Neoadjuvant ipilimumab (3mg/kg or 10mg/kg) and high dose IFN-α2b in locally/regionally advanced melanoma: safety, efficacy and impact on T-cell repertoire

BackgroundNeoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. We hypothesized that neoadjuvant ipilimumab in combination with high dose IFN2b (HDI) is safe and associated with durable pathologic complete responses (pCR).MethodsPatients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10mg/kg x4 doses bracketing definitive surgery, then every 12weeks x4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood.ResultsThirty patients (age 37-76), 15 each at 3 and 10mg/kg, 18 male and 12 female were treated. Considering immune related adverse events (irAEs) of interest, more grade 3/4 irAEs were seen with ipilimumab 10mg/kg versus 3mg/kg (p=0.042). Among 28 evaluable patients, 11 relapsed, of whom 5 died. Median follow-up for 17 patients who have not relapsed was 32months. The radiologic preoperative response rate was 36% (95% CI, 21-54); 4 patients at ipilimumab 3mg/kg and 6 at 10mg/kg and 2 (at 10mg/kg) later relapsed. The pCR was 32% (95% CI, 18-51); 5 patients at ipilimumab 3mg/kg and 4 at 10mg/kg and one (at 3mg/kg) had a late relapse. In patients with pCR, T-cell fraction was significantly higher when measured in primary melanoma tumors (p=0.033). Higher tumor T-cell clonality in primary tumor and more so following neoadjuvant therapy was significantly associated with improved relapse free survival.ConclusionsNeoadjuvant ipilimumab-HDI was relatively safe and exhibited promising tumor response rates with an associated measurable impact on T-cell fraction and clonality. Most pCRs were durable supporting the value of pCR as a primary endpoint in neoadjuvant immunotherapy trials.Trial registrationClinicalTrials.gov, NCT01608594. Registered 31 May 2012.