Kankeu Fonkoua Lionel A, Chakrabarti Sakti, Sonbol Mohamad B, Kasi Pashtoon M, Starr Jason S, Liu Alex J, Nevala Wendy K, Maus Rachel L, Bois Melanie C, Pitot Henry C, Chandrasekharan Chandrikha, Ross Helen J, Wu Tsung-Teh, Graham Rondell P, Villasboas Jose C, Weiss Matthias, Foster Nathan R, Markovic Svetomir N, Dong Haidong, Yoon Harry H
Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Department of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Int J Cancer. 2021 Jul 15;149(2):378-386. doi: 10.1002/ijc.33559. Epub 2021 Mar 26.
Through our involvement in KEYNOTE-059, we unexpectedly observed durable responses in two patients with metastatic gastroesophageal adenocarcinoma (mGEA) who received ramucirumab (anti-VEGFR-2)/paclitaxel after immune checkpoint inhibition (ICI). To assess the reproducibility of this observation, we piloted an approach to administer ramucirumab/paclitaxel after ICI in more patients, and explored changes in the immune microenvironment. Nineteen consecutive patients with mGEA received ICI followed by ramucirumab/paclitaxel. Most (95%) did not respond to ICI, yet after irRECIST-defined progression on ICI, all patients experienced tumor size reduction on ramucirumab/paclitaxel. The objective response rate (ORR) and progression-free survival (PFS) on ramucirumab/paclitaxel after ICI were higher than on the last chemotherapy before ICI in the same group of patients (ORR, 58.8% vs 11.8%; PFS 12.2 vs 3.0 months; respectively). Paired tumor biopsies examined by imaging mass cytometry showed a median 5.5-fold (range 4-121) lower frequency of immunosuppressive forkhead box P3+ regulatory T cells with relatively preserved CD8+ T cells, post-treatment versus pre-treatment (n = 5 pairs). We then compared the outcomes of these 19 patients with a separate group who received ramucirumab/paclitaxel without preceding ICI (n = 68). Median overall survival on ramucirumab/paclitaxel was longer with (vs without) immediately preceding ICI (14.8 vs 7.4 months) including after multivariate analysis, as was PFS. In our small clinical series, outcomes appeared improved on anti-VEGFR-2/paclitaxel treatment when preceded by ICI, in association with alterations in the immune microenvironment. However, further investigation is needed to determine the generalizability of these data. Prospective clinical trials to evaluate sequential treatment with ICI followed by anti-VEGF(R)/taxane are underway.
通过参与KEYNOTE-059研究，我们意外地观察到两名转移性胃食管腺癌（mGEA）患者在免疫检查点抑制（ICI）后接受雷莫西尤单抗（抗VEGFR-2）/紫杉醇治疗时出现了持久反应。为了评估这一观察结果的可重复性，我们尝试了一种在更多患者中于ICI后给予雷莫西尤单抗/紫杉醇的方法，并探索免疫微环境的变化。19例连续的mGEA患者接受了ICI，随后接受雷莫西尤单抗/紫杉醇治疗。大多数（95%）患者对ICI无反应，但在根据irRECIST标准确定的ICI进展后，所有患者在接受雷莫西尤单抗/紫杉醇治疗后肿瘤大小均减小。在ICI后接受雷莫西尤单抗/紫杉醇治疗的客观缓解率（ORR）和无进展生存期（PFS）高于同一组患者在ICI前的最后一次化疗（ORR分别为58.8%和11.8%；PFS分别为12.2个月和3.0个月）。通过成像质谱流式细胞术检查配对的肿瘤活检样本显示，治疗后与治疗前相比（n = 5对），免疫抑制性叉头框P3 +调节性T细胞频率中位数降低了5.5倍（范围4 - 121），而CD8 + T细胞相对保留。然后，我们将这19例患者的结果与另一组未接受ICI而直接接受雷莫西尤单抗/紫杉醇治疗的患者（n = 68）进行了比较。在雷莫西尤单抗/紫杉醇治疗时，包括多变量分析后，立即接受ICI的患者的中位总生存期长于未接受ICI的患者（14.8个月对7.4个月），PFS也是如此。在我们的小型临床系列中，ICI后接受抗VEGFR-2/紫杉醇治疗的结果似乎有所改善，且与免疫微环境的改变有关。然而，需要进一步研究以确定这些数据的普遍性。评估ICI序贯抗VEGF（R）/紫杉烷治疗的前瞻性临床试验正在进行中。
