乐伐替尼联合帕博利珠单抗、培美曲塞和铂类作为转移性非鳞状非小细胞肺癌的一线治疗：3期LEAP-006研究
Lenvatinib Plus Pembrolizumab, Pemetrexed, and a Platinum as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 LEAP-006 Study.
作者信息
Herbst Roy S, Cho Byoung Chul, Zhou Caicun, Burotto Mauricio, Dols Manuel Cobo, Sendur Mehmet A N, Moiseyenko Vladimir, Casarini Ignacio, Nishio Makoto, Hui Rina, Pons-Tostivint Elvire, Dudnik Julia, Ahmed Samreen, Okpara Chinyere E, Dutcus Corina, Yin Lina, Luo Yiwen, Chirovsky Diana, Bhagwati Niyati, Abreu Delvys Rodriguez
机构信息
Yale School of Medicine, Yale Cancer Center, and Smilow Cancer Hospital, New Haven, Connecticut.
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
出版信息
J Thorac Oncol. 2025 Sep;20(9):1302-1314. doi: 10.1016/j.jtho.2025.05.016. Epub 2025 May 24.
INTRODUCTION
We present the LEAP-006 (NCT03829319) phase 3 study evaluating the addition of lenvatinib to first-line pembrolizumab plus chemotherapy in metastatic nonsquamous NSCLC.
METHODS
Adults with previously untreated stage IV nonsquamous NSCLC without targetable genetic alterations were randomized 1:1 to lenvatinib 8 mg/d or placebo once daily plus pembrolizumab 200 mg every 3 weeks with pemetrexed and carboplatin or cisplatin for 4 cycles, followed by pembrolizumab (≤35 total cycles) and pemetrexed until disease progression or intolerable toxicity. Primary end points were progression-free survival and overall survival (OS). Part 1 was an open-label safety run-in of lenvatinib plus pembrolizumab and chemotherapy; part 2 was the randomized, double-blind study.
RESULTS
Participants (n = 748) were randomized to the lenvatinib (n = 375) or placebo (n = 373) arms. Median follow-up at final analysis (August 11, 2023) for OS was 36.8 months. Median (95% confidence interval [CI]) progression-free survival was 12.1 (10.4-14.1) versus 9.5 (8.3-10.7) months in the lenvatinib and placebo arms, respectively (hazard ratio, 0.88 [95% CI, 0.74-1.05]; 1-sided p = 0.07976). Median (95% CI) OS was 21.8 (18.6-24.0) versus 22.1 (19.7-24.2) months (hazard ratio, 1.05 [95% CI, 0.88-1.26]; 1-sided p = 0.70818). Grade 3 or higher treatment-related adverse events occurred in 69.7% and 55.6% of participants, respectively (grade 5, 5.6% versus 2.7%).
CONCLUSIONS
Adding lenvatinib to first-line pembrolizumab plus chemotherapy did not improve efficacy versus pembrolizumab plus chemotherapy in stage IV nonsquamous NSCLC without targetable genetic alterations. There were no new safety signals. Pembrolizumab plus chemotherapy remains a standard of care for this population.
TRIAL REGISTRATION
ClinicalTrials.gov (https://clinicaltrials.gov/), NCT03829319.
引言
我们开展了LEAP-006（NCT03829319）3期研究，评估在一线帕博利珠单抗联合化疗基础上加用乐伐替尼治疗转移性非鳞状非小细胞肺癌（NSCLC）的疗效。
方法
既往未接受过治疗、无可靶向治疗的基因改变的IV期非鳞状NSCLC成年患者按1:1随机分组，分别接受乐伐替尼8mg/d或安慰剂，每日1次，联合帕博利珠单抗200mg，每3周1次，同时联合培美曲塞和卡铂或顺铂，共4个周期，随后接受帕博利珠单抗（总疗程≤35个周期）和培美曲塞，直至疾病进展或出现不可耐受的毒性。主要终点为无进展生存期和总生存期（OS）。第1部分是乐伐替尼联合帕博利珠单抗及化疗的开放标签安全性导入期；第2部分是随机、双盲研究。
结果
参与者（n = 748）被随机分配至乐伐替尼组（n = 375）或安慰剂组（n = 373）。最终分析（2023年8月11日）时OS的中位随访时间为36.8个月。乐伐替尼组和安慰剂组的中位（95%置信区间[CI]）无进展生存期分别为12.1（10.4 - 14.1）个月和9.5（8.3 - 10.7）个月（风险比，0.88[95%CI，0.74 - 1.05]；单侧p = 0.07976）。中位（95%CI）OS分别为21.8（18.6 - 24.0）个月和22.1（19.7 - 24.2）个月（风险比，1.05[95%CI，0.88 - 1.26]；单侧p = 0.70818）。3级或更高等级的治疗相关不良事件分别发生在69.7%和55.6%的参与者中（5级，分别为5.6%和2.7%）。
结论
在一线帕博利珠单抗联合化疗基础上加用乐伐替尼，对于无可靶向治疗的基因改变的IV期非鳞状NSCLC患者，与帕博利珠单抗联合化疗相比，并未提高疗效。未发现新的安全信号。帕博利珠单抗联合化疗仍是该人群的标准治疗方案。
试验注册
ClinicalTrials.gov（https://clinicaltrials.gov/），NCT03829319
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