Newly reported data from a Phase III trial led by researchers at the Netherlands Cancer Institute demonstrated the success of immunotherapy before surgery (neoadjuvant therapy) for patients with metastatic melanoma, supporting data from previous Phase II studies. Results from the Phase III NADINA study showed that 59% of percent of patients with resectable stage III melanoma responded so well to neoadjuvant therapy using the PD-1 inhibitors ipilimumab plus nivolumab that adjuvant immunotherapy—treatment given after surgery—was no longer needed..

荷兰癌症研究所（Netherlands Cancer Institute）研究人员领导的一项III期临床试验的最新报告数据表明，转移性黑色素瘤患者术前免疫治疗（新辅助治疗）取得了成功，支持了之前II期研究的数据。III期NADINA研究的结果显示，59%的可切除III期黑色素瘤患者对使用PD-1抑制剂ipilimumab加nivolumab的新辅助治疗反应良好，因此不再需要术后辅助免疫治疗。。

Headed by Christian Blank, PhD, the team reported on the NADINA trial findings at ASCO 2024, the international congress of the American Society of Clinical Oncology in Chicago, and in a published paper in NEJM, titled “Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.” In their paper the team concluded, “Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab.”.

该团队由Christian Blank博士领导，在芝加哥举行的美国临床肿瘤学会国际会议ASCO 2024上报告了NADINA试验结果，并在NEJM上发表了一篇题为“新辅助Nivolumab和Ipilimumab在可切除的III期黑色素瘤中的作用”的论文。在他们的论文中，该团队得出结论，“在可切除的宏观III期黑色素瘤患者中，新辅助Ipilimumab加Nivolumab，然后进行手术和反应驱动的辅助治疗比手术后辅助Nivolumab导致更长的无事件生存期。”。

Standard treatment for patients with metastatic skin cancer (melanoma, stage III) consists of local lymph node removal followed by a year of adjuvant treatment with immunotherapy or targeted therapy. However, the authors wrote, “despite adjuvant systemic treatment, a substantial portion of patients have disease recurrence within the first few years of surgery.” Blank added, “… we still see disease recurrence within three to five years in nearly half of these patients.”.

转移性皮肤癌（黑色素瘤，III期）患者的标准治疗包括局部淋巴结切除，然后进行一年的免疫治疗或靶向治疗辅助治疗。然而，作者写道，“尽管进行了辅助全身治疗，但很大一部分患者在手术的头几年内都有疾病复发。”布兰克补充道，“……我们仍然看到这些患者中近一半在三到五年内复发。”。

Ten years ago Blank set up the Phase II OpACIN study, in which immunotherapy before surgery was compared to immunotherapy after surgery. The results indicated that neoadjuvant immunotherapy could induce a stronger and broader immune response against the tumor, at the cost of more side effects. “That’s why we initiated the OpACIN-neo trial, comparing three schedules with varying doses and eventually finding a safe and effective schedule,” Blank noted.

十年前，Blank建立了II期OpACIN研究，将手术前的免疫治疗与手术后的免疫治疗进行比较。结果表明，新辅助免疫疗法可以诱导针对肿瘤的更强和更广泛的免疫应答，但代价是产生更多的副作用。布兰克指出：“这就是为什么我们启动了OpACIN neo试验，比较了三种不同剂量的时间表，最终找到了一个安全有效的时间表。”。

In the subsequent PRADO trial, we applied this optimal dose to 99 patients. The patients who responded well to the treatment were able to forgo surgery and adjuvant treatment.”.

在随后的PRADO试验中，我们将此最佳剂量应用于99名患者。对治疗反应良好的患者能够放弃手术和辅助治疗。”。

In 2022, Blank and his research group published the PRADO study results, which found that 60 out of 99 patients with metastatic melanoma responded well to immunotherapy before surgery. “Conducting these studies eventually led to the design of the NADINA trial, the first Phase III trial investigating neoadjuvant checkpoint inhibition for early stage melanoma,” Blank stated..

2022年，布兰克和他的研究小组发表了PRADO研究结果，发现99例转移性黑色素瘤患者中有60例在手术前对免疫治疗反应良好。布兰克说：“进行这些研究最终导致了NADINA试验的设计，这是研究早期黑色素瘤新辅助检查点抑制的第一个III期试验。”。。

The international investigator-initiated NADINA trial is “… distinctive in that it is evaluating a neoadjuvant regimen of immunotherapy alone” the team pointed out. For the study 423 patients were randomized to two groups. One group received two immunotherapy treatments with ipilimumab and nivolumab, followed by surgery.

国际研究者发起的NADINA试验是“独特的，因为它正在评估单独的免疫治疗新辅助方案”，该团队指出。在这项研究中，423名患者被随机分为两组。一组接受ipilimumab和nivolumab的两种免疫治疗，然后进行手术。

The second group received standard treatment involving surgery followed by 12 rounds of immunotherapy with nivolumab..

第二组接受标准治疗，包括手术，然后用nivolumab进行12轮免疫治疗。。

Professor Christian Blank [Netherlands Cancer Institute]The results showed that “In 59% of patients who had received immunotherapy before surgery, the tumor was nearly entirely or completely gone, which meant that they did not require additional treatment,” Blank said. The authors further noted, “As determined by central review, 47.2% of the patients had a pathological complete response (0% residual viable tumor) and 11.8% had a pathological near-complete response (1–10% residual viable tumor), which  yielded a major pathological response of 59.0%.”.

Christian Blank教授（荷兰癌症研究所）的研究结果显示，“在手术前接受免疫治疗的患者中，59%的患者肿瘤几乎完全或完全消失，这意味着他们不需要额外的治疗，”Blank说。作者进一步指出，“根据中央审查确定，47.2%的患者有病理完全缓解（0%残留活肿瘤），11.8%的患者有病理接近完全缓解（1-10%残留活肿瘤），产生了59.0%的主要病理反应。”。

Even people who did not respond well to the therapy and had an unfavorable prognosis benefited from the therapy: they were able to start adjuvant treatment with immunotherapy or targeted therapy after surgery.

即使是对治疗反应不佳且预后不良的人也能从治疗中受益：他们能够在手术后开始免疫治疗或靶向治疗的辅助治疗。

The effects of the treatment become apparent quickly. After one year, almost 84% of patients who had received neoadjuvant treatment were still tumor-free, compared to 57% of the group receiving standard treatment. Blank further commented “Patients whose tumors were nearly entirely or completely gone, saw even better results; 95% remained tumor-free, after only six months of treatment.”.

治疗效果很快变得明显。一年后，接受新辅助治疗的患者中几乎有84%仍然没有肿瘤，而接受标准治疗的患者中有57%。布兰克进一步评论道：“肿瘤几乎完全或完全消失的患者，效果更好；95%的患者在治疗6个月后仍然没有肿瘤。”。

The authors further commented. “The results in the neoadjuvant group (an estimated event-free survival at 12 months of 83.7% and a major pathological response in 59.0% of the patients) are in line with the efficacy found in the preceding phase II trials that evaluated neoadjuvant ipilimumab plus nivolumab.”.

作者进一步评论。“新辅助组的结果（12个月时估计无事件生存率为83.7%，59.0%的患者有主要病理反应）与之前评估新辅助ipilimumab加nivolumab的II期临床试验中发现的疗效一致。”。

The data further showed that 76% of patients whose tumors were only partially gone were still tumor-free one year after the start of their treatment, compared to 57% of patients who did not respond well to neoadjuvant therapy. These two patient groups received additional adjuvant treatment after their neoadjuvant treatment and surgery.

数据进一步显示，76%的肿瘤仅部分消失的患者在治疗开始后一年仍无肿瘤，而57%的患者对新辅助治疗反应不佳。这两个患者组在新辅助治疗和手术后接受了额外的辅助治疗。

In three years, the researchers expect to know whether this positive trend continues and could improve survivorship..

研究人员希望在三年内了解这种积极趋势是否会持续下去，并能提高生存率。。

Besides a greater chance of tumor-free survival, most patients were able to cut down their treatment time to only six weeks. Blank said, “Treatment is a lot cheaper—€16,000 instead of €68,000, which would free up about 30–40 million euros in the Netherlands, and could reach a billion euros worldwide.”.

除了更大的无瘤生存机会外，大多数患者能够将治疗时间缩短至仅六周。布兰克说：“治疗费用要便宜得多——16000欧元而不是68000欧元，这将为荷兰节省约3000-4000万欧元，全球可能达到10亿欧元。”。

The treatment still needs to be registered and approved in the Netherlands to qualify for health care insurance coverage. Blank noted “We are talking with various public authorities to ensure that the treatment can eventually receive coverage.”

这种治疗仍需要在荷兰进行登记和批准，才能获得医疗保险的覆盖范围。布兰克指出：“我们正在与各公共部门进行谈判，以确保治疗最终能够得到覆盖。”

The next challenges in this field will be to improve treatment outcomes of patients who responded less favorably. “… the estimated one-year recurrence-free survival of 57.0% among the patients who had a pathological nonresponse indicates that new adjuvant therapies need to be explored in this subgroup,” the investigators further stated..

该领域的下一个挑战将是改善反应较差的患者的治疗结果。研究人员进一步指出：“在病理无反应的患者中，估计一年无复发生存率为57.0%，这表明需要在该亚组中探索新的辅助疗法。”。。

In summary, they noted, “Here, we show that two cycles of ipilimumab plus nivolumab followed by a therapeutic lymph node dissection and response-driven adjuvant treatment resulted in longer event-free survival than adjuvant treatment, with an absolute reduction of 27 percentage points in the risk of an event in the first 12 months as compared with the current standard care of up-front therapeutic lymph-node dissection followed by 12 cycles of adjuvant nivolumab … Despite the evident superiority of neoadjuvant treatment over adjuvant treatment, this first, preplanned interim analysis reflects a relatively short follow-up.

总之，他们指出，“在这里，我们表明，ipilimumab加nivolumab的两个周期，然后是治疗性淋巴结清扫和反应驱动的辅助治疗，比辅助治疗导致更长的无事件生存期，与目前的前期治疗性淋巴结清扫的标准护理相比，前12个月发生事件的风险绝对降低了27个百分点，随后是12个周期的辅助nivolumab……尽管新辅助治疗明显优于辅助治疗，但这第一次预先计划的中期分析反映了相对较短的随访。

Follow-up is ongoing for the assessment of long-term event-free and distant metastasis–free survival, health-related quality of life, and ultimately overall survival.”.

正在进行随访，以评估长期无事件和无远处转移生存率，与健康相关的生活质量以及最终的总体生存率。”。

There are many studies looking into neoadjuvant treatments for various cancer types, including lung cancer, bladder cancer, and breast cancer. “These trials often combine a neoadjuvant approach with standard adjuvant treatment after surgery, instead of adapting treatment to the response to the neoadjuvant part,” Blank explained.

有许多研究正在研究各种癌症类型的新辅助治疗，包括肺癌，膀胱癌和乳腺癌。布兰克解释说：“这些试验通常将新辅助方法与手术后的标准辅助治疗相结合，而不是根据新辅助部分的反应调整治疗。”。

“The NADINA trial is the very first trial within the oncological field that researched a purely immune-therapeutic and personalized treatment. Eventually we aspire to be able to provide personalized immunotherapy by reading out the tumor RNA in every individual patient, and providing a treatment that we know works best based on the results.”.

“NADINA试验是肿瘤学领域内第一个研究纯免疫治疗和个性化治疗的试验。最终，我们希望能够通过读取每个患者的肿瘤RNA来提供个性化的免疫治疗，并根据结果提供我们知道最有效的治疗。”。

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新健康保险黑色素瘤辅助化疗III期临床试验（临床试验）