10/24/14 New Hematology/Oncology Drug Updates Patrick Medina, - PDF document

10/24/14 ¡ New Hematology/Oncology Drug Updates Patrick Medina, PharmD, BCOP The University of Oklahoma College of Pharmacy Disclosure Dr. Medina has nothing to disclose. 2 ¡ Learning Objectives § Discuss the pharmacology and indications of medications approved in the year 2013–2014 for the management of patients with cancer or hematologic diseases § Describe recommended monitoring and management of toxicities associated with these agents § Explain the impact of these agents on the advanced practitioner 3 ¡ 1 ¡

10/24/14 ¡ Newly Marketed Agents: 2013 Through August 1, 2014 Idelalisib (Zydelig) … .. ……………… .. … ..July 23, 2014 Belinostat (Beleodaq) ……………… ........July 3, 2014 Ceritinib (Zykadia)... ……………………… April 29, 2014 Ramucirumab (Cyramza). ……………… ..April 21, 2014 Ibrutinib (Imbruvica) ………………… ........November 13, 2013 Obinutuzumab (Gazyva) ………………… .November 1, 2013 Afatinib (Gilotrif).. ………………………… .July 12, 2013 Dabrafenib (Tafinlar) ……………………… May 29, 2013 Trametinib (Mekinist).. ……………… ........May 29, 2013 Ado-trastuzumab emtansine (Kadcyla) … February 22, 2013 Pomalidomide (Pomalyst).. ……………… .February 8, 2013 4 ¡ Ado-trastuzumab emtansine is approved for which of the following cancers? A. Breast B. Colon C. Lung D. Prostate 5 ¡ HER2-Positive Breast Cancer § 20%–25% of invasive breast cancers § Overexpression can activate signaling § Promotes cell proliferation and survival 6 ¡ 2 ¡

10/24/14 ¡ Ado-Trastuzumab Emtansine (T-DM1 ) § Trastuzumab and DM1 are covalently linked via a thioether linker § DM1 is a highly potent derivative of antimicrotubule agent maytansine § Ado-trastuzumab emtansine specifically targets HER2+ tumor cells by antibody- dependent cellular cytotoxicity and inhibiting HER2 signaling § A phase I study demonstrated that MTD was 3.6 mg/kg q3wk, and systemic DM1 exposure was low (5 ng/mL maximum plasma levels) 7 ¡ MTD = maximum tolerated dose T-DM1: Ado-Trastuzumab Emtansine A New Antibody-Drug Conjugate Adapted from LoRusso PM, et al. Clin Cancer Res . 2011;17:6437–6447. T-DM1 HER2 Emtansine HER2 release Inhibition of microtubule Internalization polymerization 8 ¡ EMILIA Study Design Ado-trastuzumab emtansine PD 3.6 mg/kg q3wk IV Centrally confirmed HER2+ LABC or MBC (N = 980) Prior taxane and 1:1 ¡ R trastuzumab Progression on metastatic Capecitabine treatment or within 6 mo of 1,000 mg/m 2 orally bid adjuvant treatment d1-14, q3wk PD + Lapatinib 1,250 mg/day orally qd Primary endpoints: Independently assessed progression-free survival, overall survival, and safety LABC = locally advanced breast cancer; MBC = metastatic breast cancer. 9 ¡ Verma S, et al. N Engl J Med . 2012;367:1783–1791. 3 ¡

10/24/14 ¡ Progression-Free Survival, as Assessed by an Independent Review Committee 10 ¡ Verma S, et al. N Engl J Med . 2012;367:1783–1791. Second Interim Analysis of Overall Survival 11 ¡ Verma S, et al. N Engl J Med . 2012;367:1783–1791. Ado-Trastuzumab Emtansine § Dose: 3.6 mg/kg IV infusion • 1st dose over 90 min; subsequent doses over 30 min § Indication: The treatment of patients with HER2+ metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination § Warnings: Black box for hepatic, cardiac, and embryo-fetal toxicity • Also warnings for pulmonary, infusion reactions, hemorrhage, thrombocytopenia, and neurotoxicity § Toxicities • Frequency > 25% (all grades): Nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation • The most common grade ≥ 3 ADRs (frequency > 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue • Drug-drug interactions: Ado-trastuzumab emtansine is a CYP3A4 substrate 12 ¡ ADR = adverse drug reaction 4 ¡

10/24/14 ¡ EMILIA: Adverse Events T-DM1 Cape + lap Select adverse events (grade ≥ 3) (n = 490) (n = 488) Diarrhea 1.6% 20.7% Hand-foot syndrome 0% 16.4% Vomiting 0.8% 4.5% Nausea 0.8% 2.5% Mucosal inflammation 0.2% 2.3% Increased AST 4.3% 0.8% Increased ALT 2.9% 1.4% Thrombocytopenia 12.8% 0.2% ALT = alanine aminotransferase; AST = aspartate aminotransferase. 13 ¡ Verma S, et al. N Engl J Med . 2012;367:1783–1791. Ado-Trastuzumab Emtansine Grade 2 Grade 3 Grade 4 (> 1.5 to ≤ 3 × ULN) (> 3 to ≤ 10 × ULN) (> 10 × ULN) Do not administer Do not administer Permanently until total bilirubin until total bilirubin DC BOXED WARNINGS: recovers to grade ≤ 1, recovers to grade ≤ 1, HEPATOTOXICITY, and then treat at and then reduce 1 same dose level dose level CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY Grade 2 Grade 3 Grade 4 (> 2.5 to ≤ 5 × ULN) (> 5 to ≤ 20 × ULN) (> 20 × ULN) Monitor LFTs prior to Treat at same dose Do not administer Permanently each dose level until AST/ALT DC recovers to grade ≤ 2, and then reduce 1 dose level 14 ¡ DC = discontinue; LFT = liver function test; ULN = upper limit of normal. Biomarkers Used in Lung Cancer 15 ¡ Korpanty GJ, et al. Front Oncol . 11 August 2014. 5 ¡

10/24/14 ¡ Ceritinib § Dose: 750 mg orally once daily (on an empty stomach) § Indication: The treatment of patients with anaplastic lymphoma kinase–positive metastatic NSCLC who have progressed on or who are intolerant to crizotinib § Warnings: Severe or persistent gastrointestinal toxicity, hepatotoxicity, ILD/pneumonitis, QT interval prolongation, hyperglycemia, bradycardia, embryo-fetal toxicity § Toxicities: The most common adverse reactions (incidence ≥ 25%) are diarrhea, nausea, elevated transaminases, vomiting, abdominal pain, fatigue, decreased appetite, and constipation § Drug-drug interactions: Ceritinib is a CYP3A4 substrate as well as an inhibitor of CYP3A4 and CYP2D6 16 ¡ ILD = interstitial lung disease; NSCLC = non–small cell lung cancer. Progression-Free Survival 17 ¡ Shaw AT, et al. N Engl J Med . 2014;370:1189–1197. Adverse ¡Events ¡of ¡Grade ¡3 ¡or ¡4 ¡That ¡Were ¡Suspected ¡to ¡Be ¡Related ¡to ¡Ceri=nib ¡Therapy. ¡ 18 ¡ Shaw AT, et al. N Engl J Med . 2014;370:1189–1197. 6 ¡

10/24/14 ¡ Afatinib § Dose: 40 mg orally, once daily taken at least 1 hr before or at least 2 hr after a meal § Indication: The first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test § Warnings • Diarrhea • Bullous and exfoliative skin disorders • ILD: Occurs in 1.5% of patients. • Hepatic toxicity: Monitor with periodic liver testing • Keratitis § Toxicities: Most common adverse reactions ( ≥ 20%) are diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus § Drug-drug interactions: Pgp substrate 19 ¡ EGFR = epidermal growth factor receptor EGFR and Mutations Within the TK Domain 3% Ligand Codon 719 9% 2% variants L-domain Other Exon 20 variants variants Furin-like domain Extracellular domain L-domain Transmembrane domain Intracellular domain TK domain Survival 40% Proliferation L858R 46% substitution Exon 19 EGFR deletions TK = tyrosine kinase 20 ¡ Sequist LV, et al. J Clin Oncol. 2007;25:587–595; Shigematsu H, et al. J Natl Cancer Inst . 2005;97:339–346. Secondary Mutations in EGFR (T790M) Lead to Acquired Resistance to EGFR TKIs § T790M known as a major mechanism of acquired resistance § Data suggest that it often is present at a low frequency at baseline and selected for after treatment with EGFR TKI • EGFR TKIs may kill non–T790M-containing clones preferentially, enriching for T790M+ population 21 ¡ TKI = tyrosine kinase inhibitor Kobayashi S, et al. N Engl J Med . 2005;352:786–792 7 ¡