Arance Ana, de la Cruz-Merino Luis, Petrella Teresa M, Jamal Rahima, Ny Lars, Carneiro Ana, Berrocal Alfonso, Márquez-Rodas Ivan, Spreafico Anna, Atkinson Victoria, Costa Svedman Fernanda, Mant Andrew, Khattak Muhammad A, Mihalcioiu Catalin, Jang Sekwon, Cowey C Lance, Smith Alan D, Hawk Natalyn, Chen Ke, Diede Scott J, Krepler Clemens, Long Georgina V
Hospital Clinic Barcelona and IDIBAPS, Barcelona, Spain.
Hospital Universitario Virgen Macarena, Seville, Spain.
J Clin Oncol. 2023 Jan 1;41(1):75-85. doi: 10.1200/JCO.22.00221. Epub 2022 Jul 22.
Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).
Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.
A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).
Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
对于在程序性细胞死亡蛋白1（PD-1）或其配体（PD-L1）抑制剂治疗期间病情进展的黑色素瘤患者，需要有效的治疗方法。我们开展了II期LEAP-004研究，以评估多激酶抑制剂乐伐替尼与PD-1抑制剂帕博利珠单抗联合用于该人群的疗效（ClinicalTrials.gov标识符：NCT03776136）。
符合条件的患者为不可切除的III-IV期黑色素瘤患者，在最后一剂单独或与其他疗法（包括细胞毒性T淋巴细胞相关抗原4（CTLA-4）抑制剂）联合使用的PD-1/L1抑制剂治疗后的12周内确诊为疾病进展（PD），接受乐伐替尼20mg口服每日一次加≤35剂帕博利珠单抗200mg静脉注射每3周一次，直至疾病进展或出现不可接受的毒性。主要终点是根据实体瘤疗效评价标准（RECIST）1.1版由独立中央审查评估的客观缓解率（ORR）。
共入组并治疗了103例患者。研究的中位随访时间为15.3个月。总体人群的ORR为21.4%（95%CI，13.9至30.5），其中3例（2.9%）完全缓解，19例（18.4%）部分缓解。中位缓解持续时间为8.3个月（范围，3.2 - 15.9+）。在30例既往接受抗PD-1加抗CTLA-4治疗后出现疾病进展的患者中，ORR为33.3%。总体人群的中位无进展生存期和总生存期分别为4.2个月（95%CI，3.8至7.1）和14.0个月（95%CI，10.8至未达到）。47例（45.6%）患者发生3 - 5级治疗相关不良事件，最常见的是高血压（21.4%）；1例患者死于治疗相关事件（血小板计数减少）。
乐伐替尼加帕博利珠单抗在既往基于PD-1/L1抑制剂治疗后确诊为疾病进展的晚期黑色素瘤患者中提供了具有临床意义的持久缓解，包括那些在接受抗PD-1加抗CTLA-4治疗后出现疾病进展的患者。安全性符合预期。这些数据支持乐伐替尼加帕博利珠单抗作为该有高度未满足需求人群的潜在治疗方案。
