Taïeb Julien, Bouche Olivier, André Thierry, Le Malicot Karine, Laurent-Puig Pierre, Bez Jérémie, Toullec Clémence, Borg Christophe, Randrian Violaine, Evesque Ludovic, Corbinais Stéphane, Perrier Hervé, Buecher Bruno, Di Fiore Frederic, Gallois Claire, Emile Jean Francois, Lepage Côme, Elhajbi Farid, Tougeron David
Institut du Cancer Paris Cancer Research for Personalized Medicine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France.
Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique, Sorbonne Université, Université Sorbonne Paris Cité, Université de Paris, Paris, France.
JAMA Oncol. 2023 Oct 1;9(10):1356-1363. doi: 10.1001/jamaoncol.2023.2761.
Only 1 randomized clinical trial has shown the superiority of immune checkpoint inhibitors in patients with deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC) in the first-line setting.
To determine whether avelumab (an anti-programmed cell death ligand 1 antibody) improves progression-free survival (PFS) compared with standard second-line chemotherapy in patients with dMMR/MSI mCRC.
DESIGN, SETTING, AND PARTICIPANTS: The SAMCO-PRODIGE 54 trial is a national open-label phase 2 randomized clinical trial that was conducted from April 24, 2018, to April 29, 2021, at 49 French sites. Patients with dMMR/MSI mCRC who experienced progression while receiving standard first-line therapy were included in the analysis.
Patients were randomized to receive standard second-line therapy or avelumab every 2 weeks until progression, unacceptable toxic effects, or patient refusal.
The primary end point was PFS according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1, evaluated by investigators in patients with mCRC and confirmed dMMR and MSI status who received at least 1 dose of treatment (modified intention-to-treat [mITT] population).
A total of 122 patients were enrolled in the mITT population. Median age was 66 (IQR, 56-76) years, 65 patients (53.3%) were women, 100 (82.0%) had a right-sided tumor, and 52 (42.6%) had BRAF V600E-mutated tumors. There was no difference in patients and tumor characteristics between treatment groups. No new safety concerns in either group were detected, with fewer treatment-related adverse events of at least grade 3 in the avelumab group than in the chemotherapy group (20 [31.7%] vs 34 [53.1%]; P = .02). After a median follow-up of 33.3 (95% CI, 28.3-34.8) months, avelumab was superior to chemotherapy with or without targeted agents with respect to PFS (15 [24.6%] vs 5 [8.2%] among patients without progression; P = .03). Rates of PFS rates at 12 months were 31.2% (95% CI, 20.1%-42.9%) and 19.4% (95% CI, 10.6%-30.2%) in the avelumab and control groups, respectively, and 27.4% (95% CI, 16.8%-39.0%) and 9.1% (95% CI, 3.2%-18.8%) at 18 months. Objective response rates were similar in both groups (18 [29.5%] vs 16 [26.2%]; P = .45). Among patients with disease control, 18 (75.7%) in the avelumab group compared with 9 (19.1%) in the control group had ongoing disease control at 18 months.
The SAMCO-PRODIGE 54 phase 2 randomized clinical trial showed, in patients with dMMR/MSI mCRC, better PFS and disease control duration with avelumab over standard second-line treatment, with a favorable safety profile.
ClinicalTrials.gov Identifier: NCT03186326.
仅有1项随机临床试验显示，在一线治疗中，免疫检查点抑制剂在错配修复缺陷和/或微卫星不稳定（dMMR/MSI）转移性结直肠癌（mCRC）患者中具有优越性。
确定在dMMR/MSI mCRC患者中，与标准二线化疗相比，阿维鲁单抗（一种抗程序性细胞死亡配体1抗体）是否能改善无进展生存期（PFS）。
设计、设置和参与者：SAMCO-PRODIGE 54试验是一项全国性开放标签2期随机临床试验，于2018年4月24日至2021年4月29日在法国49个地点进行。纳入分析的患者为在接受标准一线治疗期间病情进展的dMMR/MSI mCRC患者。
患者被随机分配接受标准二线治疗或每2周一次的阿维鲁单抗治疗，直至疾病进展、出现不可接受的毒性作用或患者拒绝。
主要终点是根据实体瘤疗效评价标准（RECIST）1.1版评估的PFS，由研究人员对接受至少1剂治疗的mCRC患者、确诊dMMR和MSI状态的患者进行评估（改良意向性治疗[mITT]人群）。
mITT人群共纳入122例患者。中位年龄为66（四分位间距，56 - 76）岁，65例（53.3%）为女性，100例（82.0%）患有右侧肿瘤，52例（42.6%）患有BRAF V600E突变肿瘤。治疗组之间的患者和肿瘤特征无差异。两组均未发现新的安全问题，阿维鲁单抗组至少3级的治疗相关不良事件少于化疗组（20例[31.7%] vs 34例[53.1%]；P = 0.02）。中位随访33.3（95%CI，28.3 - 34.8）个月后，在PFS方面，阿维鲁单抗优于化疗（无论是否联合靶向药物）（无进展患者中分别为15例[24.6%] vs 5例[8.2%]；P = 0.03）。阿维鲁单抗组和对照组12个月时的PFS率分别为31.2%（95%CI，20.1% - 42.9%）和19.4%（95%CI，10.6% - 30.2%），18个月时分别为27.4%（95%CI，16.8% - 39.0%）和9.1%（95%CI，3.2% - 18.8%）。两组的客观缓解率相似（18例[29.5%] vs 16例[26.2%]；P = 0.45）。在病情得到控制的患者中，阿维鲁单抗组18例（75.7%）在18个月时仍处于病情控制中，而对照组为9例（19.1%）。
SAMCO-PRODIGE 54 2期随机临床试验表明，在dMMR/MSI mCRC患者中，与标准二线治疗相比，阿维鲁单抗具有更好的PFS和疾病控制持续时间，且安全性良好。
ClinicalTrials.gov标识符：NCT03186326。
