Combination of Everolimus and Itacitinib in Patients with Hodgkin Lymphoma Relapsed/refractory to Brentuximab Vedotin (BV) and Checkpoint Inhibitors (CPI)

Introduction:Patients (pts) with classic Hodgkin lymphoma (cHL) who have failed or are intolerant of BV and CPI have few available treatment options. Genetic alterations in JAK/STAT pathway are frequently detected in cHL tumors making them an ideal therapeutic target. Since pre-clinical studies showed synergistic activity of JAK and mTOR inhibition in JAK-mutated cell lines, we designed a combination trial using an oral JAK inhibitor with potent selectivity for JAK1, itacitinib adipate, and an oral mTOR inhibitor, everolimus, for patients with cHL relapsed/refractory (R/R) to BV and CPI. Methods: We conducted an open-label, investigator-initiated, phase I/II trial using everolimus and itacitinib for pts with cHL who had at least 2 prior lines of therapy. Eligible pts were R/R to BV and CPI (or intolerant/not a candidate for either agent). A 3+3 design was used to define the recommended phase II dose (RP2D). Therapy was continued until progression or intolerance. All pts received PJP and anti-viral prophylaxis. DLT was defined as the occurrence of any ≥ grade 3 non-hematological or selected grade 4 hematological adverse event (AE) during Cycle 1 (by CTCAE v5 criteria). Responses were evaluated by Lugano 2014 criteria. Enrollment began in Feb 2019 with data cut off in Jan 2023. Results: We enrolled 23 cHL pts with median age 38 yrs (22–67), 65% male. Median number of prior treatments was 6 (2–12) including 74% post auto-SCT, 17% post allo-SCT and 15% post CD30 CART. All pts had prior BV and 21 (91%) had prior CPI except for 2 due to GVHD. No DLTs occurred in phase I and the RP2D was everolimus 5 mg and itacitinib 400 mg daily. All pts experienced at least one AE during the study, but most were manageable and low grade. Hematological events included thrombocytopenia (78%), anemia (57%) and neutropenia (39%). Most common non-hematological AEs included hypercholesterolemia (57%), hyperlipidemia (43%), hypertension (35%), acneiform rash (39%) and stomatitis (17%). These were attributed to everolimus and managed with supportive care. There were no study-related deaths. Six (26%) pts experienced grade at least one 3/4 non-hematological AE (all reversible) and one patient discontinued study treatment due to toxicity (infection/hypoxia). The best overall response rate was 70% (95% CI: 50%–85%) and complete response rate was 22% (95% CI: 12%–50%). At median follow-up 30 months (range 3–47), the 2-year PFS was 23% (95% CI: 12%–46%) and OS was 74% (95% CI: 59%–92%). The research was funded by: Incyte Keywords: Combination Therapies, Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. J. Svoboda Consultant or advisory role: Seagen, Pharmacyclics, Incyte, Genmab, BMS, Atara, Astra Zeneca, Adaptive, ADCT Research funding: TG, Seagen, Pharmacyclics, Merck, Incyte, BMS, Astra Zeneca, Adaptive D. L. Landsburg Consultant or advisory role: Karyopharm, Epizyme, Morphosys, Calithera, ADCT Research funding: Curis, Triphase S. D. Nasta Research funding: Roche, Gilead, Rafael, Pharmacyclics S. K. Barta Consultant or advisory role: Janssen, Kyowa Kirin, Affimed, Daiichi Sankyo Research funding: Kyowa Kirin, Acrotech, Seagen E. A. Chong Consultant or advisory role: Beigene, Tessa, BMS, KITE, Novartis M. E. Hughes Consultant or advisory role: AstraZeneca, AbbVie, Janssen, Genzyme Research funding: Acerta Pharma, HOPA M. Ruella Employment or leadership position: viTToria Consultant or advisory role: BMS, GSK, Bayer, NanoString, AbClon Research funding: Beckman Coulter, NanoString, AbClon S. J. Schuster Consultant or advisory role: BMS, Genentech, Nordic Nanovector, Loxo, Roche, AstraZeneca, Fate, Genmab, Mustang Biotech, BeiGene, Regeneron, MorphoSys, Novartis, Incyte, Legend Biotech Research funding: Merck, AbbVie, BMS, Genentech, TG, DTRM, Adaptive, Roche, Pharmacyclics, Novartis, Incyte