Shitara Kohei, Tamiya Motohiro, Okishio Kyoichi, Hosaka Hisashi, Shinozaki Katsunori, Seki Nobuhiko, Hara Hiroki, Narita Yukiya, Shiraishi Takeshi, Tamura Yosuke, Tsuji Akihito, Tsuji Kunihiro, Watanabe Naohiro, Tanaka Hiroshi, Yamaguchi Toshifumi, Yamaguchi Kensei, Izumi Hiroki, Ushida Yasunori, Suna Hideaki
Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
Cancer Res Commun. 2025 Jun 1;5(10):1809-1820. doi: 10.1158/2767-9764.CRC-25-0169.
It is challenging to identify the appropriate patients who benefit from anti-PD-1/PD-L1 monotherapy. For predicting effectiveness of anti-PD-1/PD-L1 monotherapy, this open-label phase II study (ONO-4538-88) evaluated the potential of the tumor-infiltrating lymphocyte (TIL) biomarker: the balance between cytotoxic T cells and regulatory T cells.
Patients with advanced non-small cell lung cancer (NSCLC) or gastric cancer were screened between March 2021 and January 2022. Eligible patients who met the prespecified TIL biomarker criteria received nivolumab monotherapy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival and progression-free survival. Conventional biomarkers (tumor proportion score, combined positive score, tumor mutation burden, and microsatellite instability) were exploratorily analyzed, and safety was also assessed.
Thirty-seven patients with NSCLC and 127 patients with gastric cancer were eligible for TIL analysis: 6 (16.2%) and 15 patients (11.8%) met the TIL biomarker criteria, respectively; a part of them were assessed. For NSCLC and gastric cancer, the ORR was 80% (4/5 patients) and 36.4% (4/11 patients), respectively; all the five patients and 5/11 patients had a reduction in tumor size, respectively; the median overall survival was not reached and 25 months, respectively; and the median progression-free survival was not reached and 5.59 months, respectively. Treatment-related adverse events occurred in 13/19 patients overall: 5/6 patients for NSCLC and 8/13 patients for gastric cancer.
Although the low positive rate of the TIL biomarker limits interpretation, the promising ORRs suggest signs of the TIL biomarker's predictability for nivolumab monotherapy.
In this phase II study, we examined the predictive utility of the TIL biomarker for nivolumab monotherapy. Although the positivity of the TIL biomarker was limited, the promising efficacy and safety profile in the TIL biomarker-positive patients may suggest the potential utility of the TIL biomarker.
识别能从抗PD - 1/PD - L1单药治疗中获益的合适患者具有挑战性。为预测抗PD - 1/PD - L1单药治疗的有效性，这项开放标签的II期研究（ONO - 4538 - 88）评估了肿瘤浸润淋巴细胞（TIL）生物标志物的潜力：细胞毒性T细胞与调节性T细胞之间的平衡。
在2021年3月至2022年1月期间对晚期非小细胞肺癌（NSCLC）或胃癌患者进行筛查。符合预先设定的TIL生物标志物标准的合格患者接受纳武利尤单抗单药治疗。主要终点是客观缓解率（ORR）。次要终点包括总生存期和无进展生存期。对传统生物标志物（肿瘤比例评分、联合阳性评分、肿瘤突变负荷和微卫星不稳定性）进行探索性分析，并评估安全性。
37例NSCLC患者和127例胃癌患者符合TIL分析条件：分别有6例（16.2%）和15例（11.8%）符合TIL生物标志物标准；其中部分患者接受了评估。对于NSCLC和胃癌，ORR分别为80%（5例中的4例）和36.4%（11例中的4例）；5例患者全部和11例中的5例患者肿瘤大小均有所缩小；中位总生存期分别未达到和为25个月；中位无进展生存期分别未达到和为5.59个月。总体上19例患者中有13例发生了与治疗相关的不良事件：NSCLC患者中有5/6例，胃癌患者中有8/13例。
尽管TIL生物标志物的阳性率较低限制了解读，但令人鼓舞的ORR表明TIL生物标志物对纳武利尤单抗单药治疗具有预测性的迹象。
在这项II期研究中，我们检验了TIL生物标志物对纳武利尤单抗单药治疗的预测效用。尽管TIL生物标志物的阳性率有限，但TIL生物标志物阳性患者中令人鼓舞的疗效和安全性概况可能表明TIL生物标志物具有潜在效用。
