Cambridge University Hospitals National Health Service Foundation Trust, Department of Oncology, Cambridge, UK.
Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
Ann Oncol. 2021 May;32(5):590-599. doi: 10.1016/j.annonc.2021.02.004. Epub 2021 Feb 17.
Gastroesophageal adenocarcinoma (GEA) and squamous esophageal cancer (ESCC) are responsible for >1 million deaths annually globally. Until now, patients with metastatic GEA and ESCC could anticipate survival of <1 year. Anti- programmed cell death protein 1 (anti-PD-1) monotherapy has demonstrated modest efficacy in previously treated GEA and ESCC. In 2020, four pivotal trials have established anti-PD-1 therapy as a new standard of care for selected GEA and ESCC patients as first-line advanced and adjuvant therapy. In this review, we discuss the recent results of the CheckMate 649, ATTRACTION-4, KEYNOTE-590 and CheckMate 577 trials. We consider these results in the context of current standards of care and historical trials of immune checkpoint blockade in GEA and ESCC. We explore biomarker selection for anti-PD-1 therapy and appraise the future of combination therapies. In CheckMate 649, treatment with oxaliplatin-fluoropyrimidine chemotherapy plus nivolumab in patients with combined positive score ≥5 GEA tumors provided a clinically meaningful and statistically significant improvement in overall survival. The ATTRACTION-4 trial did not see a similar overall survival benefit, despite a clear improvement in progression-free survival. We review potential explanations for this result. KEYNOTE-590 showed profoundly improved survival when pembrolizumab was added to cisplatin-fluoropyrimidine chemotherapy in ESCC patients with combined positive score ≥10 tumors; this benefit was less convincing in unselected ESCC. Finally, CheckMate 577 provides proof-of-concept for the improvement in disease-free survival with adjuvant nivolumab in high-risk resected GEA and ESCC following trimodality therapy. Immune checkpoint blockade has come of age in GEA and ESCC, and will now be integrated into first-line and earlier lines of therapy, providing benefit for a larger proportion of patients. Biomarker standardization will be critical to select the patients most likely to benefit from treatment. For patients with immune evasive tumors, novel combinations under development show promise; however, global trials are needed.
胃食管腺癌（GEA）和食管鳞状细胞癌（ESCC）每年在全球导致超过 100 万人死亡。到目前为止，转移性 GEA 和 ESCC 患者的预期生存时间不到 1 年。抗程序性死亡蛋白 1（抗 PD-1）单药治疗已证明在先前治疗的 GEA 和 ESCC 中具有适度疗效。2020 年，四项关键试验确立了抗 PD-1 治疗作为一种新的标准治疗方法，用于选定的 GEA 和 ESCC 患者作为一线晚期和辅助治疗。在这篇综述中，我们讨论了 CheckMate 649、ATTRACTION-4、KEYNOTE-590 和 CheckMate 577 试验的最新结果。我们根据当前的标准治疗方法和 GEA 和 ESCC 中免疫检查点阻断的历史试验来考虑这些结果。我们探讨了抗 PD-1 治疗的生物标志物选择，并评估了联合治疗的未来。在 CheckMate 649 中，奥沙利铂-氟嘧啶化疗加nivolumab 治疗联合阳性评分≥5 的 GEA 肿瘤患者，在总生存期方面提供了具有临床意义和统计学意义的改善。ATTRACTION-4 试验没有看到类似的总生存期获益，尽管无进展生存期有明显改善。我们回顾了这种结果的潜在解释。KEYNOTE-590 显示在联合阳性评分≥10 的 ESCC 患者中，顺铂-氟嘧啶化疗加 pembrolizumab 治疗可显著改善生存；在未经选择的 ESCC 患者中，这一获益不那么令人信服。最后，CheckMate 577 为三联疗法后高危切除的 GEA 和 ESCC 患者接受辅助 nivolumab 治疗时疾病无进展生存期的改善提供了概念验证。免疫检查点阻断在 GEA 和 ESCC 中已经成熟，现在将被整合到一线和更早的治疗线中，为更多的患者提供获益。生物标志物标准化对于选择最有可能从治疗中获益的患者至关重要。对于具有免疫逃避肿瘤的患者，正在开发的新组合显示出希望；然而，还需要全球试验。
