Efficacy and Safety of Once-Daily Oral Paltusotine in Patients with Carcinoid Syndrome: results from a Phase 2 Multicentre Study

Background: Carcinoid syndrome (CS) is a common paraneoplastic syndrome in patients with neuroendocrine tumours and can be debilitating. Here, we describe results of the first clinical trial of paltusotine, a new oral, once‐daily, nonpeptide, selective somatostatin 2 receptor agonist, in patients with CS. Methods: This phase 2, randomised, open‐label study (18 sites; 5 countries) enrolled adults with stable grade 1 or 2 neuroendocrine tumours and symptomatic CS. Patients were treatment naive or currently untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day on ≥2 days over a 2‐week period) or washed out of SRLs (demonstrated control on SRL with symptom worsening after washout). Patients were randomised to once‐daily paltusotine 40 mg or 80 mg for 8 weeks; one optional up‐titration (to 80 mg or 120 mg) was permitted. This trial is registered with ClinicalTrials.gov, NCT05361668. Findings: Between March 27, 2023 and December 11, 2023, 36 patients (untreated, n=9; SRL washout, n=27) were randomly assigned to treatment (18 to paltusotine 40 mg/day, 18 to 80 mg/day). Nine patients had a paltusotine dose increase during randomised treatment. In patients completing 8 weeks of treatment (n=30), mean (SE) change in daily flushing frequency was a reduction of 1·7 (0·3) episodes per day and in daily BM frequency was a reduction of 1·1 (0·3) episodes per day. The most commonly reported adverse events (AEs) were diarrhoea (n=15 [42%]), abdominal pain (n=9 [25%]), and headache (n=8 [22%]). No severe or serious AEs were considered treatment related, and no treatment‐related AEs led to study discontinuation. Interpretation: In this phase 2 study, treatment with once‐daily, oral paltusotine reduced the frequency and severity of CS symptoms and was well‐tolerated. These findings support further development of paltusotine for the treatment of CS.