
J Clin Oncol. 2024 Dec 20;42(36):4282-4293. doi: 10.1200/JCO.24.00003. Epub 2024 Sep 19.
To assess safety and immune biomarkers after preoperative radiation therapy (RT) and anti-PD1 therapy in breast cancer.
A phase I/IIb trial of pembrolizumab with RT was conducted in patients with triple-negative breast cancer (TNBC) and hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. All received pembrolizumab followed by a second cycle + RT (anti-PD1/RT) of 24 Gy/three daily fractions delivered to the breast tumor and then neoadjuvant chemotherapy (NAC). Blood and tumor biopsies were obtained at baseline, after anti-PD1, and after anti-PD-RT. Coprimary end points were safety and change in tumor-infiltrating lymphocytes (TILs). Secondary end points were pathologic complete response (pCR), residual cancer burden (RCB) rates, and event-free survival (EFS).
Sixty-six patients with stage I-III breast cancer (54 TNBC, 12 HR+/HER2-) were enrolled. The median follow-up was 32 months. Safety end point was met. Incidence of grade ≥3 toxicities was 41%. The pCR rate was 59.2%, 33.3%, and 54.5% for the TNBC, HR+/HER2-, and entire cohort, respectively. A total of 77.8% of TNBC and 41.6% of HR+/HER2- had a near pCR (RCB 0-1). The 3-year EFS was 80%. In the entire cohort, PD-L1 expression increased after anti-PD1 (median Combined Positive Score [CPS], 7.49-23.20; 95% CI, -41.88 to -6.30; = .044) and anti-PD1/RT (median CPS, 7.49-23.41; 95% CI, -41.88 to -6.30; = .009), compared with baseline. In TNBC, adding RT to anti-PD1 significantly decreased TILs (28.9%-17.1%; 95% CI, 2.46 to 21.09; = .014). Baseline TILs correlated with PD-L1 expression and TNF-a.
Preoperative RT with pembrolizumab is safe and results in high pCR rates and 3-year EFS, despite the lack of pembrolizumab during NAC. PD-L1 and TILs may be predictive biomarkers for preoperative anti-PD1/RT response. Reduction in TILs after adding RT to anti-PD1 highlights the importance of treatment sequencing.
评估乳腺癌术前放射治疗（RT）和抗PD-1治疗后的安全性和免疫生物标志物。
对三阴性乳腺癌（TNBC）和激素受体阳性/人表皮生长因子受体2阴性（HR+/HER2-）乳腺癌患者进行了帕博利珠单抗联合RT的I/IIb期试验。所有患者均接受帕博利珠单抗治疗，随后进行第二个周期+RT（抗PD-1/RT），将24 Gy分三次每日剂量照射乳腺肿瘤，然后进行新辅助化疗（NAC）。在基线、抗PD-1治疗后和抗PD-RT治疗后采集血液和肿瘤活检样本。共同主要终点是安全性和肿瘤浸润淋巴细胞（TILs）的变化。次要终点是病理完全缓解（pCR）、残余癌负担（RCB）率和无事件生存期（EFS）。
纳入了66例I-III期乳腺癌患者（54例TNBC，12例HR+/HER2-）。中位随访时间为32个月。达到了安全性终点。≥3级毒性的发生率为41%。TNBC、HR+/HER2-和整个队列的pCR率分别为59.2%、33.3%和54.5%。共有77.8%的TNBC和41.6%的HR+/HER2-接近pCR（RCB 0-1）。3年EFS为80%。在整个队列中，与基线相比，抗PD-1治疗后（中位联合阳性评分[CPS]，7.49-23.20；95%CI，-41.88至-6.30；P=.044）和抗PD-1/RT治疗后（中位CPS，7.49-23.41；95%CI，-41.88至-6.30；P=.009），PD-L1表达增加。在TNBC中，抗PD-1治疗加RT显著降低了TILs（28.9%-17.1%；95%CI，2.46至21.09；P=.014）。基线TILs与PD-L1表达和TNF-α相关。
术前使用帕博利珠单抗进行RT是安全的，尽管在NAC期间未使用帕博利珠单抗，但仍可导致高pCR率和3年EFS。PD-L1和TILs可能是术前抗PD-1/RT反应的预测生物标志物。抗PD-1治疗加RT后TILs减少突出了治疗顺序的重要性。
