Purpose: Treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid dMMR/MSI tumors and in-depth biomarker analyses were performed to inform precision immunotherapy approaches. Patients and methods: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol (DRUP), a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response (OR) or stable disease ≥ 16 weeks). Whole-genome sequencing and RNA-sequencing were performed on pre-treatment tumor biopsies. Results: 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% (95% CI: 53 – 70) with an OR in 45% (95% CI: 36 – 54). After a median follow-up of 14.5 months (95% CI: 13 – 19), median progression-free survival was 18 months (95% CI 9 – not reached) and median overall survival was not reached. While CB was not or only weakly associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, where markers of adaptive immunity dominated the biomarker landscape. Conclusions: Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor-type specific biomarkers for guiding immunotherapy.

中文翻译：

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dMMR/MSI 癌症的先天免疫状况可预测纳武单抗治疗的结果：药物重新发现方案的结果


目的：评估纳武单抗在晚期难治性实体 dMMR/MSI 肿瘤患者中的治疗效果，并进行深入的生物标志物分析，为精准免疫治疗方法提供信息。患者和方法：用尽标准护理治疗方案的 dMMR/MSI 肿瘤患者被纳入药物再发现方案 (DRUP)，这是一项泛癌临床试验，根据癌症患者的肿瘤分子谱和非药物治疗方案来治疗癌症患者。标签抗癌药物（NCT02925234）。患者接受纳武单抗治疗（四个周期，每 2 周 240 mg，此后每 4 周 480 mg）。主要终点是临床获益（CB：客观缓解（OR）或疾病稳定≥16周）。对治疗前的肿瘤活检进行全基因组测序和 RNA 测序。结果：纳入了 130 名可评估患者，患有 16 种不同的癌症类型。 62% (95% CI: 53 – 70) 观察到 CB，45% (95% CI: 36 – 54) 观察到 OR。中位随访 14.5 个月（95% CI：13 – 19）后，中位无进展生存期为 18 个月（95% CI 9 – 未达到），且中位总生存期尚未达到。虽然 CB 与适应性免疫细胞浸润标志物没有或仅有微弱的相关性，但 CB 与广泛的先天免疫受体/配体的表达密切相关。这与黑色素瘤的发现形成鲜明对比，黑色素瘤中适应性免疫标志物主导了生物标志物景观。结论：纳武单抗被证明对晚期 dMMR/MSI 肿瘤非常有效。关键先天免疫受体/配体的表达是良好治疗结果的主要预测因素，与黑色素瘤的研究结果形成鲜明对比，并加强了指导免疫治疗的肿瘤类型特异性生物标志物的基本原理。