Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer,Lung Cancer

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Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer
Lung Cancer ( IF 5.3 ) Pub Date : 2021-07-21 , DOI: 10.1016/j.lungcan.2021.06.028
David E Kozono ₁ , Thomas E Stinchcombe ₂ , Joseph K Salama ₂ , Jeffrey Bogart ₃ , W Jeffrey Petty ₄ , Michael J Guarino ₅ , Lyudmila Bazhenova ₆ , James M Larner ₇ , Jared Weiss ₈ , Thomas A DiPetrillo ₉ , Steven J Feigenberg ₁₀ , Xin Chen ₁₁ , Zhaowen Sun ₁₁ , Silpa Nuthalapati ₁₂ , Lindsey Rosenwinkel ₁₃ , Eric F Johnson ₁₄ , Bruce A Bach ₁₅ , Yan Luo ₁₅ , Everett E Vokes ₁₆

Affiliation

Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Duke Cancer Institute, Durham, 2 Seeley Mudd, 10 Bryan Searle Drive, Durham, NC 27710, USA.
Department of Radiation Oncology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Department of Hematology and Oncology, Wake Forest School of Medicine, Bowman Gray Center for Medical Education, 475 Vine Street, Winston-Salem, NC 27101, USA.
Christiana Care Health System, Helen F Graham Cancer Center, 4701 Ogletown Stanton Road, Suite 3400, Newark, DE 19713, USA.
Department of Medicine, Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
University of Virginia, Emily Couric Clinical Cancer Center, 1240 Lee Street, Charlottesville, VA 22903, USA.
Lineberger Comprehensive Cancer Center at the University of North Carolina, Cancer Hospital, 101 Manning Drive, Chapel Hill, NC 27514, USA.
Department of Radiation Oncology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
Greenebaum Comprehensive Cancer Center, University of Maryland, 22 South Greene Street, Baltimore, MD 21201, USA.
Data and Statistical Sciences, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA.
Clinical Pharmacology and Pharmacometrics, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA.
Global Pharmaceutical R&D, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA.
Oncology Early Development, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA.
Oncology Development, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA.
Department of Medicine, University of Chicago, 5801 South Ellis Avenue, Chicago, IL 60637, USA.

Objectives

Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC).

Materials and methods

Patients received veliparib orally twice daily (BID) in escalating doses (60–240 mg, Day –3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m²), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120–240 mg BID, Days –2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m², Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy.

Results

Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7–32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0–not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0–not reached).

Conclusions

When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

中文翻译：

Veliparib 联合以卡铂/紫杉醇为基础的放化疗治疗 III 期非小细胞肺癌

目标

Veliparib 是一种有效的聚 (ADP)-核糖聚合酶 (PARP) 1 和 2 抑制剂，可阻碍细胞毒性和放射疗法引起的 DNA 损伤的修复。该 1 期研究评估了 veliparib 联合放化疗对无法切除的 III 期非小细胞肺癌 (NSCLC) 患者的疗效。

材料和方法

患者每天两次口服维利帕尼 (BID)，剂量递增（60–240 mg，最后一次放疗后第 3 天至第 1 天）联合每周一次的卡铂（曲线下面积 [AUC] 2 mg/mL/min），紫杉醇 (45 mg/m ² ) 和每日放疗（60 Gy，分 30 次），然后是两个周期的维利帕尼（120–240 mg BID，每个 21 天周期的第 2 至 5 天）、卡铂（AUC 6 mg/mL/min，每个周期的第 1 天）和紫杉醇（200 mg/m ²，每个周期的第 1 天）巩固。终点包括 veliparib 最大耐受剂量 (MTD)、推荐的 2 期剂量 (RP2D)、药代动力学、安全性和有效性。

结果

登记了 48 名患者。veliparib 的 MTD/RP2D 为 240 mg BID 联合放化疗，随后 120 mg BID 联合巩固治疗。在整个治疗期间，该队列中最常见的任何级别不良事件 (AE) 是恶心 (83%)、食管炎 (75%)、中性粒细胞减少症 (75%) 和血小板减少症 (75%)。观察到 veliparib 的剂量正比例药代动力学。中位无进展生存期 (mPFS) 为 19.6 个月（95% CI：9.7–32.6）。中位总生存期估计为 32.6 个月（95% CI：15.0-未达到）。在接受 RP2D 治疗的患者中，mPFS 为 19.6 个月（95% CI：3.0-未达到）。