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Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.
Nature Medicine ( IF 82.9 ) Pub Date : 2020-04-06 , DOI: 10.1038/s41591-020-0805-8
Myriam Chalabi 1, 2, 3 , Lorenzo F Fanchi 2, 4 , Krijn K Dijkstra 2, 4 , José G Van den Berg 5 , Arend G Aalbers 6 , Karolina Sikorska 7 , Marta Lopez-Yurda 7, 8 , Cecile Grootscholten 1 , Geerard L Beets 6, 9 , Petur Snaebjornsson 5 , Monique Maas 10 , Marjolijn Mertz 11 , Vivien Veninga 2, 4 , Gergana Bounova 4, 12 , Annegien Broeks 13 , Regina G Beets-Tan 9, 10 , Thomas R de Wijkerslooth 1 , Anja U van Lent 14 , Hendrik A Marsman 15 , Elvira Nuijten 7 , Niels F Kok 6 , Maria Kuiper 1 , Wieke H Verbeek 1 , Marleen Kok 3, 16 , Monique E Van Leerdam 1 , Ton N Schumacher 2, 4 , Emile E Voest 1, 2, 4 , John B Haanen 2, 3
Affiliation  

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.



中文翻译:

新辅助免疫疗法导致 MMR 熟练和 MMR 缺陷早期结肠癌的病理反应。

PD-1 加 CTLA-4 阻断剂对晚期错配修复 (MMR) 缺陷 (dMMR) 结直肠癌非常有效,但对 MMR 熟练 (pMMR) 肿瘤无效。我们假设新辅助免疫疗法在早期结肠癌中的疗效更高。在探索性 NICHE 研究(ClinicalTrials.gov:NCT03026140)中,dMMR 或 pMMR 肿瘤患者在手术前接受单剂易普利姆玛和两剂纳武单抗,pMMR 组加或不加塞来昔布。主要目标是安全性和可行性;40 例 21 dMMR 和 20 pMMR 肿瘤患者接受治疗,3 例患者在安全磨合中接受 nivolumab 单药治疗。治疗耐受性良好,所有患者均无延误地接受了根治性切除术,达到了主要终点。在接受 ipilimumab + nivolumab(20 dMMR 和 15 pMMR 肿瘤)的患者中,35 个可评估疗效和转化终点。在 20/20 (100%; 95% 精确置信区间 (CI): 86–100%) dMMR 肿瘤中观察到病理反应,其中 19 个主要病理反应(MPR,≤10% 残留活肿瘤)和 12 个病理完全反应。在 pMMR 肿瘤中,4/15(27%;95% 准确置信区间:8-55%)显示出病理反应,其中 3 个 MPR 和 1 个部分反应。CD8+ PD-1 + T 细胞浸润可预测 pMMR 肿瘤的反应。这些数据表明,在具有至少 3 年无病生存数据的大型研究中得到验证后,新辅助免疫疗法可能有可能成为特定结肠癌患者群体的标准治疗。

更新日期:2020-04-24
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