NEW OPTIONS FOR PATIENTS: 2019 ORAL ONCOLOGY UPDATE Kirollos Hanna, PharmD, BCPS, BCOP Assistant Professor of Pharmacy Mayo Clinic College of Medicine Hematology/Oncology Clinical Pharmacist M Health Fairview FACULTY DISCLOSURES Kirollos S. Hanna, PharmD, BCPS, BCOP has the following disclosures with commercial interests to disclose: Consultant – Seattle Genetics, Hyloris Pharmaceuticals; Speaker's Bureau - Seattle Genetics, Abbvie; Stock/ Shareholder – CVS; Advisory Boards - Aztrazeneca, Incyte, Sandoz, Rigel, Taiho, Heron, Astellas, Seattle Genetics, Abbvie The content of this activity may include information regarding the use of products that may be inconsistent with, or outside the approved labeling for, these products in the United States. Pharmacists should note that the use of these products outside current approved labeling is considered experimental and are advised to consult the prescribing information for these products. DRUG APPROVALS AND EXPANSION 2018 – 2019 • 2018 – 63 Oral updates • 2018 – 27 2019 – 8 novel • 2019 – 33 updates therapies updates • 2019 – 18 Overall updates Novel Hematology/Oncology (Cancer) Approvals & Safety Notifications. FDA; FDA website. Accessed October 19, 2019. THE ROLE OF HCPS IN OC MANAGEMENT Maintenance •AE management •Adherence and Need for Coordination compliance •Cyclic labs •Cyclic labs •Methods of •Refills Medically Initiation communication •Drug-drug interactions •Refills Integrated •Inappropriate dosing •Provider appointments •Baseline labs and •Updated insurance plans monitoring Model •Need for education •Insurance and procurement Pharmacists provide clinical considerations and operational best practices to optimize oral chemotherapy dispensing and management. Timmers L, et al. BMC Cancer. 2017;17(1):122; Mulkerin DL, et al. J Oncol Pract. 2016;12(10):e912-e923; Battis B, et al. J Oncol Pharm Pract. 2017;23(8):582-590. TIMELINE SINCE SPRING FORUM: NOVEL AGENTS Apr 12: Erdafitnib - Bladder Apr 19: PemAxi - Renal May 2: Ivosidenib - AML May 14: AvelAxi - Renal May 15: Venetoclax - CLL May 24: Ruxolitinib - aGVHD May 24: Alpelisib - Breast May 28: LenR – FL and MZL May 29: Gilteritinib - OS for AML July 3: Selinexor – MM July 30: Darolutamide - Prostate Aug 2: Pexidartinib – TGCT Aug 15: Entrectinib – NTRK/ROS Aug 16: Fedratinib – MF Aug 15: PemLen – Endometrial Sep 17: Apalutamide – Prostate Hematology/Oncology (Cancer) Approvals & Safety Notifications. FDA; FDA website. Accessed October 19, 2019. TIMELINE SINCE SPRING FORUM: COMBINATIONS Apr 12: Erdafitnib - Bladder Apr 19: PemAxi - Renal May 2: Ivosidenib - AML May 14: AvelAxi - Renal May 15: Venetoclax - CLL May 24: Ruxolitinib - aGVHD May 24: Alpelisib - Breast May 28: LenR – FL and MZL May 29: Gilteritinib - OS for AML July 3: Selinexor – MM July 30: Darolutamide - Prostate Aug 2: Pexidartinib – TGCT Aug 15: Entrectinib – NTRK/ROS Aug 16: Fedratinib – MF Aug 15: PemLen – Endometrial Sep 17: Apalutamide – Prostate Hematology/Oncology (Cancer) Approvals & Safety Notifications. FDA; FDA website. Accessed October 19, 2019. NOVEL ORAL THERAPIES UROTHELIAL CARCINOMA: ERDAFITINIB • Indication: locally advanced or mUC FGFR3/FGFR2 alterations, following platinum-containing chemotherapy • BLC2001 Study: open-label, phase 2 Endpoint ITT Efficacy (n=87) Endpoint FGFR Efficacy (n=64) FGFR3 Point Mutation ORR (95% CI) 32.2% (22.4, 42.0) (n=64) 40.6% (28.6, 52.7) ORR (95% CI) CR 2.3% FGFR3 Fusion (n=18) 11.1% (0, 25.6) PR 29.9% ORR (95% CI) FGFR2 Fusion (n=6) 0 Median DoR 5.4 (4.2, 6.9) ORR (95% CI) Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019;381(4):338-348. ERDAFITINIB PEARLS All Grade Grade 3-4 Adverse Reaction (8 mg/day) (%) (%) Any 100 67 • Novel mechanism of action, 1st targeted therapy and orally Gastrointestinal disorders 92 24 Metabolism and nutrition available option in UC treatment 90 16 • MOA: Pan-FGFR inhibitor (FGFR 1-4) disorders General disorders and admin. • Approved for FGFR 2-3 mutations or 69 13 fusions site conditions Skin and subcutaneous • 8 mg PO daily (w/ or w/o food) 75 16 with dose increase to 9 mg daily if disorders criteria are met Eye disorders 62 11 • Day 14 to 21 phosphorus < 5.5 mg/dL Nervous system disorders 57 5 • No ocular disorders Infections and infestations 56 20 • No grade ≥ 2 AEs Respiratory, thoracic, and 40 7 • Increase occurred in 41% of pts mediastinal disorders • Restricted distribution (US Renal and urinary tract disorders 38 10 Bioservices specialty pharmacy): Musculoskeletal and connective 31 0 Tablets: 3 mg, 4 mg, 5 mg tissue disorders Balversa (erdafitinib) [prescribing information]. Horsham, PA: Janssen Products; April 2019. ERDAFITINIB OCULAR TOXICITY • Central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) were reported in 25% of patients • First onset of 50 days • Grade 3 in 3% of patients • Usually resolve or improve after dose hold • Ongoing in 13% of patients at the study cutoff • 9% dose interruptions, 14% reductions, 3% discontinuations • Dry eye symptoms occurred in 28% of patients with grade 3 in 6% of patients • All patients should receive dry eye prophylaxis with ocular demulcents as needed • Monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterward, and urgently at any time for visual symptoms • Assessment of visual acuity, slit lamp examination, fundoscopy, optical coherence tomography Balversa (erdafitinib) [prescribing information]. Horsham, PA: Janssen Products; April 2019. AML: IVOSIDENIB • Indication: newly-diagnosed AML with IDH1 mutation in patients ≥ 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy • AG120-C-001 Study: open-label, single-arm, phase 1 Endpoint ITT Efficacy (n=125) r/r AML Efficacy ORR 41.6% 39.1% CR 21.6% 21.8% CRh 12.8% 11.7% Median time to CR/Cri 2.7 months 2.0 months Median duration of CR/Cri 8.2 months 6.5 months Median time to response 1.9 months 1.9 months Dinardo CD, Stein EM, De botton S, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386-2398. IVOSIDENIB PEARLS trAEs of Grade ≥ 3 in > 1% of the Overall • IDH1 Inhibitor Population. ITT r/r AML Event Population (n=179) • 500 mg daily; avoid high fat (n=258) meals ≥ trAE 20.7% 25.6% Prolonged QTc 7.8% 7% • Warnings: QT prolongation, Differentiation Syndrome 3.9% 4.7% Guillain-Barre’ Syndrome, DS Anemia 2.2% 2.3% Thrombocytopenia 1.7% 1.9% • Drug Interactions: CYP 3A4 Leukocytosis 1.7% 1.2% Inducers and Inhibitors; avoid QT prolonging drugs and 3A4 Febrile Neutropenia 0.6% 1.2% substrates Diarrhea 0.6% 1.2% Hypoxia 1.1% 1.2% Dinardo CD, Stein EM, De botton S, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386-2398. MULTIPLE MYELOMA: SELINEXOR • Indication: r/r MM after ≥ 4 prior therapies (2 PIs, 2 IMiDs, and anti-CD38 monoclonal antibody) • Storm Trial: phase 2b, single-arm, open-label, multicenter Endpoint ITT Efficacy (n=87) ORR (95% CI) 25.3% (16.4, 36) Stringent Complete Response (sCR) 1% Complete Response (CR) 0 Very Good Partial Response (VGPR) 5% Partial Response (PR) 19% Xpovio (selinexor) [prescribing information]. Newton, MA: Karyopharm Therapeutics Inc; July 2019. SELINEXOR PEARLS Any • 80 mg in combination with Grade ≥ 3 Select Event Grade (n=202) dexamethasone taken orally on (n=202) Days 1 and 3 of each week Thrombocytopenia 74% 61% Fatigue 73% 22% • 5-HT3 antagonist and/or other Nausea 72% 9% anti-nausea agents prior to and Anemia 59% 40% during treatment Weight decrease 47% 0.5% First Second Third Diarrhea 44% 6% Reduction Reduction Reduction Hyponatremia 39% 22% 100 mg 80 mg 60 mg D/C Neutropenia 34% 21% once once once weekly weekly weekly Constipation 25% 1.5% Xpovio (selinexor) [prescribing information]. Newton, MA: Karyopharm Therapeutics Inc; July 2019. SELINEXOR MOA Adapted from Karyopharm, Selinexor Mechanism of Actions. https://www.xpovio.com/hcp/. Accessed October 19, 2019. PROSTATE: DAROLUTAMIDE • Indication: non-metastatic castration-resistant prostate cancer • ARAMIS Study: phase 3, multicenter, double-blind, placebo-controlled Darolutamide Efficacy Placebo Efficacy Endpoint (n=955) (n=554) Metastasis-free survival Number of Events 23% 39% Median, months (95% CI) 40.4 (34.3, NR) 18.4 (15.5, 22.3) Hazard Ratio (95% CI) 0.41 (0.34, 0.50) P-value <0.0001 Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380(13):1235-1246. DAROLUTAMIDE PEARLS • 300mg BID w/ food • Gonadotropin-releasing hormone (GnRH) analog required Placebo Efficacy Darolutamide Efficacy (n=954) Event (n=554) All Grade Grade ≥ 3 All Grade Grade ≥ 3 Fatigue 16% 0.6% 11% 1.1% Pain in extremity 6% 0 3% 0.2% Anemia 3% 0.1% 1% 0 Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380(13):1235-1246. TENOSYNOVIAL GIANT CELL TUMOR: PEXIDARTINIB • Indication: symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery • ENLIVEN study: phase 3, international, multicenter, randomized Pexidartinib Efficacy Placebo Efficacy Endpoint (n=61) (n=59) ORR (95% CI) 38% (27, 50) 0 (0, 6) CR 15% 0 PR 23% 0 P-value <0.0001 DoR 6.9+, 24.9+ NA Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019. PEXIDARTINIB PEARLS • First systemic therapy for TGCT Pexidartinib Placebo (n=61) (n=59) Any Grade Any Grade • 400 mg BID w/o food Select Event Grade ≥ 3 Grade ≥ 3 • Dose reduce with strong 3A4 or UGT Hair Color Changes 67% 0 3.4% 0 inhibitors Rash 28% 1.6% 7% 0 Pruritus 18% 0 3.4% 0 • Avoid PPIs Fatigue 64% 0 41% 0 Peripheral Edema 20% 0 7% 0 Total Daily Modified Third Eye Edema 30% 1.6% 5% 0 Dose Daily Dose Reduction Dysgeusia 26% 0 1.7% 0 800 mg 400 mg 200 mg BID Neuropathy 10% 0 5% 0 600 mg 400 mg 200 mg BID Vomiting 20% 1.6% 5% 0 400 mg 200 mg 200 mg QD Hypertension 15% 4.9% 10% 0 Tap WD, Gelderblom H, Palmerini E, et al.