Disclosures I have nothing to disclose. New Drug Update JORDAN BASKETT, PHARMD, BCOP CLINICAL ONCOLOGY PHARMACIST DUKE UNIVERSITY HOSPITAL Recently Approved Agents for Leukemia & Lymphoma Objectives Duvelisib September 2018 CLL/SLL, FL Calaspargase pegol-mknl December 2018 ALL 1. Review pharmacology of newly approved oncology Blastic plasmacytoid agents Tagraxofusp-erzs December 2018 dendritic cell neoplasm 2. Discuss literature supporting approval of the agents Ivosidenib July 2018 AML, IDH1+ 3. Identify clinical pearls for new agents Gilteritinib November 2018 AML, FLT3+ 4. Evaluate place in therapy for newly approved agents Glasdegib November2018 AML Moxetumomab September 2018 Hairy cell leukemia pasudotox-tdfk Mycosis fungoides or Mogamulizumab-kpkc August 2018 Sézary syndrome Duvelisib (Copiktra®) Compared to Idelalisib Approved Duvelisib Idelalisib • September 2018 PI3K-δ and PI3K-γ inhibitor PI3K-δ inhibitor MOA • Inhibits PI3K-δ and PI3K-γ in normal and malignant B-cells Monotherapy In combination with rituximab for CLL/SLL Indication BBW: BBW: • Infection • Hepatotoxicity • Relapsed/refractory CLL/SLL and FL after ≥ 2 prior systemic therapies • Diarrhea, colitis (18%) • Diarrhea, colitis (14%) Dosing & Administration • Cutaneous reactions • Intestinal perforation • Pneumonitis (5%) • Pneumonitis (4%) • 25 mg PO BID Administer Pneumocystis jirovecii (PJP) prophylaxis during treatment and until absolute CD4+ T cell count is > 200 cells/uL Consider antiviral prophylaxis for cytomegalovirus reactivation Copiktra (duvelisib) [package insert]. Needham, MA: Verastem, Inc; 2018. Flinn IW, et al. Blood 2018;132(23):2446-2455. Furman RR, et al. N Engl J Med 2014;370(11):997-1007. 1 Calaspargase pegol-mknl Audience Response #1 (AsparlasTM) How does the mechanism of action for duvelisib differ from idelalisib? Approved A. Duvelisib inhibits PI3K-δ alone • December 2018 B. In addition to inhibiting PI3K-δ, duvelisib also inhibits PI3K-γ MOA • Conjugated enzyme that reduces circulating levels of asparagine, resulting in cytotoxicity C. Duvelisib inhibits PI3K-γ alone to leukemic cells Indication • Treatment of ALL in pediatric & young adult patients age 1 month to 21 years Dosing & Administration • 2500 units/m2 IV over 1 hour, no more frequently than every 21 days Asparlas (calaspargase pegol-mknl) [package insert]. Boston, MA: Servier Pharmaceuticals LLC; 2018. Compared to Pegaspargase Tagraxofusp-erzs (ElzonrisTM) May be substituted for pegaspargase in multi-agent chemotherapy plans Approved Pegaspargase (SS-PEG) Calaspargase pegol (SC-PEG) • December 2018 E.coli L-asparaginase with a succinimidyl E.coli L-asparaginase with a succinimidyl MOA carbamate (SC) linker = succinate (SS) linker more stable molecule • CD123-directed cytotoxin At least 14 days between doses At least 21 days between doses Indication Mean AUC from time 0-25 days: Mean AUC from time 0-25 days: • Blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients ≥ 365 IU x h/mL 404 IU x h/mL 2 years old Mean half-life of plasma asparaginase Mean half-life of plasma asparaginase activity: 127 hr activity: 322 hr Dosing & Administration • 12 mcg/kg IV infusion over 15 minutes once daily on days 1-5 of a 21-day cycle Asparlas (calaspargase pegol-mknl) [package insert]. Boston, MA: Servier Pharmaceuticals LLC; 2018. Angiolillo AL, et al. J Clin Oncol 2014;32(34):3874-3882. Elzonris (tagraxofusp-erzs) [package insert]. New York, NY: Stemline Therapeutics, Inc; 2018. Tagraxofusp-erzs: Pearls & Place in Therapy Ivosidenib (Tibsovo®) STML-401-0114 trial Approved • 29 treatment-naïve patients: • July 2018 (relapsed/refractory) • CR or clinical CR: 72% (95% CI, 52.8% to 87.3%) • May 2019 (front-line) • ORR: 90% (95% CI, 72.6% to 97.8%) MOA • 45% (13/29) were bridged to stem cell transplant • Mutated IDH1 inhibitor • OS: not reached (median f/u of 23 mo) • AEs (≥40%): increased ALT/AST, hypoalbuminemia, peripheral edema, Indication thrombocytopenia • Relapsed/refractory IDH1-mutated AML • Newly diagnosed IDH1-mutated AML in patients ≥ 75 years old or in patients who have •Premedicate with H1-histamine antagonist, acetaminophen, corticosteroids, and H2- comorbidities histamine antagonist prior to each infusion Dosing & Administration •Administer first cycle inpatient & monitor patient for a minimum of 24 hours •Warning: capillary leak syndrome (19% incidence) • 500 mg PO daily • Median onset: 5 days • Avoid taking with a high-fat meal • Duration: ~4 days • Monitor serum albumin & patient weight Pemmaraju N, et al. N Engl J Med 2019;380(17):1628-1637. Tibsovo (ivosidenib) [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc; 2018. Elzonris (tagraxofusp-erzs) [package insert]. New York, NY: Stemline Therapeutics, Inc; 2018. 2 Ivosidenib in the… Ivosidenib: Relapsed/Refractory Setting Front-line Setting Pearls & Place in Therapy • Phase I/II dose-escalation & dose- • Ongoing phase I study •Available as 250 mg tablets expansion study • Determine safety & efficacy in patients •Increases risk for differentiation syndrome and hyperleukocytosis • Evaluate safety & efficacy in all with untreated AML •Reduce dose with strong CYP3A4 inhibitors & avoid concomitant use with CYP3A4 previously treated patients • CR + CRh: 41.2% (95% CI, 24.6 to 59.3) inducers • CR + CRh: 30.2% (95% CI, 23.5 to 37.5) • CR: 26.5% (95% CI, 12.9 to 44.4) •Dose adjust for differentiation syndrome, noninfectious leukocytosis not improved with • CR: 21.6% (95% CI, 14.7 to 29.8) • 38.1% of attained transfusion hydroxyurea, QTc prolongation • 35% of patients attained transfusion independence for ≥56 consecutive days •Recommended to treat for a minimum of 6 months independence on treatment • 500 mg daily was associated with • Induced durable remissions & AML, ≥ 60 yo, not a candidate for intensive remission induction therapy or declines transfusion independence, durable transfusion independence in an elderly - Ivosidenib IDH1 mutant remissions & a low frequency of ≥ grade patient population; also well tolerated - Low-intensity therapy (azacitidine, decitabine) 3 adverse events Relapsed/Refractory AML Most common AEs (≥ 20%): diarrhea, leukocytosis, febrile neutropenia, nausea, fatigue, IDH1 mutant - Ivosidenib dyspnea, QT prolongation, peripheral edema, anemia, pyrexia, cough Note: All recommendations are category 2A unless otherwise indicated Tibsovo (ivosidenib) [package insert]. Cambridge, MA: Agios Pharmaceuticals, Inc; 2018. DiNardo CD, et al. N Engl J Med 2018;378(25):2386-2398. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2019) Roboz GJ, et al. Blood 2018;132:561; doi: https://doi.org/10.1182/blood-2018-99-110595. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 12, 2019. Audience Response #2 Gilteritinib (Xospata®) Based on the trials discussed, what conclusions did authors make in Approved regards to using ivosidenib in the relapsed/refractory and front-line settings? • November 2018 A. Ivosidenib was associated with transfusion independence MOA • Selective inhibitor of multiple receptor tyrosine kinases, including FLT3 & AXL B. Ivosidenib induces durable remissions Indication C. Ivosidenib is well-tolerated • FLT3-mutated relapsed/refractory AML D. All of the above Dosing & Administration • 120 mg PO daily Gilteritinib (Xospata) [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2018. ADMIRAL Trial Phase III, open-label, multicenter, randomized trial (ongoing) Design TM - October 2015 to October 2019 Glasdegib (Daurismo ) Compare gilteritinib to salvage chemotherapy in patients with Objective relapsed/refractory FLT3 positive AML Approved Primary: OS Endpoints • November 2018 Secondary: safety MOA • Patients treated with gilteritinib had significantly longer OS than those who received standard • Selective inhibitor of Smoothened protein in Hedgehog signaling pathway salvage chemotherapy • OS: 9.3 mo vs. 5.6 mo (95% CI, 0.49 to 0.83; p=0.0007) Indication • 1 year survival rates: 37% vs. 17% • Less toxic compared to chemotherapy (serious side effects, 7.1% vs. 9.2%) • Newly diagnosed AML in adults ≥ 75 years old or in patients who have comorbidities that preclude the use of intensive induction chemotherapy • AEs occurring ≥ 10% in the first 30 days: anemia, increased ALT & AST, febrile neutropenia Dosing & Administration Relapsed/Refractory AML • 100 mg PO daily on days 1-28 in combination with low dose cytarabine (LDAC) 20 mg SC BID on days 1-10 of each 28 day cycle - Gilteritinib FLT3 mutant - Hypomethylating agents (azacitidine or decitabine) + sorafenib (FLT3-ITD mutation only) Note: All recommendations are category 2A unless otherwise indicated Gorcea CM, Burthem J, Tholouli E. Future Oncol 2018;14(20):1995-2004. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2019) Daurismo (Glasdegib) [package insert]. New York, NY: Pfizer Inc; 2018. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 12, 2019. 3 2 BRIGHT 1003 Trial Design Phase II, randomized, open-label, multicenter study Adverse Events Evaluate efficacy of glasdegib + LDAC vs. LDAC in patients with untreated AML Objective or high-risk myelodysplastic syndrome who are unsuitable for intensive chemotherapy n, (%) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Total Primary: OS Endpoints Secondary: clinical efficacy, safety & tolerability, PK/PD, and effect on Any AE 0 1 (1.4) 11 (15.9) 52 (75.4) 5 (7.2) 69 (100) corrected QT interval Diarrhea 30 (43.5) 18 (26.1) 1 (1.4) 0 0 49 (71) OS, full analysis set