Everolimus or lanreotide: Who is the true winner for GI-NETs?

636 Background: Everolimus and lanreotide are established therapies for gastrointestinal neuroendocrine tumors (GI-NETs), but no direct head-to-head trials exist. Methods: Systematic search of MEDLINE, Cochrane, ClinicalTrials.gov identified 52 RCTs; 4 studies (n=1,149) comparing everolimus/lanreotide vs placebo in GI-NETs were included. Primary endpoint was PFS per RECIST; secondary endpoints were DCR, OS, and safety. Frequentist network meta-analysis using inverse variance weighting with placebo as common comparator was done. Missing data was handled through conservative estimation and using standard error approximation formulas. Confounding was controlled through meta-regression for age, tumor type, and prior treatment using R netmeta package. Results: Four studies (n=1,149) formed a star network: RADIANT-3 (everolimus vs placebo, pNETs), CLARINET (lanreotide vs placebo, GEP-NETs), REMINET (lanreotide vs placebo, post-first-line), and RADIANT-2 (everolimus+octreotide vs placebo+octreotide). For PFS, pooled indirect comparison showed HR 0.815 (95%CrI: 0.610-1.088), indicating no significant difference between agents (moderate certainty). DCR favored lanreotide (OR 0.432, 95%CrI: 0.205-0.910, low certainty). Grade 3-4 adverse events were significantly lower with lanreotide (33% vs 64-77% for everolimus). Moderate heterogeneity existed between lanreotide studies (I²=27.3%). Conclusions: Everolimus and lanreotide demonstrate comparable PFS efficacy for GI-NETs through indirect comparison. Lanreotide favored better disease control rates and significantly higher safety profile. Treatment selection should consider tumor type, patient characteristics, and tolerability preferences. Direct comparative trials would help to confirm these findings. Summary table. Comparison Outcome Effect Size 95% CrI P-value I² GRADE Interpretation Everolimus vs Placebo PFS HR 0.418 0.344-0.508 <0.001 N/A ⊕⊕⊕⊕ Favors everolimus Lanreotide vs Placebo PFS HR 0.471* 0.318-0.698 <0.001 27.30% ⊕⊕⊕⊖ Favors lanreotide Everolimus vs lanreotide PFS HR 0.815 0.610-1.088 0.162 27.30% ⊕⊕⊕⊖ No significant difference Everolimus vs Placebo DCR OR 1.65 1.03-2.64 0.036 N/A ⊕⊕⊕⊖ Favors everolimus Lanreotide vs Placebo DCR OR 3.83 2.14-6.84 <0.001 N/A ⊕⊕⊕⊖ Favors lanreotide Everolimus vs lanreotide DCR OR 0.432 0.205-0.910 0.028 N/A ⊕⊕⊖⊖ Favors lanreotide Everolimus vs Placebo Grade 3-4 AEs RR 2.17 1.71-2.75 <0.001 N/A ⊕⊕⊕⊖ Higher toxicity Lanreotide vs Placebo Grade 3-4 AEs RR 1.50 0.61-3.69 0.378 N/A ⊕⊕⊖⊖ No significant difference Everolimus vs lanreotide Grade 3-4 AEs RR 2.17** 1.33-3.54