Cercek Andrea, Foote Michael B, Rousseau Benoit, Smith J Joshua, Shia Jinru, Sinopoli Jenna, Weiss Jill, Lumish Melissa, Temple Lindsay, Patel Miteshkumar, Wilde Callahan, Saltz Leonard B, Argiles Guillem, Stadler Zsofia, Artz Oliver, Maron Steven, Ku Geoffrey, Gu Ping, Janjigian Yelena Y, Molena Daniela, Iyer Gopa, Coleman Jonathan, Abida Wassim, Cohen Seth, Soares Kevin, Schattner Mark, Strong Vivian E, Yaeger Rona, Paty Philip, Shcherba Marina, Sugarman Ryan, Romesser Paul B, Zervoudakis Alice, Desai Avni, Segal Neil H, El Dika Imane, Widmar Maria, Wei Iris, Pappou Emmanouil, Fumo Gerard, Aparo Santiago, Gonen Mithat, Gollub Marc, Jayaprakasam Vetri S, Kim Tae-Hyung, Garcia Aguilar Julio, Weiser Martin, Diaz Luis A
Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.
N Engl J Med. 2025 Jun 19;392(23):2297-2308. doi: 10.1056/NEJMoa2404512. Epub 2025 Apr 27.
Among patients with mismatch repair-deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown.
We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated.
A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients.
Among patients with early-stage dMMR solid tumors that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients. (Funded by Swim Across America and others; ClinicalTrials.gov number, NCT04165772.).
在错配修复缺陷（dMMR）的局部晚期直肠癌患者中，新辅助检查点阻断使很大一部分患者无需进行手术。这种方法是否能扩展到所有早期dMMR实体瘤，而不论肿瘤部位如何，尚不清楚。
我们开展了一项2期研究，对适合进行根治性手术的I期、II期或III期dMMR实体瘤患者，给予新辅助多斯塔利单抗（一种程序性细胞死亡蛋白1 [PD-1]阻断剂）治疗6个月。在两个队列中评估治疗反应：队列1中的患者患有dMMR局部晚期直肠癌，队列2中的患者患有dMMR非直肠实体瘤。临床完全缓解的患者可选择进行非手术治疗；有残留病灶的患者则接受手术切除。在该分析中，在队列1中评估的主要终点是12个月时持续的临床完全缓解。评估无复发生存率和安全性。
共有117例患者纳入分析。在队列1中，所有49例完成治疗的患者均有临床完全缓解，并选择进行非手术治疗。共有37例患者在12个月时出现持续的临床完全缓解，这一结果符合疗效标准。在队列2中，54例完成治疗的患者中有35例有临床完全缓解，33例选择进行非手术治疗。在两个队列中完成治疗的103例患者中，84例有临床完全缓解，82例未接受手术。在总共117例患者中，2年无复发生存率为92%（95%置信区间，86%至99%）；复发的中位随访时间为20.0个月（范围，0至60.8个月）。大多数患者（95%）出现可逆的1级或2级不良事件（60%）或无不良事件（35%）。在任何患者的治疗期间或治疗后，根治性切除的选择均未受到影响。
在适合进行根治性手术的早期dMMR实体瘤患者中，新辅助PD-1阻断使很大一部分患者得以保留器官。（由美国横渡泳渡协会等资助；ClinicalTrials.gov编号，NCT04165772。）
