Targeting Cancer Cachexia: A Mechanistic Evaluation of Anti-GDF-15 Antibody-Based Combination Therapies.

Abstract

BACKGROUND: In a recent Phase 2 trial in patients with cancer cachexia, the anti-GDF-15 antibody ponsegromab resulted in increased body weight, appetite, muscle mass and physical activity. This study provides compelling evidence that targeting the GDF-15 pathway may offer a viable therapeutic strategy, while raising new mechanistic questions about how GDF-15 neutralization could be optimally integrated with other interventions to reverse the multifactorial cachexia syndrome. This series of experiments aimed to evaluate the effects of anti-GDF-15 antibody treatment in combination with muscle anabolic (anti-myostatin antibody) or appetite stimulant (ghrelin receptor agonist anamorelin) modulators using mouse cancer cachexia models. METHODS: The effects of anti-GDF-15 monoclonal antibody alone and in combination with an anti-myostatin antibody or anamorelin fumarate were examined in GDF-15-dependent (HT-1080 and RENCA) and partially dependent (TOV21G) mouse tumour models. Comprehensive assessments included food intake, body weight, body composition (including fat, lean and muscle mass), muscle function and treadmill running. Circulating myostatin was measured in patient samples from an advanced NSCLC clinical study. RESULTS: Anti-myostatin antibody treatment had limited efficacy in improving cachexia in mouse tumour models with high circulating GDF-15 (HT-1080 and RENCA), but improved cachexia (when combined with anti-GDF-15 antibody) in a tumour model with low circulating GDF-15 levels (TOV21G). In the TOV21G model, combining anti-myostatin and anti-GDF-15 antibodies led to even greater increases in body weight and hindlimb muscle mass compared with anti-GDF-15 antibody alone (p&#x2009;<&#x2009;0.001 for muscle mass); however, the increase in muscle strength and treadmill running did not reach statistical significance over monotherapy. When anamorelin was combined with anti-GDF-15 antibody, body weight was elevated compared with the HT-1080 tumour-bearing vehicle group (p&#x2009;<&#x2009;0.0001) but did not reach statistical significance over anti-GDF-15 antibody alone. Similar observations of the combination treatment were found for food intake, fat mass and gastrocnemius (p&#x2009;<&#x2009;0.05). Circulating myostatin was negatively correlated with weight loss in patients with cancer (p&#x2009;<&#x2009;0.01). CONCLUSION: These data provide proof-of-principle that mechanistically distinct approaches targeting muscle anabolism and appetite may act additively with GDF-15 neutralization, particularly in cancer cachexia settings with lower GDF-15 dependence. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01360554.