@article {KhushalaniA476, author = {Nikhil Khushalani and Andrew Brohl and Joseph Markowitz and Lyudmila Bazhenova and Gregory Daniels and Heather Yeckes-Rodin and Siqing Fu and Lori McCormick and Michael Kurman and Mireille Gillings and Gloria Lee and Zeynep Eroglu}, title = {797 Significant anti-tumor activity of HBI-8000, a class I histone deacetylase inhibitor (HDACi) in combination with nivolumab (NIVO) in anti-PD1 therapy-na{\"\i}ve advanced melanoma (TN-Mel)}, volume = {8}, number = {Suppl 3}, pages = {A476--A477}, year = {2020}, doi = {10.1136/jitc-2020-SITC2020.0797}, publisher = {BMJ Specialist Journals}, abstract = {Background Anti-PD1 based therapy has been the mainstay of treatment for advanced melanoma for several years. HBI-8000 is a Class I selective oral HDACi with immunomodulatory effects including enhanced cell-mediated toxicity, enhanced tumor infiltration by cytotoxic T-cells and reduced tumor infiltration by T-regulatory cells. In a phase 1b/2 trial in melanoma, kidney cancer and non-small cell lung cancer, the recommended phase 2 dose of HBI-8000 was determined to be 30mg orally twice weekly (BIW) combined with nivolumab administered at the approved dosing schedule (JITC 2018;P346). This report describes the tolerability of this combination in all enrolled melanoma patients, and efficacy in the expansion cohort of anti-PD1 TN-MEL.Methods Patients with unresectable or advanced melanoma and measurable disease, of ECOG performance status 0-1, and with adequate hematologic and biochemical parameters were enrolled. Treated brain metastases not requiring steroids were permitted. Tumor response was assessed by RECIST v1.1 and iRECIST with staging every 8 weeks; treatment continued for 24 months, disease progression or unacceptable toxicity. Data cut-off was Jan 31, 2020 for the reported analysesResults Forty-nine patients (32 anti-PD1 na{\"\i}ve, 17 with prior anti-PD1 therapy) were treated with HBI-8000 (47 patients at 30 mg BIW; 2 patients at 40mg BIW in Phase 1b) in combination with nivolumab. The median age was 63 years (range 28-84); 57\% were male. In the anti-PD1 na{\"\i}ve cohort, most (30/32) had normal LDH. The most common all grade treatment related adverse events (AEs) included fatigue (n=25), diarrhea (n=24), abdominal pain (n=14), and lymphopenia (n=13). Although HBI-8000 related thrombocytopenia (n=25) and neutropenia (n=15) were common, clinically significant bleeding or febrile neutropenia were not observed. The most frequent \>/= G3 AEs related to HBI-8000 were hypophosphatemia (n=7), neutropenia (n=4), thrombocytopenia (n=3) and lymphopenia (n=2). Twelve patients discontinued treatment for AEs. Among 31 anti-PD1 na{\"\i}ve patients evaluable for response, there were 23 objective responses (4 CR, 19 PR; ORR 74\%), 5 stable disease (disease control rate 90\%), and 3 progressive disease. Median time to response was 1.9 months. At a median follow-up for this cohort of 8.9 months (range, 0.9-35.5 months), the median duration of response and median progression-free survival have not been reached.Conclusions The combination of HBI-8000 and nivolumab is well tolerated and demonstrates very encouraging efficacy in patients with anti-PD1-na{\"\i}ve advanced melanoma. Follow-up to assess durability of response is ongoing, and further investigation of this promising combination is planned.Trial Registration NCT02718066Ethics Approval The study was approved by participating study sites{\textquoteright} Institutional Review Boards and the Sponsor has conducted the trial in full compliance with all GCP and FDA regulations.}, URL = {https://jitc.bmj.com/content/8/Suppl_3/A476.2}, eprint = {https://jitc.bmj.com/content/8/Suppl_3/A476.2.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }