SACI-IO HR+: a randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer.

To evaluate if pembrolizumab (programmed cell death protein 1 inhibitor) enhances the activity of SG, we conducted a randomized phase II study comparing SG with or without pembrolizumab in HR-positive/HER2-negative MBC.

为了评估帕博利珠单抗（程序性细胞死亡蛋白1抑制剂）是否增强SG的活性，我们进行了一项随机II期研究，比较了在HR阳性/HER2阴性的MBC中，SG联合或不联合帕博利珠单抗的效果。

materials_and_methods

Patients with HR-positive/HER2-negative MBC pretreated with endocrine therapy and 0-1 chemotherapy regimens for MBC (no prior TOP1i) were randomly assigned 1:1 to receive SG plus pembrolizumab or SG.

经过内分泌治疗和0-1个化疗方案治疗的HR阳性/HER2阴性的MBC患者（之前未使用过TOP1i）被随机分为两组，一组接受SG联合帕博利珠单抗治疗，另一组仅接受SG治疗。

Primary endpoint was progression-free survival(PFS).

主要终点是无进展生存期（PFS）。

Key secondary endpoints included PFS in the programmed death-ligand 1 (PD-L1)-positive population (pharmDx 22C3 combined positive score ≥1), overall survival(OS), objective response rate(ORR), and toxicity.

关键次要终点包括程序性死亡配体1（PD-L1）阳性人群中的无进展生存期（PFS）（pharmDx 22C3联合阳性评分≥1），总生存期（OS），客观缓解率（ORR）和毒性。

Baseline tumor tissue and plasma samples were collected for correlative analyses.

收集了基线肿瘤组织和血浆样本，用于相关性分析。

Results

Between March 2021 and January 2024, 104 patients started treatment; 47% (49) had not received chemotherapy for MBC.

在2021年3月至2024年1月之间，共有104名患者开始治疗；其中47%（49名）未接受过MBC的化疗。

At 15.5-month median follow-up, SG plus pembrolizumab did not significantly improve PFS compared with SG [8.4 versus 6.7 months; hazard ratio(HzR) 0.76, 95% confidence interval(CI) 0.48-1.19, P = 0.12].

在15.5个月的中位随访期间，SG联合帕博利珠单抗与SG相比，并未显著改善PFS [8.4个月对比6.7个月；风险比（HzR）0.76，95%置信区间（CI）0.48-1.19，P = 0.12]。

Median OS was 20.0 versus 18.0 months (P = 0.18); ORR was 28.8% versus 19.2% (P = 0.36).

中位总生存期（OS）为20.0个月对比18.0个月（P = 0.18）；客观缓解率（ORR）为28.8%对比19.2%（P = 0.36）。

In the PD-L1-positive population (44%; 39/88 with tissue), median PFS (11.1 versus 5.6 months; HzR 0.51, 95% CI 0.24-1.12, P = 0.09) and OS (18.5 versus 12.5 months; HzR 0.59, 95% CI 0.18-1.98, P = 0.39) numerically increased with the combination.

在PD-L1阳性人群中（占44%；88人中有39人有组织样本），中位无进展生存期（PFS）（11.1对比5.6个月；HzR 0.51，95% CI 0.24-1.12，P = 0.09）和总生存期（OS）（18.5对比12.5个月；HzR 0.59，95% CI 0.18-1.98，P = 0.39）在联合治疗组中数值上有所增加。

Most frequent grade ≥2 adverse events were neutropenia, alopecia, fatigue, anemia, nausea, leukopenia, and diarrhea.

最常见的2级或更高级别的不良事件包括中性粒细胞减少症、脱发、疲劳、贫血、恶心、白细胞减少症和腹泻。

Neither TROP2 expression by immunohistochemistry, immunofluorescence, or plasma epigenome-based analysis, or tumor-infiltrating lymphocytes were associated with outcomes.

通过免疫组织化学、免疫荧光或血浆表观基因组分析的TROP2表达，或肿瘤浸润淋巴细胞均与临床结果无相关性。

Higher circulating tumor DNA fraction and PIK3CA mutations were associated with worse PFS.

较高的循环肿瘤DNA分数和PIK3CA突变与较差的无进展生存期（PFS）相关。

Plasma epigenome-pathway analysis suggested that high cell cycle or epithelial-mesenchymal transition activation may confer sensitivity or resistance to SG, respectively.

血浆表观基因组-通路分析表明，高细胞周期或上皮-间质转化激活可能分别赋予SG敏感性或耐药性。

Conclusions

Addition of pembrolizumab to SG did not significantly improve outcomes in HR-positive/HER2-negative MBC unselected by PD-L1.

在HR阳性/HER2阴性转移性乳腺癌（MBC）患者中，添加帕博利珠单抗到SG治疗并未显著改善临床结果，这些患者未根据PD-L1状态进行选择。

In the PD-L1-positive population, the trend in PFS and OS favoring SG plus pembrolizumab warrants further investigation in larger randomized trials.

在PD-L1阳性人群中，PFS和OS的趋势倾向于SG联合帕博利珠单抗，这需要在更大规模的随机试验中进一步研究。