Medical Oncology Department, Hospital Clinic Barcelona-ICMHO, Barcelona, Spain.
Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain; Pangaea Biotech, Hospital Universitario Quirón, Dexeus, Barcelona, Spain.
Lung Cancer. 2014 May;84(2):161-7. doi: 10.1016/j.lungcan.2014.02.011. Epub 2014 Mar 2.
Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors.
We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR12w). Pre-treatment plasma samples were required to assess T790M resistant mutation.
A total of 33 patients were enrolled in the phase I-II trial. The maximum tolerated dose was erlotinib 150 mg p.o., QD, and 400mg p.o., QD, on days 1-7 and 15-21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR12w was 28% (IC 95%: 18.0-37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43-8.45) and overall survival (OS) 10.3 months (95% CI: 2.4-18.1).
Full dose of continuous erlotinib with vorinostat 400mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression.
伏立诺他或琥珀酰亚胺基羟肟酸（SAHA）是一种新型组蛋白去乙酰化酶抑制剂，由于药物诱导的乙酰化蛋白（包括热休克蛋白 90）的积累，具有明显的抗增殖作用。我们前瞻性地研究了伏立诺他联合厄洛替尼在 EGFR 突变的 NSCLC 患者中的活性，这些患者在接受酪氨酸激酶抑制剂治疗后出现进展。
我们进行了这项前瞻性、非随机、多中心、I/II 期试验，以评估厄洛替尼和伏立诺他的最大耐受剂量、毒性谱和疗效。纳入的患者为晚期 NSCLC，携带 EGFR 突变，在至少 12 周的厄洛替尼治疗后疾病进展。推荐剂量 II 期（RDP2）用于评估联合用药的疗效。主要终点为 12 周时无进展生存率（PFSR12w）。需要预先治疗的血浆样本来评估 T790M 耐药突变。
共有 33 例患者入组 I/II 期试验。最大耐受剂量为厄洛替尼 150mg po，QD，和 400mg po，QD，在 28 天周期的第 1-7 天和第 15-21 天。在接受 RDP2 治疗的 25 例患者中，最常见的毒性包括贫血、疲劳和腹泻。未观察到应答。12 周时无进展生存率（PFSR12w）为 28%（IC95%：18.0-37.2）；中位无进展生存期（PFS）为 8 周（IC95%：7.43-8.45），总生存期（OS）为 10.3 个月（95%CI：2.4-18.1）。
伏立诺他全剂量联合厄洛替尼，连续给药，伏立诺他剂量为 400mg po，QD，在不同周给药，可安全给药。然而，在 TKI 进展后的 EGFR 突变 NSCLC 患者中，该联合用药并无明显疗效。
