Groarke John D, Crawford Jeffrey, Collins Susie M, Lubaczewski Shannon, Roeland Eric J, Naito Tateaki, Hendifar Andrew E, Fallon Marie, Takayama Koichi, Asmis Timothy, Dunne Richard F, Karahanoglu Isik, Northcott Carrie A, Harrington Magdalena A, Rossulek Michelle, Qiu Ruolun, Saxena Aditi R
From the Internal Medicine Research Unit (J.D.G., I.K., M.A.H., A.R.S.) and Clinical Pharmacology (R.Q.), Pfizer, Cambridge, MA; Duke Cancer Institute, Duke University Medical Center, Durham, NC (J.C.); Global Biometrics and Data Management, Pfizer R&D UK, Sandwich (S.M.C.), and Edinburgh Cancer Research Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (M.F.) - both in the United Kingdom; Translational Clinical Sciences, Pfizer, Collegeville, PA (S.L.); Knight Cancer Institute, Oregon Health and Science University, Portland (E.J.R.); the Cancer Supportive Care Center, Shizuoka Cancer Center, Shizuoka (T.N.), and the Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto (K.T.) - both in Japan; Cedars-Sinai Medical Center, Los Angeles (A.E.H.); the Ottawa Hospital Cancer Centre, Ottawa (T.A.); Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY (R.F.D.); Translational Clinical Sciences, Pfizer, Groton, CT (C.A.N.); and the Internal Medicine Research Unit, Pfizer, Tampa, FL (M.R.).
N Engl J Med. 2024 Dec 19;391(24):2291-2303. doi: 10.1056/NEJMoa2409515. Epub 2024 Sep 14.
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.
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.
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.
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. (Funded by Pfizer; ClinicalTrials.gov number, NCT05546476.).
恶病质是癌症常见的并发症，与死亡风险增加相关。生长分化因子15（GDF - 15）是一种循环细胞因子，其水平在癌症恶病质中升高。在一项涉及癌症恶病质患者的小型开放标签1b期研究中，人源化单克隆抗体ponsegromab可抑制GDF - 15，与体重、食欲和身体活动改善以及血清GDF - 15水平受到抑制相关。
在这项2期随机双盲12周试验中，我们将血清GDF - 15水平升高（≥1500 pg/毫升）的癌症恶病质患者按1:1:1:1的比例分配，分别接受100 mg、200 mg或400 mg剂量的ponsegromab或接受安慰剂，每4周皮下注射一次，共注射三剂。主要终点是12周时体重相对于基线的变化。关键次要终点是食欲和恶病质症状、身体活动的数字测量指标以及安全性。
共有187例患者接受随机分组。其中，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组患者的体重增加显著高于安慰剂组，100 mg组组间中位数差异为1.22 kg（95%可信区间，0.37至2.25），200 mg组为1.92（95%可信区间，0.92至2.97），400 mg组为2.81（95%可信区间，1.55至4.08）。相对于安慰剂，400 mg ponsegromab组在食欲、恶病质症状以及身体活动的各项测量指标上均有改善。ponsegromab组70%的患者和安慰剂组80%的患者报告了任何原因引起的不良事件。
在癌症恶病质且GDF - 15水平升高的患者中，使用ponsegromab抑制GDF - 15可导致体重增加、整体活动水平提高以及恶病质症状减轻，这些结果证实了GDF - 15作为恶病质驱动因素的作用。（由辉瑞公司资助；ClinicalTrials.gov编号，NCT05546476。）
