Uddiptya Goswami: ESMO 2025 Supportive Care Breakthrough – The PROACC-1 Trial

Uddiptya Goswami, Consultant Medical Oncology and Hematology at Apollo Cancer Centre, Chennai, shared a post on LinkedIn:

“ESMO 2025 Supportive Care Breakthrough: The PROACC-1 Trial

Why This Trial Matters:

Cancer cachexia is a devastating syndrome affecting 50-80% of advanced cancer patients and directly causes up to 30% of cancer deaths. Until now, there have been NO FDA-approved pharmacologic therapies for this condition.

Mechanism of Action:

Target: GDF-15 (Growth Differentiation Factor 15) which is a stress-responsive cytokine elevated in cachexia

• Acts on GFRAL receptors in the hindbrain to suppress appetite

Drug: Ponsegromab is a humanized monoclonal antibody

• Binds and blocks GDF-15
• Prevents cachexia signaling cascade
• Restores appetite and metabolic balance

Key Trial Details (NCT05546476):

Study Design:

• Phase 2, randomized, double-blind trial
• 187 patients with NSCLC (40%), pancreatic (32%), or colorectal cancer (29%)
• Inclusion: Cancer cachexia + elevated GDF-15 ≥1500 pg/mL
• Four arms: Ponsegromab 100mg, 200mg, 400mg vs placebo (subcutaneous Q4W)

Primary Endpoint Results (12 weeks):

• 100mg arm: +1.22 kg vs placebo
• 200mg arm: +1.92 kg vs placebo
• 400mg arm: +2.81 kg vs placebo ✓ (most effective dose)

Game-Changing Extended Results (64 weeks):
The open-label extension study showed sustained, progressive benefit:

• Week 24: 2.7 kg average weight gain
• Week 52: 4.4 kg average weight gain
• Week 64: 5.2 kg average weight gain

Secondary Benefits (400mg group):

• Improved appetite and cachexia symptoms
• Increased physical activity levels
• Enhanced lumbar skeletal muscle mass
• Better quality of life scores

Safety Profile:

• Adverse events: 70% (ponsegromab) vs 80% (placebo)
• No new safety signals over 64 weeks
• Well-tolerated with manageable side effects

Implications for Practice:

1. First drug to demonstrate significant, sustained weight gain in cancer cachexia
2. Longest follow-up data available (64 weeks with continued benefit)
3. May improve tolerance to cancer-directed therapies and overall outcomes
4. Phase 3 registration-enabling trials planned for 2025-2026
5. Confirms GDF-15 as a validated, druggable target in cachexia

Clinical Pearls:

• Screen ALL advanced cancer patients for cachexia (>5% weight loss in 6 months)
• Consider GDF-15 testing (>1500 pg/mL predicts ponsegromab response)
• Remember: Cachexia ≠ malnutrition alone – it’s a complex metabolic syndrome
• Early intervention is critical – harder to reverse in advanced stages
• Multimodal approach: Nutrition + exercise + pharmacotherapy = best outcome.“

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