Key Clinical Summary: Cancer Cachexia Update - Focus on Emerging Therapies

This is a micro-learning module summary of the Cancer Cachexia Education session which you can find here.

Before participating please read our CME and disclosure information which can be found here. This program is supported by an independent education grant from Pfizer Global Medical Grants. This online education program has been designed for healthcare professionals globally.

Introduction

This summary explores recent advances in cancer cachexia therapeutics, outlining the current management landscape, supportive pharmacologic interventions, and the emergence of novel agents targeting underlying biology. It reviews mechanistic data on growth differentiation factor 15 (GDF‑15), ghrelin receptor agonism, multimodal anabolic–catabolic modulation, and melanocortin‑4 receptor antagonism, alongside clinical trial efficacy and safety outcomes for key agents.

Biological Basis and Unmet Needs in Cachexia Management

• Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle loss, with or without fat depletion, that cannot be reversed by conventional nutritional support and leads to progressive functional impairment.
• Affecting up to 80% of patients with advanced malignancies, cachexia contributes significantly to morbidity, mortality, and impaired tolerance of anticancer therapy.
• Despite its prevalence, therapeutic progress has historically been limited, with current management relying on nutritional counseling, exercise, and short‑term pharmacologic interventions such as megestrol acetate or corticosteroids. These agents provide modest appetite and weight benefits but fail to improve quality of life (QoL) or functional endpoints.
• Recent mechanistic insights into cachexia biology, particularly the role of GDF‑15 signaling, ghrelin receptor pathways, and anabolic–catabolic imbalance, have catalyzed the development of targeted therapies. Several agents are now advancing through phase 2 and 3 trials, offering the potential to shift cachexia management toward disease‑modifying strategies.

Current Supportive Therapies

• Guidelines from ASCO and ESMO emphasize dietary counseling and psychosocial support as foundational interventions. Recommended pharmacologic options remain limited and include:
• Megestrol acetate: Improves appetite and induces weight gain, primarily via fat accumulation. Risks include thromboembolism and adrenal suppression.
• Corticosteroids: Provide rapid appetite stimulation and fatigue relief but are unsuitable for long‑term use due to muscle wasting, hyperglycemia, and mood changes.
• Olanzapine: Provides appetite and weight benefits, though without effects on QoL or functional improvement.
• These agents highlight the unmet need for therapies that address cachexia’s biology rather than symptoms alone.

Multimodal Interventions

• Trials such as MENAC and MIRACLE have investigated integrated approaches combining exercise, nutrition, and anti‑inflammatory agents.
• Results demonstrated stabilization of weight but limited impact on muscle mass or physical activity.
• These findings underscore the complexity of cachexia and the necessity of biologically targeted pharmacologic strategies.

Clinical Trial Endpoints in Cancer Cachexia

• The Cancer Cachexia Endpoints Working Group has emphasized the need for standardized measures beyond weight. Key domains include: Physical function (e.g., handgrip strength, stair climb power); appetite and dietary intake; QoL metrics (FAACT scales); body composition (skeletal muscle index, lean mass); biomarkers (GDF‑15, cytokine profiles); integration of these endpoints will be critical to demonstrating clinically meaningful benefit in future trials.

Emerging Pharmacologic Therapies

Ghrelin Receptor Agonist: Anamorelin

• Approved in Japan for cancer cachexia.
• Phase 3 ROMANA 1 and 2 trials demonstrated significant increases in lean body mass, body weight, and symptom scores versus placebo, although functional endpoints such as handgrip strength did not improve.

Anabolic–Catabolic Transforming Agent: S‑pindolol benzoate (ACM‑001)

• Multimodal mechanism: β2‑agonism enhances protein synthesis, β1‑blockade reduces muscle breakdown, and 5‑HT1A activity improves appetite and fatigue.
• ACT‑ONE trial: High‑dose S‑pindolol achieved significant weight gain compared with placebo.
• Secondary endpoints showed increases in lean body mass, handgrip strength, and trends toward improved physical performance.

Melanocortin‑4 Receptor Antagonist: TCMCB07

• Targets hypothalamic melanocortin signaling to rebalance food intake and energy expenditure.
• A study in metastatic colorectal cancer aims to preserve muscle and fat mass relative to placebo.

Anti‑GDF‑15 Monoclonal Antibody: Ponsegromab

• GDF-15 is a stress-induced cytokine that signals through GFRAL/RET in the hindbrain to suppress appetite, and is linked to weight loss and tissue wasting.
• Phase 1b study: Well tolerated, with improvements in weight, physical activity, and patient‑reported symptoms.
• Phase 2 PROACC‑1 trial:
• Randomized, placebo‑controlled study across patients with NSCLC, pancreatic, and colorectal cancer and elevated GDF‑15.
• Dose‑dependent weight gain at 12 weeks versus placebo.
• Significant improvements in patient-reported symptoms, overall physical activity, and muscle mass compared with placebo.
• Safety profile comparable to placebo.
• This study supports GDF-15 as a primary driver of cachexia and an important therapeutic target in this area of significant unmet medical need.

A phase 3 trial is underway

Broader Anti‑GDF‑15/GFRAL Pipeline

• Several agents are in early development, including:
• Rilogrotug (AV 380) – anti‑GDF‑15 mAb, phase 1.
• Visugromab – anti‑GDF‑15 mAb, phase 1/2 in solid tumors and NSCLC.
• AZD‑8853 – anti‑GDF‑15 mAb, phase 1/2a in solid tumors.
• NGM‑120, JMT‑203 – anti‑GFRAL mAbs, phase 1/2 in solid tumors and prostate cancer.
• These programs reflect growing recognition of GDF‑15/GFRAL signaling as a central driver of cachexia and a therapeutic target with potential overlap in oncology and immunology.

Conclusions

Cancer cachexia remains a major unmet need in oncology, with current therapies offering limited symptomatic relief. Advances in understanding the molecular drivers, particularly GDF‑15 signaling, have enabled the development of targeted biologics such as ponsegromab, which has demonstrated improvements in weight, appetite, physical activity, and muscle mass in phase 2 trials. Complementary strategies including ghrelin receptor agonists, multimodal agents, and melanocortin‑4 antagonists are in clinical development. Future management of cachexia will likely involve a multimodal framework integrating supportive care with biologically targeted therapies, guided by standardized endpoints that capture functional and QoL outcomes most meaningful to patients.