Purpose: Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. Here, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of CNS-specific outcomes. Methods: This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was ORR. Secondary endpoints were safety, PFS, and OS. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on D1-7 of each 21-days cycle. In previously published cohort 1, olaparib was dosed on D1-7; in cohort 2 olaparib was dosed continuously. Results: Sixty-six patients were enrolled across the two cohorts, 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, best overall intracranial response was CR in 6/15 patients, PR in 4/15 patients, and SD in 3/15 patients for a CNS disease control rate of 87% (95% CI: 59.5-98.3%). Conclusions: Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination in SCLC.

中文翻译：

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奥拉帕尼和替莫唑胺在 SCLC 中由 I/II 研究者发起的研究：最终分析和 CNS 结果


目的：替莫唑胺联合 PARP 抑制在小细胞肺癌 （SCLC） 中显示出前景。我们之前报告了奥拉帕尼/替莫唑胺治疗复发性 SCLC 的 I/II 期试验的前 50 名患者 （队列 1） 的结果。在这里，我们报告了该试验的最终分析，包括具有替代给药策略的第二个队列和 CNS 特异性结果的探索性分析。方法： 这是一项开放标签的 I/II 期试验，测试奥拉帕尼和替莫唑胺联合治疗复发性 SCLC。主要终点是 ORR。次要终点是安全性、 PFS 和 OS。我们在两个队列中测试了递增剂量的奥拉帕尼/替莫唑胺，这两个队列在每个 21 天周期的第 1-7 天服用替莫唑胺。在先前发表的队列 1 中，奥拉帕尼在 D1-7 给药;在队列 2 中，奥拉帕尼连续给药。结果： 两个队列共招募 66 名患者，队列 1 50 名，队列 2 16 名。队列 1 的确认 ORR 为 41.7% （20/48 可评估），队列 2 的确认 ORR 为 7% （1/14 可评估;由于缺乏观察到的疗效，在剂量递增至入组后关闭）。在入组时 15/66 例未经治疗的脑转移患者 （22.7%） 中，最佳总体颅内反应为 6/15 例患者的 CR、4/15 患者的 PR 和 3/15 患者的 SD，中枢神经系统疾病控制率为 87% （95% CI： 59.5-98.3%）。结论： 奥拉帕尼/替莫唑胺可能对复发性 SCLC 有效，尤其是对 CNS 疾病患者。关于最佳给药方案的持续分析将为未来在 SCLC 中使用这种组合的可能性提供信息。