Background

Establishing alternatives to lifelong chemotherapy for patients with advanced pancreatic cancer has been proposed to address chemotherapy resistance and cumulative toxicity. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in this setting, and concurrent immune checkpoint blockade could offer synergistic tumour control. The aim of this study was to test the safety and antitumour activity of maintenance with PARP inhibition combined with immune checkpoint blockade in patients with advanced pancreatic cancer who had a stable response to platinum-based chemotherapy.

Methods

We conducted an open-label, randomised, phase 1b/2 study of niraparib plus anti-PD-1 (nivolumab) or anti-CTLA-4 (ipilimumab) therapy for patients with advanced pancreatic cancer whose cancer had not progressed after at least 16 weeks of platinum-based therapy. Patients were randomly assigned (1:1) via permuted block randomisation (block sizes 2 and 4) to niraparib 200 mg orally per day plus either nivolumab 240 mg intravenously every 2 weeks (later changed to 480 mg intravenously every 4 weeks based on manufacturer update) or ipilimumab 3 mg/kg intravenously every 4 weeks for four doses. The primary endpoints were safety and progression-free survival at 6 months. Treatment groups were not compared for activity, which was assessed in each group against a clinically meaningful progression-free survival at 6 months of 44% (null hypothesis). Superiority of a treatment regimen could be declared if 6-month progression-free survival was 60%, and inferiority if 6-month progression-free survival was 27%. All patients who received at least one dose of study treatment and had at least one post-treatment assessment of response according to Response Evaluation Criteria in Solid Tumours version 1.1 were included in the efficacy population. The safety population consisted of all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03404960, and enrolment is completed and follow-up is ongoing.

Findings

91 patients were enrolled between Feb 7, 2018, and Oct 5, 2021 and were randomly assigned to niraparib plus nivolumab (n=46) or niraparib plus ipilimumab (n=45). Of these patients, 84 were evaluable for the progression-free survival endpoint (niraparib plus nivolumab=44; niraparib plus ipilimumab=40). Median follow-up was 23·0 months (IQR 15·0–31·5). 6-month progression-free survival was 20·6% (95% CI 8·3–32·9; p=0·0002 vs the null hypothesis of 44%) in the niraparib plus nivolumab group; and 59·6% (44·3–74·9; p=0·045) in the niraparib plus ipilimumab group. Ten (22%) of 46 patients in the niraparib plus nivolumab group and 23 (50%) of 45 patients in the niraparib plus ipilimumab group had a grade 3 or worse treatment-related adverse event. The most common grade 3 or worse adverse events in the niraparib plus nivolumab group were hypertension (in four [8%] patients), anaemia (two [4%]), and thrombocytopenia (two [4%]) whereas in the niraparib plus ipilimumab group these were fatigue (in six [14%]), anaemia (five [11%]), and hypertension (four [9%]). There were no treatment-related deaths.

Interpretation

The primary endpoint of 6-month progression-free survival was met in the niraparib plus ipilimumab maintenance group, whereas niraparib plus nivolumab yielded inferior progression-free survival. These findings highlight the potential for non-cytotoxic maintenance therapies in patients with advanced pancreatic cancer.

Funding

Bristol Myers Squibb, GlaxoSmithKline, the Basser Center Young Leadership Council, The Konner Foundation, The Pearl and Philip Basser Innovation Research Award, the Anonymous Foundation, and the US National Institutes of Health.

中文翻译：

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Niraparib 加 nivolumab 或 niraparib 加 ipilimumab 治疗铂敏感晚期胰腺癌患者：一项随机 1b/2 期试验

 背景

有人建议为晚期胰腺癌患者建立终身化疗的替代方案，以解决化疗耐药性和累积毒性问题。聚（ADP-核糖）聚合酶（PARP）抑制剂在这种情况下已显示出功效，并且同时免疫检查点阻断可以提供协同肿瘤控制。本研究的目的是测试对铂类化疗有稳定反应的晚期胰腺癌患者维持 PARP 抑制联合免疫检查点阻断的安全性和抗肿瘤活性。

 方法

我们对尼拉帕利联合抗 PD-1（纳武单抗）或抗 CTLA-4（伊匹单抗）治疗的晚期胰腺癌患者进行了一项开放标签、随机、1b/2 期研究，这些患者的癌症在至少 16 年后仍未进展。数周的铂类治疗。通过置换区组随机化（区组大小 2 和 4）将患者随机分配 (1:1) 组为每天口服 200 mg 尼拉帕尼加每 2 周静脉注射 240 mg 纳武单抗（后来根据制造商更新更改为每 4 周静脉注射 480 mg） ) 或 ipilimumab 3 mg/kg，每 4 周静脉注射 4 剂。主要终点是安全性和 6 个月无进展生存期。没有比较治疗组的活性，而是根据 6 个月 44% 的有临床意义的无进展生存率（零假设）对每组进行评估。如果 6 个月无进展生存率为 60%，则可以宣布治疗方案优越；如果 6 个月无进展生存率为 27%，则可以宣布治疗方案较差。所有接受至少一剂研究治疗并根据实体瘤 1.1 版疗效评估标准进行至少一次治疗后疗效评估的患者均被纳入疗效人群。安全人群包括接受至少一剂研究治疗的所有患者。该研究已在 ClinicalTrials.gov 注册，NCT03404960，入组已完成，随访正在进行中。

 发现

2018年2月7日至2021年10月5日期间入组了91名患者，并被随机分配至尼拉帕尼加纳武单抗组（n = 46）或尼拉帕尼加伊匹单抗组（n = 45）。在这些患者中，84 例可评估无进展生存终点（尼拉帕利加纳武单抗 = 44；尼拉帕利加伊匹单抗 = 40）。中位随访时间为 23·0 个月（IQR 15·0–31·5）。尼拉帕尼联合纳武单抗组的 6 个月无进展生存率为 20·6%（95% CI 8·3–32·9；p=0·0002对比零假设 44%）；尼拉帕尼加伊匹单抗组为 59·6% (44·3–74·9；p=0·045)。尼拉帕利加纳武单抗组 46 名患者中的 10 名患者 (22%) 和尼拉帕利加伊匹单抗组 45 名患者中 23 名患者 (50%) 出现 3 级或更严重的治疗相关不良事件。尼拉帕尼加纳武利尤单抗组中最常见的 3 级或更严重不良事件是高血压（四名 [8%] 患者）、贫血（两名 [4%]）和血小板减少症（两名 [4%]），而尼拉帕尼加纳武利尤单抗组中最常见的 3 级或更严重不良事件是高血压（四名 [8%] 患者）、贫血（两名 [4%]）和血小板减少症（两名 [4%]）易普利姆玛组的这些症状包括疲劳（6 例 [14%]）、贫血（5 例 [11%]）和高血压（4 例 [9%]）。没有出现与治疗相关的死亡。

 解释

尼拉帕利加伊匹单抗维持组达到了 6 个月无进展生存期的主要终点，而尼拉帕利加纳武单抗的无进展生存期较差。这些发现凸显了对晚期胰腺癌患者进行非细胞毒性维持治疗的潜力。

 资金

百时美施贵宝、葛兰素史克、巴瑟中心青年领导委员会、康纳基金会、珀尔和菲利普巴瑟创新研究奖、匿名基金会和美国国立卫生研究院。