PT - JOURNAL ARTICLE AU - Tarhini, Ahmad AU - Lin, Yan AU - Lin, Huang AU - Rahman, Zahra AU - Vallabhaneni, Priyanka AU - Mendiratta, Prateek AU - Pingpank, James F. AU - Holtzman, Matthew P. AU - Yusko, Erik C. AU - Rytlewski, Julie A. AU - Rao, Uma N. M. AU - Ferris, Robert L. AU - Kirkwood, John M. TI - Neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFN-α2b in locally/regionally advanced melanoma: safety, efficacy and impact on T-cell repertoire AID - 10.1186/s40425-018-0428-5 DP - 2018 Dec 01 TA - Journal for ImmunoTherapy of Cancer PG - 112 VI - 6 IP - 1 4099 - http://jitc.bmj.com/content/6/1/112.short 4100 - http://jitc.bmj.com/content/6/1/112.full SO - J Immunother Cancer2018 Dec 01; 6 AB - Background Neoadjuvant 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 IFNα2b (HDI) is safe and associated with durable pathologic complete responses (pCR).Methods Patients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10 mg/kg × 4 doses bracketing definitive surgery, then every 12 weeks × 4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10 mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood.Results Thirty patients (age 37–76), 15 each at 3 and 10 mg/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 10 mg/kg versus 3 mg/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 32 months. The radiologic preoperative response rate was 36% (95% CI, 21–54); 4 patients at ipilimumab 3 mg/kg and 6 at 10 mg/kg and 2 (at 10 mg/kg) later relapsed. The pCR was 32% (95% CI, 18–51); 5 patients at ipilimumab 3 mg/kg and 4 at 10 mg/kg and one (at 3 mg/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.Conclusions Neoadjuvant 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 registration ClinicalTrials.gov, NCT01608594. Registered 31 May 2012.List of where and when study presented elsewhere: Partly presented at the 2016 and 2017 ASCO Annual Meetings.