PMID- 30352626 OWN - NLM STAT- MEDLINE DCOM- 20191025 LR - 20211204 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 6 IP - 1 DP - 2018 Oct 23 TI - Neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFN-alpha2b in locally/regionally advanced melanoma: safety, efficacy and impact on T-cell repertoire. PG - 112 LID - 10.1186/s40425-018-0428-5 [doi] LID - 112 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 IFNalpha2b (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 x 4 doses bracketing definitive surgery, then every 12 weeks x 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. FAU - Tarhini, Ahmad AU - Tarhini A AUID- ORCID: 0000-0002-3193-9702 AD - UPMC Hillman Cancer Center, Pittsburgh, USA. tarhina1@ccf.org. AD - Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute and Case Comprehensive Cancer Center, 9500 Euclid Ave CA6-157, Cleveland, OH, 44195, USA. tarhina1@ccf.org. FAU - Lin, Yan AU - Lin Y AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Lin, Huang AU - Lin H AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Rahman, Zahra AU - Rahman Z AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Vallabhaneni, Priyanka AU - Vallabhaneni P AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Mendiratta, Prateek AU - Mendiratta P AD - Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute and Case Comprehensive Cancer Center, 9500 Euclid Ave CA6-157, Cleveland, OH, 44195, USA. FAU - Pingpank, James F AU - Pingpank JF AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Holtzman, Matthew P AU - Holtzman MP AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Yusko, Erik C AU - Yusko EC AD - Adaptive Biotechnologies, Seattle, USA. FAU - Rytlewski, Julie A AU - Rytlewski JA AD - Adaptive Biotechnologies, Seattle, USA. FAU - Rao, Uma N M AU - Rao UNM AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Ferris, Robert L AU - Ferris RL AD - UPMC Hillman Cancer Center, Pittsburgh, USA. FAU - Kirkwood, John M AU - Kirkwood JM AD - UPMC Hillman Cancer Center, Pittsburgh, USA. LA - eng SI - ClinicalTrials.gov/NCT01608594 GR - P30 CA047904/CA/NCI NIH HHS/United States GR - P50 CA097190/CA/NCI NIH HHS/United States GR - P50 CA121973/CA/NCI NIH HHS/United States GR - T32 CA175294/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181023 PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (Interferon alpha-2) RN - 0 (Interferon-alpha) RN - 0 (Interferon-alpha2b) RN - 0 (Ipilimumab) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents, Immunological/pharmacology/*therapeutic use MH - Female MH - Humans MH - Interferon alpha-2 MH - Interferon-alpha/pharmacology/*therapeutic use MH - Ipilimumab/pharmacology/*therapeutic use MH - Male MH - Melanoma/*drug therapy/pathology MH - Middle Aged MH - Neoadjuvant Therapy/*methods MH - Skin Neoplasms/*drug therapy/pathology PMC - PMC6199801 OTO - NOTNLM OT - Anti-CTLA-4 OT - Immunotherapy OT - Interferon OT - Ipilimumab OT - Melanoma COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The study was initiated after approval from the institutional review board (IRB) and was conducted in accordance with the Declaration of Helsinki. A University of Pittsburgh IRB approved written informed consent (IRB# PRO12020161) was obtained from all patients. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: Dr. Tarhini received research grant support Merck, Bristol Myers Squibb and Adaptive Biotechnologies. Dr. Tarhini served as a consultant for Merck, Bristol Myers Squibb, HUYA, Pfizer, Sanofi Genzyme, Novartis, Genentech-Roche, Array Biopharma, NewLink Genetics. John M Kirkwood declared consulting or advisory role to BMS, Merck, Novartis, Roche, Genentech, EMD Serrono, Array Biopharma, Prometheus. Erik C. Yusko and Julie A. Rytlewski are employees or Adaptive Biotechnologies. The rest of the authors declare no potential conflicts of interest relevant to the study. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/10/26 06:00 MHDA- 2019/10/28 06:00 PMCR- 2018/10/23 CRDT- 2018/10/25 06:00 PHST- 2018/07/31 00:00 [received] PHST- 2018/10/10 00:00 [accepted] PHST- 2018/10/25 06:00 [entrez] PHST- 2018/10/26 06:00 [pubmed] PHST- 2019/10/28 06:00 [medline] PHST- 2018/10/23 00:00 [pmc-release] AID - 10.1186/s40425-018-0428-5 [pii] AID - 428 [pii] AID - 10.1186/s40425-018-0428-5 [doi] PST - epublish SO - J Immunother Cancer. 2018 Oct 23;6(1):112. doi: 10.1186/s40425-018-0428-5.