Dose effect of ipilimumab in patients with advanced melanoma: Results from a phase II, randomized, dose-ranging study

Abstract

9025 Background: Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Data from a phase II study showed that patients with previously treated advanced melanoma had proportionately more complete/partial responses (CR/PR) and stable disease (SD) with ipilimumab induction 10 mg/kg every 3 weeks (Q3W) X 4 compared with lower doses using the same schedule. Methods: In this randomized, double-blind, multicenter, phase II trial, patients with unresectable stage III/IV melanoma who had progressive disease (PD) on or were intolerant to prior therapies received ipilimumab induction dosing at 0.3, 3, or 10 mg/kg Q3W X 4. Eligible patients received maintenance therapy Q12W starting at Week 24 at their assigned blinded dose. Patients with PD could cross over to open-label ipilimumab 10 mg/kg induction plus maintenance in another study. The primary endpoint was the best overall response rate (BORR [CR or PR]). Efficacy was measured with modified World Health Organization (mWHO) criteria. Per protocol, tumor evaluation after PD by mWHO (ie, an overall > 25% increase in measurable tumor burden) before treatment with non-ipilimumab neoplastic therapy was permitted. Results: There were 217 patients treated. There was a statistically significant trend indicating an increase in BORR with increasing dose (p = 0.0015). The difference in BORR between 10 and 0.3 mg/kg was 11.2% [95% CI, 3.9 - 18.5]. Rates of immune-related adverse events (irAEs) increased with increasing dose. Conclusions: These data favor 10 mg/kg as the optimal dose. 0.3 mg/kg appears to be clinically ineffective. Follow-up for patients is ongoing. Ipilimumab dose (mg/kg) 10 (n = 72) 3 (n = 72) 0.3 (n = 73) BORR - % [95% CI] CR - n 11.1 [4.9 - 20.7] 2 4.2 [0.9 - 11.7] 0 0 [0.0 - 4.9] 0 Disease control rate (DCR = PR + CR + SD) - % [95% CI] 29.2 [19.0 - 41.1] 26.4 [16.7 - 38.1] 13.7 [6.8 - 23.8] Any irAE - % 70.4 64.8 26.4 Grade 3/4 irAE - % Any 25.4 7.0 Gastrointestinal 15.5 2.8 0 Hepatobiliary 2.8 0 0 Endocrine 1.4 2.8 0 Skin 4.2 1.4 0 Bowel perforations - % 0 0 0 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb