编者按：在2024年欧洲肿瘤内科学会（ESMO）大会上，荷兰阿姆斯特丹的Myriam Chalabi教授公布了NICHE-2研究的三年无病生存率（DFS）最新结果，为局部晚期错配修复缺陷型（dMMR）结肠癌患者的新辅助免疫治疗提供了突破性的证据。NICHE-2研究以其大规模样本和显著的疗效提升，填补了NICHE-1研究中样本量少的不足，进一步验证了新辅助免疫治疗的临床潜力。本文不仅总结了NICHE-2的关键发现，还结合了NICHE-3研究的最新结果，为读者呈现该领域的最新进展。

NICHE-2研究：三年无病生存率达到100%

题目：局部晚期dMMR结肠癌的新辅助免疫治疗：NICHE-2研究的3年无病生存期

研究背景

研究方法

研究结果

安全性

此前报道的NICHE-2研究已显示出较好安全性，仅有4%的患者出现了3级或4级免疫相关不良事件，且只有2例患者因治疗导致手术延迟超过2周。在最新的随访数据中，中位随访时间已达到36.5个月，所有患者均未出现疾病复发，进一步确认了新辅助免疫治疗的长期有效性和安全性。

图1. 在NICHE-2研究中，接受伊匹木单抗联合纳武利尤新辅助治疗的dMMR结肠癌患者中，术前达到ctDNA清除的患者中，94%实现了pCR，70%达到MPR

研究结论

NICHE-3研究：新药组合带来高缓解率  

题目：纳武利尤单抗联合瑞拉利单抗新辅助治疗dMMR结肠癌患者：NICHE-3研究的结果

研究背景

研究方法

研究结果

研究结论

总结

摘要原文

LBA24 - Neoadjuvant immunotherapy in locally advanced MMR-deficient colon cancer: 3-year disease-free survival from NICHE-2

Background

Patients with MMR-deficient (dMMR) colon cancer have limited benefit from standard-of-care chemotherapy, with recurrence rates of up to 40% in stage 3 disease. In NICHE-2, we previously showed a 99% pathologic response rate, including 95% major pathologic responses (MPR) and 68% pathologic complete responses (pCR). Here we present the previously unreported primary endpoint of 3-year disease-free survival (DFS).

Methods

Patients with locally advanced dMMR colon cancer received ipilimumab on Day 1 and nivolumab on Day 1+15, followed by surgery within 6 weeks. The study had two independent primary endpoints: safety and 3-year DFS. As reported previously, the safety endpoint was met. For DFS, a 3-year DFS rate of 93% would be deemed successful, at a power of 80% and a 2-sided alpha of 2.5%, assuming an 82% 3-year DFS in historical controls. Circulating tumor DNA (ctDNA) was analyzed using the SignateraTM tumor-informed assay on plasma samples from baseline, Day 15, pre-surgery and 3 weeks post-surgery (minimal residual disease (MRD)) timepoints.

Results

Of the 111 patients in the efficacy analysis, 64% had cT4 tumors. With a median follow-up after surgery of 36.5 months (range 7.8 – 83.4), all patients were alive and there were no disease recurrences, resulting in a 3-year DFS of 100%. In 108 patients with available plasma samples, baseline ctDNA was detected in 92%. On Day 15, 45% of these patients had cleared ctDNA. While not different at baseline, ctDNA levels on Day 15 and pre-surgery were significantly lower in pCR vs MPR groups. Pre-surgery ctDNA clearance was observed in 94% of patients with a pCR and 70% with an MPR. 16 patients remained ctDNA+ pre-surgery, albeit with significant reductions in ctDNA levels, and included 2 of 3 partial responders and 1 of 1 non-responder. All patients were ctDNA negative at the MRD timepoint.

Conclusions

Here we show a 100% 3-year DFS in patients with dMMR colon cancer treated with one dose of ipilimumab and two doses of nivolumab prior to surgery. The survival data are also supported by negative ctDNA at the MRD timepoint in all patients, while on-treatment ctDNA dynamics provide an additional monitoring instrument for future trials on organ preservation.

Clinical trial identification

NCT03026140.

503O - Neoadjuvant nivolumab (nivo) plus relatlimab (rela) in MMR-deficient colon cancer: Results of the NICHE-3 study

Background

Immune checkpoint inhibitors (ICI) have shown unprecedented responses in MMR-deficient (dMMR) colorectal cancers. In the NICHE-2 study, major pathologic responses (MPR) and pathologic complete responses (pCR) were observed in 95% and 68% of patients, respectively, following a short neoadjuvant regimen of nivolumab/ipilimumab. Data on nivo/rela in patients with melanoma suggest a favorable toxicity profile. Here we present data from NICHE-3, in which we investigated the efficacy and safety of nivo/rela in locally advanced resectable dMMR colon cancer (CC).

Methods

Patients with dMMR CC were treated with 2 doses of nivo/rela (480mg/480mg) on day 1 and 29, followed by surgery within 8 weeks of enrollment. A Simon’s 2 stage design was used where >46/59 responders were needed in stages 1+2 for the study to be deemed successful. Pathologic response was defined as ≤50% residual viable tumor (RVT). Secondary endpoints included pCR, MPR (≤10% RVT), safety and survival. We previously showed data from stage 1 (19pts). Here we present the primary endpoint from the fully accrued study.

Results

A total of 59 patients were treated. Median age was 65 years and 78% of patients had clinical stage III disease. Of the 59 patients, 56 have undergone surgery, and surgery is scheduled for 3 treated patients. Pathologic response was observed in 54/56 (96%) patients and included 91% MPR and 68% pCR. Grade 3-4 immune related adverse events were observed in 6/59 (10%) patients and led to delay of surgery in 3 patients. Endocrinopathies requiring long-term suppletion occurred in 14 (24%) patients consisting of 10 cases of hypothyroidism (17%) and 5 (8%) of adrenal insufficiency. To date, one patient had recurrence of disease.

Conclusions

Here we present data from NICHE-3 showing that neoadjuvant nivo/rela led to a pathologic response rate of 96% in patients with dMMR CC, with a pCR rate of 68%, similar to response rates observed with nivo/ipi. Toxicity of nivo/rela in this study was manageable but resulted in high rates of long-term endocrinopathies.

This study adds to a growing body of evidence of the role of ICI in dMMR CRC and provides a basis for larger studies and exploration of organ-sparing strategies.

Clinical trial identification

NCT03026140; EudraCT 2016-002940-17.