Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study.
Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study.
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DOI：
10.1016/s1470-2045(22)00197-8
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发表时间：
2022-05
期刊：
影响因子：
51.1
通讯作者：
Andre, Thierry
中科院分区：
文献类型：
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作者：
Diaz, Luis A.;Shiu, Kai-Keen;Kim, Tae-Won;Jensen, Benny Vittrup;Jensen, Lars Henrik;Punt, Cornelis;Smith, Denis;Garcia-Carbonero, Rocio;Benavides, Manuel;Gibbs, Peter;de la Fourchardiere, Christelle;Rivera, Fernando;Elez, Elena;Le, Dung T.;Yoshino, Takayuki;Zhong, Wen Yan;Fogelman, David;Marinello, Patricia;Andre, Thierry
Pembrolizumab在新诊断的MSI-H/dMMR转移性结直肠癌（mCRC）中显示出优于化疗的无进展生存期（PFS）。然而，其对该患者队列总生存期（OS）的影响尚不清楚。在这里，我们给出了KEYNOTE-177的最终OS分析。这项3期、开放标签研究涉及23个国家的193个研究中心。使用交互式语音应答系统/集成网络应答系统，将年龄至少18岁、东部肿瘤协作组体能状态评分为0或1、新诊断为MSI-H/dMMR mCRC的患者以1：1的比例随机分组，每层4人一组，接受帕博利珠单抗200 mg静脉给药，每3周一次，或接受研究者选择的mFOLFOX 6或FOLFIRI静脉给药，每2周一次，伴或不伴贝伐珠单抗5 mg/kg静脉给药，每2周一次，或西妥昔单抗静脉给药（首次剂量400 mg/m2，随后每次剂量250 mg/m2），每周一次。接受化疗的患者可以在进展后交叉使用pembrolizumab治疗35次。双主要终点为意向治疗人群的OS和PFS。KEYNOTE-177在ClinicalTrials.gov NCT 02563002上注册，不再招募患者。在2016年2月11日至2018年2月19日期间，307例患者随机接受派姆单抗（n = 153）或化疗（n = 154）。60%的患者从化疗交叉至抗PD-1/抗PD-L1治疗（56例患者接受研究中派姆单抗治疗，37例患者接受研究外治疗）。最终分析时（中位随访44.5个月[IQR，39.7-49.8]），OS的风险比[HR]为0.74（95%可信区间[CI] 0.53-1.03; P=0.0359;中位未达到[95% CI 49.2-未达到] vs 36.7个月[95% CI，27.6-未达到]）。由于未达到统计学显著性所需的预先规定的α 0.0246，因此未证明派姆单抗与化疗相比对OS的优效性。PFS的更新HR为0.59（95% CI 0.45-0.79;中位数16.5 [95% CI 5.4-38.1] vs 8.2个月[95% CI 6.1-10.2]）。严重不良事件发生在62/153例（41%）接受pembrolizumab的患者和75/143例（52%）接受化疗的患者中。分别有33/153例（22%）和95/143例（66%）患者发生≥3级治疗相关不良事件。帕博利珠单抗导致的常见≥3级不良事件为丙氨酸氨基转移酶升高、结肠炎、腹泻和疲乏，153例患者中各有3例（2%），化疗导致中性粒细胞计数降低（143例患者中的24例[17%]）、中性粒细胞减少症（143例患者中的22例[15%]）、腹泻（143例患者中的14例[10%]）和疲乏（143例患者中的13例[9%]）。未发生归因于帕博利珠单抗的死亡; 1例因肠穿孔导致的死亡归因于化疗。Pembrolizumab与化疗相比继续提供持久的抗肿瘤活性，OS无显著差异，治疗相关事件较少。这些结果支持pembrolizumab作为MSI-H/dMMR mCRC患者的有效一线治疗。Merck Sharp & Dohme Corp.，作为默克公司的子公司，股份有限公司、关闭KY，USA.
Pembrolizumab has demonstrated superior progression-free survival (PFS) versus chemotherapy in newly-diagnosed MSI-H/dMMR metastatic colorectal cancer (mCRC). However, its impact on overall survival (OS) in this cohort of patients was unknown. Here we present the final OS analysis of KEYNOTE-177. The phase 3, open-label study involved 193 sites in 23 countries. Patients aged at least 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and who had newly-diagnosed MSI-H/dMMR mCRC were randomized 1:1 in blocks of four per stratum using an interactive voice response system /integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to investigator’s choice of intravenous mFOLFOX6 or FOLFIRI every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose) weekly. Patients receiving chemotherapy could cross over to pembrolizumab for 35 treatments after progression. Dual-primary endpoints were OS and PFS in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov NCT02563002 and is no longer enrolling patients. Between February 11, 2016 and February 19, 2018, 307 patients were randomized to pembrolizumab (n = 153) or chemotherapy (n = 154). Sixty percent of patients crossed over from chemotherapy to anti-PD-1/anti-PD-L1 therapy (56 patients to on-study pembrolizumab, 37 patients to off-study therapy). At final analysis (median follow-up of 44.5 months [IQR, 39.7–49.8]), the hazard ratio [HR] for OS was 0.74 (95% confidence interval [CI] 0.53–1.03; P=0.0359; median not reached [95% CI 49.2-not reached] versus 36.7 months [95% CI, 27.6-not reached]) with pembrolizumab versus chemotherapy. Superiority of pembrolizumab versus chemotherapy for OS was not demonstrated as the prespecified α of 0.0246 needed for statistical significance was not achieved. The updated HR for PFS was 0.59 (95% CI 0.45–0.79; median 16.5 [95% CI 5.4–38.1] versus 8.2 months [95% CI 6.1–10.2]). Serious adverse events occurred in 62 of 153 (41%) patients who received pembrolizumab and 75 of 143 (52%) patients who received chemotherapy. Grade ≥3 treatment-related adverse events occurred in 33 of 153 (22%) versus 95 of 143 (66%) patients, respectively. Common grade ≥3 adverse events attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhea, and fatigue in 3 of 153 (2%) patients each, and to chemotherapy were decreased neutrophil count (24 of 143 [17%] patients), neutropenia (22 of 143 [15%]), diarrhea (14 of 143 [10%]), and fatigue (13 of 143 [9%]). No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy. Pembrolizumab versus chemotherapy continued to provide durable antitumor activity, with no significant difference in OS, and fewer treatment-related events. These findings support pembrolizumab as effective first-line therapy in patients with MSI-H/dMMR mCRC. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.