# Cachexia pharmacotherapy: GDF-15 blockade, anamorelin, olanzapine

Source: https://onco.cc/technologies/cachexia-appetite-pharmacotherapy/  
OnCo record `cachexia-appetite-pharmacotherapy` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Cachexia pharmacotherapy covers three drug approaches to cancer wasting: ponsegromab, an antibody that blocks the appetite-suppressing hormone GDF-15 and is in phase 3; anamorelin, a ghrelin mimic approved only in Japan; and low-dose olanzapine, a generic tablet available everywhere that ASCO added to guidance in 2024. None has yet been shown to improve physical function.

## Summary

Historic options (progestins, corticosteroids, cannabinoids) improve appetite briefly but add fat or water, not muscle, and carry thrombotic or catabolic harms. Anamorelin, an oral ghrelin receptor agonist, increased lean body mass by about 1 kg over placebo in the ROMANA 1 and 2 phase 3 trials in NSCLC (Lancet Oncology 2016) without improving handgrip strength, which led the EMA to refuse it in 2017; Japan approved it in 2021 and real-world use there is substantial. Ponsegromab, a GDF-15-neutralising antibody, increased weight by 2.8 kg versus placebo at the highest dose over 12 weeks in a 187-patient phase 2 trial in patients with elevated GDF-15 (NEJM 2024), with gains in appetite, activity and lean mass, and is in phase 2/3 in pancreatic cancer cachexia. Low-dose olanzapine (2.5 mg) improved appetite and weight in a 124-patient randomised trial at Tata Memorial (JCO 2023) and was added to ASCO guidance in 2024 as a reasonable option. The field's endpoint problem, whether weight or lean mass gains translate into function and survival, is being addressed through regulatory endpoint qualification and combination with exercise and nutrition.

## Fields

- Kind: Technology
- Status: phase-3
- Last checked: 2026-09-08
- Principle: GDF-15 acts on GFRAL in the hindbrain to suppress appetite and drive catabolism; ghrelin agonism stimulates growth hormone and appetite; olanzapine antagonises serotonergic and histaminergic appetite-suppressing pathways and blocks nausea.
- Strengths: First mechanism-based cachexia drug (ponsegromab) with a selection biomarker; Olanzapine is generic, oral and available everywhere; Anamorelin's lean mass effect is reproducible
- Limitations: Weight gain has not yet been shown to prolong survival; Anamorelin unavailable outside Japan; Ponsegromab phase 3 data pending; cost will matter

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cachexia
- Ponsegromab phase 2 (NEJM 2024): https://doi.org/10.1056/NEJMoa2409515
- ROMANA 1 and 2 (Lancet Oncol 2016): https://doi.org/10.1016/S1470-2045(15)00558-6
- Olanzapine for anorexia (JCO 2023): https://doi.org/10.1200/JCO.22.01997

## Connected records

- ideas: [A cheap old tablet to restore appetite](https://onco.cc/ideas/idea-bio2-low-dose-olanzapine-appetite/), [Get the one approved appetite drug licensed beyond a single country](https://onco.cc/ideas/idea-bio2-anamorelin-access/), [Qualify a physical function endpoint so anti-wasting drugs can be approved](https://onco.cc/ideas/idea-bio2-cachexia-function-endpoint/), [Treat cachexia as a disease: GDF-15 blockade plus anabolic and nutrition bundles](https://onco.cc/ideas/idea-moon-cachexia-as-treatable-disease/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- fronts: [Diet, Exercise & Lifestyle](https://onco.cc/fronts/nutrition-lifestyle/), [Supportive Care & Survivorship](https://onco.cc/fronts/supportive-care/)
- technologies: [Antiemetics for chemotherapy-induced nausea and vomiting](https://onco.cc/technologies/antiemetic-therapy/), [Cachexia-directed therapy (GDF-15 blockade)](https://onco.cc/technologies/cachexia-therapy/), [CT body composition and sarcopenia measurement](https://onco.cc/technologies/ct-body-composition-sarcopenia/), [Nutrition support and cachexia management](https://onco.cc/technologies/oncology-nutrition/), [Resistance training and protein for cachexia and sarcopenia](https://onco.cc/technologies/resistance-training-cachexia/)
- drugs: [Megestrol acetate](https://onco.cc/drugs/megestrol/), [Progestins (megestrol acetate, medroxyprogesterone, levonorgestrel IUD)](https://onco.cc/drugs/megestrol-progestins/)
- companies: [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/)
- institutions: [National Cancer Center Hospital](https://onco.cc/institutions/ncc-japan/), [Tata Memorial Centre](https://onco.cc/institutions/tata-memorial/)
- pathways: [Cancer cachexia](https://onco.cc/pathways/cachexia-biology/)
- terms: [Body composition (lean mass, fat mass, visceral fat)](https://onco.cc/terms/body-composition/), [Cancer cachexia](https://onco.cc/terms/cachexia/), [Sarcopenia](https://onco.cc/terms/sarcopenia/)
- trials: [Low-dose olanzapine for cancer anorexia (Tata Memorial)](https://onco.cc/trials/olanzapine-appetite-tmh/), [Nanocrystalline Megestrol Acetate in Concurrent Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer](https://onco.cc/trials/nct07150663/), [Ponsegromab phase 2 in cancer cachexia](https://onco.cc/trials/ponsegromab-phase-2/), [ROMANA 1 and ROMANA 2](https://onco.cc/trials/romana-1-2/)
- people: [Sudeep Gupta](https://onco.cc/people/gupta-sudeep/)
- bottlenecks: [Cachexia, toxicity and the limits of the patient](https://onco.cc/bottlenecks/b-cachexia-supportive/), [Most of the world has almost no cancer care](https://onco.cc/bottlenecks/b-global-access/), [No incentive to repurpose cheap drugs](https://onco.cc/bottlenecks/b-generic-repurposing/)
- key papers: [Randomized Double-Blind Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients With Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer](https://onco.cc/key-papers/paper-sandhya-j-clin-oncol/)
- roadmaps: [Diet, exercise and lifestyle roadmap: causes established → interventions that disappointed → exercise proven as treatment](https://onco.cc/roadmaps/nutrition-lifestyle-roadmap/), [Supportive care and survivorship roadmap: making treatment bearable → proving it extends life → caring for tens of millions afterwards](https://onco.cc/roadmaps/survivorship-roadmap/)

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