美国辉瑞制药公司John D. Groarke团队研究了Ponsegromab治疗癌症恶病质的疗效。这一研究成果发表在2024年12月19日出版《新英格兰医学杂志》上。

恶病质是癌症的常见并发症，与死亡风险增加有关。生长分化因子15（GDF-15）是一种循环细胞因子，在癌症恶病质中水平升高。在一项涉及癌症恶病质患者的小型、开放标签、1b期研究中，抑制GDF-15的人源化单克隆抗体ponsegromab与体重、食欲和体力活动的改善以及血清GDF-15水平的抑制有关。

在这项临床2期、随机、双盲、为期12周的试验中，研究组将患有癌症恶病质且血清GDF-15水平升高（≥1500 pg/ml）的患者按1:1:1:1的比例分配为接受100 mg、200 mg或400 mg剂量的ponsegromab，或接受安慰剂，每4周皮下注射三次。主要终点是12周时体重与基线相比的变化。关键次要终点是食欲和恶病质症状、身体活动的数字测量和安全性。

共有187名患者接受了随机分组。在这些患者中，40%患有非小细胞肺癌，32%患有胰腺癌，29%患有结直肠癌。在12周时，ponsegromab组的患者体重增加明显大于安慰剂组，100 mg组的组间差异中位数为1.22kg（95%可信区间，0.37至2.25），200 mg组为1.92kg（95%可信间隔，0.92至2.97），400mg组为2.81kg（95%可信间隔，1.55至4.08）。与安慰剂组相比，400 mg ponegromab组在食欲和恶病质症状以及身体活动方面都有所改善。全因不良事件发生在70%的患者中，而在安慰剂组中为80%。

研究结果表明，在癌症恶病质和GDF-15水平升高的患者中，ponsegromab对GDF-15的抑制导致体重增加和整体活动水平增加，并减轻恶病质症状，研究结果证实了GDF-15作为恶病质驱动因素的作用。

附：英文原文

Title: Ponsegromab for the Treatment of Cancer Cachexia

Author: John D. Groarke, Jeffrey Crawford, Susie M. Collins, Shannon Lubaczewski, Eric J. Roeland, Tateaki Naito, Andrew E. Hendifar, Marie Fallon, Koichi Takayama, Timothy Asmis, Richard F. Dunne, Isik Karahanoglu, Carrie A. Northcott, Magdalena A. Harrington, Michelle Rossulek, Ruolun Qiu, Aditi R. Saxena

Issue&Volume: 2024-12-19

Abstract:

BACKGROUND

Cachexia is a common complication of cancer and is associated with an increased risk of death. The level of growth differentiation factor 15 (GDF-15), a circulating cytokine, is elevated in cancer cachexia. In a small, open-label, phase 1b study involving patients with cancer cachexia, ponsegromab, a humanized monoclonal antibody inhibiting GDF-15, was associated with improved weight, appetite, and physical activity, along with suppressed serum GDF-15 levels.

METHODS

In this phase 2, randomized, double-blind, 12-week trial, we assigned patients with cancer cachexia and an elevated serum GDF-15 level (≥1500 pg per milliliter) in a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg or to receive placebo, administered subcutaneously every 4 weeks for three doses. The primary end point was the change from baseline in body weight at 12 weeks. Key secondary end points were appetite and cachexia symptoms, digital measures of physical activity, and safety.

RESULTS

A total of 187 patients underwent randomization. Of these patients, 40% had non–small-cell lung cancer, 32% had pancreatic cancer, and 29% had colorectal cancer. At 12 weeks, patients in the ponsegromab groups had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg (95% credible interval, 0.37 to 2.25) in the 100-mg group, 1.92 (95% credible interval, 0.92 to 2.97) in the 200-mg group, and 2.81 (95% credible interval, 1.55 to 4.08) in the 400-mg group. Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400-mg ponsegromab group relative to placebo. Adverse events of any cause were reported in 70% of the patients in the ponsegromab group and in 80% of those in the placebo group.

CONCLUSIONS

Among patients with cancer cachexia and elevated GDF-15 levels, the inhibition of GDF-15 with ponsegromab resulted in increased weight gain and overall activity level and reduced cachexia symptoms, findings that confirmed the role of GDF-15 as a driver of cachexia.

DOI: 10.1056/NEJMoa2409515

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2409515