The Global Cachexia Pathway: Module 3 Translating Emerging Cachexia Science

This is a summary of a presentation by Dr Richard Dunne, MD, which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This activity is supported by an independent medical educational grant from Pfizer. This online education program has been designed for Healthcare Professionals globally.

Where Are We Now?

Biological understanding of cachexia and the development of targeted approaches are advancing rapidly, but the routine clinical pathway has not yet caught up. There are currently no agents approved specifically for cancer cachexia in the US or EU. Therefore, for an appropriately selected patient, clinical-trial participation may be the only route to accessing a targeted cachexia therapy.

GDF-15: The Biology Clinicians Need to Know

Tumour/host stress → ↑ GDF-15 → GFRAL/RET signalling in the hindbrain → anorexia, nausea and food aversion → reduced intake

GDF-15 is a stress hormone/cytokine released in response to tumour and host inflammatory stress.
Rising circulating GDF-15 levels track with weight loss and predict worse prognosis in solid tumours.
GDF-15 binds to its highly specific receptor, GFRAL, which signals via RET in the area postrema of the hindbrain.
This specific neurological pathway drives reduced intake, nausea, and severe food aversion.

The anorexia is being driven, not chosen. Telling a patient with cachexia to simply "eat more" is an inadequate clinical plan because it ignores the profound, biologically driven aversion to food.

Why GDF-15 is an Attractive Target – But Not Yet a Routine Clinical Test

GDF-15 is highly attractive to researchers for two reasons:

As a therapeutic target: GFRAL expression is largely confined to the hindbrain, meaning that blocking this signal is not expected to disturb the many other tissues where GDF-15 is active.
As a potential biomarker: It is measurable in serum, prognostic across solid tumours, and is being used to select appropriate patients for clinical trials.

What This Means Today

Do: Diagnose and assess cachexia using established clinical criteria.
Do: Consider whether an appropriate clinical trial is available for your patient.
Do not: Order GDF-15 routinely. There is no validated diagnostic threshold for routine practice, and measuring it outside a clinical-trial setting does not change standard management.

Anti-GDF-15 Therapy: What Proof of Concept Has Shown

Evidence Snapshot: Investigational Anti-GDF-15 Antibody

Design: Phase 2, biomarker-selected, placebo-controlled study of 187 patients with lung, pancreatic, or colorectal cancer receiving an investigational anti-GDF-15 agent (ponsegromab).
Results (Median weight difference vs placebo at 12 weeks):
- 100 mg: 1.22 kg
- 200 mg: 1.92 kg
- 400 mg: 2.81 kg
Secondary Outcomes: At the highest dose, patients reported improvements in appetite/cachexia symptoms, physical activity, and skeletal muscle index.
Long-term Extension: A 1-year open-label extension (n=117) showed mean weight gains of 2.7 kg at week 24, 4.4 kg at week 52, and 5.2 kg at week 64.

Important Interpretation: Weight gain, increased muscle index, and improved activity are not the same as demonstrating improved survival or other definitive long-term clinical outcomes. Ponsegromab and other targeted agents remain investigational for cancer cachexia, are not commercially available, and no recommendation for their unapproved use is being made.

GDF-15 is Only One Pathway

Cancer cachexia is biologically multifactorial; a syndrome driven by multiple mechanisms is unlikely to be solved by targeting one pathway alone.

Domain	Emerging/Biological Pathways
Central appetite regulation	GDF-15–GFRAL; MC4R antagonists; ghrelin receptor agonists
Muscle catabolism	Myostatin and activin A via activin type II receptors
Inflammation	IL-6, IL-1, TNF, and interferon-γ signalling
Emerging biology	Interorgan signalling and metabolic reprogramming

Earlier single-mediator strategies have sometimes improved measures of body composition without necessarily improving patient function or survival. The future model of care relies on targeted therapy layered onto good multimodal supportive care – not instead of it.

Who Should Make You Think About a Cachexia Clinical Trial?

Think Trial Early Checklist:

Consider clinical-trial referral when a patient:

Meets consensus criteria for cancer cachexia and this is formally documented.
Retains a good performance status, particularly ECOG 0–1.
Has disease that is not yet in the refractory cachexia phase.
Is starting, or is early in, systemic anticancer therapy.
Has a cancer type and treatment context matching an available protocol.

Timing is critical. Trials typically recruit at the start of first-line therapy, meaning that referral should happen around diagnosis. Waiting until the patient exhibits severe functional decline often removes the opportunity.

What May Exclude a Patient?

Check Before Referring: Eligibility varies significantly between individual protocols. Always consult the specific trial protocol, national/regional trial registries (e.g., ClinicalTrials.gov, EU Clinical Trials Information System), or your institutional clinical-trials office. Common exclusions include:

A mechanical or obstructive cause of reduced intake (e.g., gastric outlet obstruction).
Current reliance on tube feeding or parenteral nutrition.
Weight loss primarily attributable to a non-malignant condition.
Poor performance status or progression to refractory cachexia.

Have This Information Ready Before Referral

Thorough initial assessment makes trial referral seamless. Ensure the following are documented:

Weight history: Percentage weight loss over the preceding 6 months, current BMI, and BMI-adjusted weight-loss grade.
Function and inflammation: ECOG performance status, alongside routine CRP and albumin.
Imaging: A recent staging CT (specifically the L3 slice to support body composition assessment).
Treatment context: Current/planned regimen, line of therapy, and planned treatment start date.

Example of a Current Trial Opportunity

The ongoing RIVER-mPDAC study (NCT06989437) is an example of an actively recruiting phase 2b/3 trial evaluating ponsegromab alongside first-line chemotherapy in patients with metastatic pancreatic cancer. Note: This is an example of how trial eligibility intersects with cancer type, treatment line, and timing, not a recommendation for a specific intervention. Eligibility is protocol-specific, and the agent remains investigational without established efficacy.

Close the Loop Across the Pathway

The complete approach to cachexia management requires three connected stages:

1. RECOGNISE EARLIER: Identify clinically meaningful weight loss, even when BMI appears normal (e.g., 6.1% loss with normal BMI).
2. SUPPORT MULTIMODALLY: Initiate nutrition, exercise/rehabilitation, and symptom management alongside systemic chemotherapy.
3. REFER WHILE THERE IS STILL TIME: Screen for clinical-trial eligibility early, while the patient retains an ECOG 0–1 performance status.

Put it into practice: Three actions for tomorrow's clinic

1. Recognise that anorexia is biologically driven. Do not interpret a patient's reduced intake simply as a lack of motivation, and do not expect instructions to "eat more" to overcome the biological drivers of cachexia.
2. Think about trials while the patient is still well enough. For an appropriate patient with documented cachexia and an ECOG 0–1, consider trial availability at diagnosis. Waiting for obvious visual deterioration will remove the option.
3. Never substitute emerging therapy for supportive care. Investigational targeted approaches (like anti-GDF-15 agents) should be viewed as potential additions to, not replacements for, rigorous nutrition, exercise/rehabilitation, and symptom control.

Recognize earlier. Support multimodally. Refer while there is still time.

References

Groarke JD, et al. Ponsegromab for the Treatment of Cancer Cachexia. New England Journal of Medicine. 2024;391(24):2291-2303.
Kadakia KC, et al. Emerging Targets in Cancer Cachexia. ASCO Educational Book. 2023;43:e389942.
Filippini DM, et al. GDF-15 and Cancer Cachexia. Biomedicines. 2025;13(8):1931.
Crawford J, et al. Open-label extension results. ESMO 2025, LBA102 [Abstract].
Ali IY, et al. RIVER-mPDAC phase 2b/3. J Clin Oncol. 2026;44(2_suppl):TPS791 (NCT06989437) [Abstract].

Content is accurate as of the date of release.