PMID-26906526 – Anamorelin ROMANA 1 and 2 NSCLC Cachexia Phase III
Temel JS et al. "Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials," Lancet Oncology, 2016;17(4):519-531. doi:10.1016/S1470-2045(15)00558-6
Quick Reference
| Property | Value |
|---|---|
| PMID | 26906526 |
| DOI | 10.1016/S1470-2045(15)00558-6 |
| Year | 2016 |
| Journal | Lancet Oncology |
| Study Type | Phase III Randomized Controlled Trial |
| Evidence Level | I |
| Sample | n=979 (ROMANA 1: 484; ROMANA 2: 495) NSCLC patients with cachexia |
| Peptide(s) Studied | Anamorelin (ghrelin receptor agonist, ghrelin axis peptide) |
Key Findings
- Two parallel Phase III RCTs (ROMANA 1 and ROMANA 2) of anamorelin 100mg daily in NSCLC patients with cachexia (>=5% weight loss or BMI <20 kg/m2)
- Anamorelin significantly increased lean body mass (LBM) vs placebo in both trials: median increase ~1.0 kg at 12 weeks (p<0.001 for both trials)
- Total body weight also significantly increased with anamorelin vs placebo
- Co-primary endpoint of handgrip strength (HGS) was NOT significantly improved in either trial — a critical limitation
- Anamorelin increased appetite, food intake, and patient-reported quality of life measures
- The drug was well tolerated; most common adverse events were nausea (5%) and hyperglycemia (3%), consistent with ghrelin-axis activation
- The disconnect between body composition improvement (LBM increase) and functional outcome (no HGS improvement) raised questions about the clinical meaningfulness of the anabolic effect
Study Design
Two international, randomized, double-blind, placebo-controlled Phase III trials conducted in parallel. NSCLC patients (unresectable stage III/IV) with cachexia were randomized 2:1 to anamorelin 100mg orally once daily or placebo for 12 weeks. Co-primary endpoints: change in LBM (by DEXA) and change in HGS (by dynamometry). Secondary endpoints included body weight, appetite (FAACT-A/CS), and safety.
Limitations
- Failure to meet the co-primary endpoint of handgrip strength limits regulatory and clinical impact
- The LBM increase may reflect fluid retention rather than true muscle anabolism, as DEXA cannot distinguish the two
- 12-week duration may be insufficient to detect functional improvements; muscle strength gains typically require longer anabolic stimulation
- High dropout rate due to cancer progression and death in this advanced disease population
- No survival endpoint — unable to assess whether weight maintenance translates to survival benefit
Clinical Relevance
The ROMANA trials represent the largest and most rigorous RCT evidence for a ghrelin-axis peptide in cancer cachexia. While the body composition improvements are significant, the failure to improve handgrip strength prevented FDA approval and highlighted the challenge of translating anabolic effects into functional benefit in advanced cancer patients. This is a critical reference for understanding the therapeutic ceiling of ghrelin-axis stimulation in cachexia and informs the design of future cachexia interventions combining anabolic agents with exercise or multimodal approaches.
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#research #RCT #evidence-level-I #cancer