Background 

The double-blind, randomized, placebo-controlled phase 3 study of orally administered PLX3397 in patients with pigmented villonodular synovitis or giant cell tumor of the tendon sheath (ENLIVEN) showed that pexidartinib provides a robust objective tumor response in adults with tenosynovial giant cell tumors (TGCT) not amenable to improvement with surgery. Based on these results, in 2019, pexidartinib received accelerated approval in the United States in this population as a breakthrough therapy under an orphan drug designation. However, the ability of pexidartinib to relieve pain in ENLIVEN was not fully detailed, and the relationship between pain relief and objective tumor response was not described.

Questions/purposes 

(1) What level of pain relief was achieved by pexidartinib treatment in ENLIVEN? (2) How was pain relief related to objective tumor responses? (3) How durable was pain relief?

Methods 

The current study included planned primary and exploratory assessments of patient-assessed worst pain at the site of the tumor in the ENLIVEN trial. ENLIVEN was a phase 3 randomized, placebo-controlled clinical trial in which adults with TGCT not amenable to improvement with surgery received pexidartinib or placebo for 24 weeks, after which eligible patients could receive open-label pexidartinib. Of 174 patients assessed for eligibility, 121 were randomized (50% [60] to placebo, 50% [61] to pexidartinib), and 120 were given either placebo or pexidartinib (59 received placebo and 61 received pexidartinib) and were included in an intent-to-treat analysis. Fifty-nine percent (71 of 120) of the overall treated population was female, and 88% (106 of 120) were White. Mean age was 45 ± 13 years. Tumors were mostly in the lower extremities (92% [110 of 120]), most commonly in the knee (61% [73 of 120]) and ankle (18% [21 of 120]). As a secondary outcome, patients scored worst pain at the site of the tumor in the past 24 hours on an 11-point numeric rating scale (NRS). The primary definition of a pain response was a decrease of at least 30% in the weekly mean worst-pain NRS score and increase of less than 30% in narcotic analgesic use between baseline and week 25. Planned exploratory assessments of pain included the frequency of a pain response using alternative thresholds, including a decrease in worst-pain NRS score of 50% or more and a decrease of at least 2 points (minimum clinically important difference [MCID]), the magnitude of pain reduction between baseline and week 25, correlation between worst-pain NRS score and tumor shrinkage by RECIST 1.1 criteria, and the durability of the pain response during the open-label extension. Pain responses during the randomized portion of the trial were compared according to intention-to-treat analysis, with a one-sided threshold of p < 0.025 to reduce the risk of false-positive results. Pain assessment was complete for 59% (35 of 59) of patients in the placebo group and 54% (33 of 61) of patients in the pexidartinib group. Demographic and disease characteristics did not differ between the two treatment groups.

Results 

A difference in the primary assessment of a pain response was not detected between pexidartinib and placebo (response percentage 31% [19 of 61] [95% CI 21% to 44%] versus 15% [9 of 59] [95% CI 8% to 27%]; one-sided p = 0.03). In the exploratory analyses, pexidartinib provided a modest improvement in pain (response percentage 26% [16 of 61] [95% CI 17% to 38%] versus 10% [6 of 59] [95% CI 5% to 20%]; one-sided p = 0.02 using the 50% threshold and 31% [19 of 61] [95% CI 21% to 44%] versus 14% [8 of 59] [95% CI 7% to 25%]; one-sided p = 0.02 using the MCID threshold). The least-squares mean change in the weekly mean worst-pain NRS score between baseline and week 25 was larger in patients treated with pexidartinib than placebo (-2.5 [95% CI -3.0 to -1.9] versus -0.3 [95% CI -0.9 to 0.3]; p < 0.001), although the mean difference between the two groups (-2.2 [95% CI -3.0 to -1.4]) was just over the MCID. Improvement in the weekly mean worst-pain NRS score correlated with the reduction in tumor size (r = 0.44; p < 0.001) and tumor volume score (r = 0.61; p < 0.001). For patients in the open-label extension, the change in the worst-pain NRS score from baseline was similar to the change at the end of the randomized portion and just above the MCID (mean -2.7 ± 2.2 after 25 weeks and -3.3 ± 1.7 after 50 weeks of receiving pexidartinib).

Conclusion 

Based on the current study, a modest reduction in pain, just larger than the MCID, may be an added benefit of pexidartinib in these patients, although the findings are insufficient to justify the routine use of pexidartinib for pain relief.

Level of Evidence 

Level II, therapeutic study.

中文翻译：

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Pexidartinib 为腱鞘巨细胞瘤患者提供适度的疼痛缓解：ENLIVEN 的结果

 背景

针对色素沉着绒毛结节性滑膜炎或腱鞘巨细胞瘤患者口服 PLX3397 的双盲、随机、安慰剂对照 3 期研究 (ENLIVEN) 表明，pexidartinib 对患有腱鞘巨细胞瘤的成人患者提供了稳健的客观肿瘤反应(TGCT) 不适合通过手术改善。基于这些结果，2019年，pexidartinib在美国作为孤儿药指定的突破性疗法在该人群中获得加速批准。然而，ENLIVEN 中 Pexidartinib 缓解疼痛的能力尚未完全详细，也没有描述疼痛缓解与客观肿瘤反应之间的关系。

 问题/目的

(1) ENLIVEN 中 Pexidartinib 治疗达到什么程度的疼痛缓解？ (2) 疼痛缓解与客观肿瘤反应有何关系？ (3) 疼痛缓解的持久性如何？

 方法

目前的研究包括对 ENLIVEN 试验中患者评估的肿瘤部位最严重疼痛进行计划的初步和探索性评估。 ENLIVEN 是一项 3 期随机、安慰剂对照临床试验，其中无法通过手术改善的 TGCT 成人接受 Pexidartinib 或安慰剂 24 周，之后符合条件的患者可以接受开放标签 Pexidartinib。在评估资格的 174 名患者中，121 名患者被随机分配（50% [60] 接受安慰剂，50% [61] 接受培西达替尼），120 名患者接受安慰剂或培西达替尼治疗（59 名接受安慰剂，61 名接受培西达替尼），并被纳入一项研究中。意向治疗分析。接受治疗的总体人群中，59%（120 人中的 71 人）是女性，88%（120 人中的 106 人）是白人。平均年龄为 45 ± 13 岁。肿瘤主要位于下肢（92% [120 例中的​​ 110 例]），最常见于膝盖（61% [120 例中的​​ 73 例]）和踝关节（18% [120 例中的​​ 21 例]）。作为次要结果，患者在过去 24 小时内肿瘤部位的疼痛程度在 11 点数字评定量表 (NRS) 上得分最高。疼痛反应的主要定义是从基线到第 25 周，每周平均最疼痛 NRS 评分下降至少 30%，麻醉镇痛药使用量增加不到 30%。计划的探索性疼痛评估包括以下频率：使用替代阈值的疼痛反应，包括最疼痛 NRS 评分降低 50% 或更多以及降低至少 2 分（最小临床重要差异 [MCID]）、基线和第 25 周之间疼痛减轻的程度，根据 RECIST 1.1 标准，最疼痛 NRS 评分与肿瘤缩小之间的相关性，以及开放标签扩展期间疼痛反应的持久性。 根据意向治疗分析比较试验随机部分期间的疼痛反应，单侧阈值 p < 0.025 以降低假阳性结果的风险。安慰剂组中 59% 的患者（59 名中的 35 名）和培昔达替尼组中的 54%（61 名中的 33 名）患者完成了疼痛评估。两个治疗组之间的人口统计学和疾病特征没有差异。

 结果

Pexidartinib 和安慰剂之间在疼痛反应的初步评估中未发现差异（反应百分比 31% [61 人中的 19 人] [95% CI 21% 至 44%] 与 15% [59 人中的 9人] [95% CI 8] % 至 27%]；单侧 p = 0.03）。在探索性分析中，培昔达替尼对疼痛有一定的改善（反应百分比为 26% [61 人中的 16 人] [95% CI 17% 至 38%] 对比 10% [59 人中的 6人] [95% CI 5% 至 20%] ；使用 50% 阈值和 31% [61 中的 19] [95% CI 21% 至 44%] 对比 14% [59 中的 8] [95% CI 7% 至 25%]，单侧 p = 0.02；使用 MCID 阈值时，单侧 p = 0.02）。在基线和第 25 周之间，接受培昔达替尼治疗的患者每周平均最疼痛 NRS 评分的最小二乘平均变化大于安慰剂组（-2.5 [95% CI -3.0 至 -1.9] 对比 -0.3 [95% CI - 0.9 至 0.3]；p < 0.001），尽管两组之间的平均差异（-2.2 [95% CI -3.0 至 -1.4]）略高于 MCID。每周平均最疼痛 NRS 评分的改善与肿瘤大小（r = 0.44；p < 0.001）和肿瘤体积评分（r = 0.61；p < 0.001）的减小相关。对于开放标签扩展中的患者，最严重疼痛 NRS 评分相对于基线的变化与随机部分结束时的变化相似，略高于 MCID（25 周后平均值为 -2.7 ± 2.2，25 周后平均值为 -3.3 ± 1.7 接受pexidartinib 50周后）。

 结论

根据目前的研究，疼痛的适度减轻（仅大于 MCID）可能是 Pexidartinib 对这些患者的额外益处，尽管研究结果不足以证明常规使用 Pexidartinib 缓解疼痛的合理性。

 证据水平

第二级，治疗研究。