Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Biostatistic Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Lung Cancer. 2020 Apr;142:132-137. doi: 10.1016/j.lungcan.2020.02.005. Epub 2020 Feb 12.
Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC).
GEM (1000 mg/m) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS).
In total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients.
The combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit.
顺铂和培美曲塞一线治疗后进展的恶性胸膜间皮瘤（MPM）患者的二线化疗不是标准治疗方法。在临床前模型中，与单独使用吉西他滨（GEM）相比，联合使用甲磺酸伊马替尼（IM）和 GEM 可进一步抑制肿瘤生长并提高生存率。这项 II 期研究评估了 IM 和 GEM 联合治疗通过免疫组化（IHC）表达 PDGFR-β 和/或 cKIT 的铂类-培美曲塞预处理的 MPM 患者的抗肿瘤活性。
GEM（1000mg/m）于第 3 天和第 10 天给药；IM（400mg）于第 1-5 天和第 8-12 天在 21 天周期内口服。主要终点是 3 个月无进展生存期（PFS）率。该研究遵循 Simon 的最佳两阶段设计。需要达到 3 个月 PFS 目标 75%。概率误差α=10%，功率 80%，计算的样本量为 22 例患者。特别是在第一步中，需要 9 例患者中的 6 例和全球 22 例患者中的 14 例在 3 个月时无进展性疾病。次要终点包括反应率、反应持续时间、毒性和总生存期（OS）。
共纳入 23 例患者（ECOG PS 0-1/2：9/13；一线/≥二线治疗：10/13）。4 例患者（17.4%）达到部分缓解，11 例（47.8%）达到稳定疾病，疾病控制率为 65.3%。中位随访 34.5 个月后，中位 PFS 和 OS 分别为 2.8 个月和 5.7 个月，3 个月 PFS 率为 39.1%（23 例患者中的 9 例）。所有级别药物相关不良事件发生在 17 例（73.9%）患者中。4 例（17%）患者出现 3 级治疗相关不良事件。
在通过 IHC 表达 PDGFR-β 和/或 cKIT 的铂类-培美曲塞预处理的 MPM 患者中，IM 和 GEM 联合使用耐受性良好，但未显示出显著的 PFS 获益。
