A Breath of Fresh Air: New Drugs in Lung Cancer Jaelyn R. Westfield, PharmD Jaelyn R. Westfield, PharmD PGY-2 Hematology/Oncology Pharmacy Resident November 14, 2020 Huntsman Cancer Institute [email protected] 1 2 Disclosure Pharmacist Learning Objectives No Relevant Financial Conflicts of Interest 1. Describe potential side effects of entrectinib, selpercatinib, • CE presenter, Jaelyn R. Westfield, PharmD capmatinib, and lurbinectedin • CE mentor, Courtney C. Cavalieri, PharmD, BCOP 2. Demonstrate understanding of how new agents fit into treatment algorithms for small cell and non-small cell lung cancer Off-Label Uses of Medications: None 3. Compare the mechanism of action of entrectinib, selpercatinib, capmatinib, and lurbinectedin 4 5 Technician Learning Objectives 1. Differentiate preparation processes for lurbinectedin administered through a central versus peripheral line 2. Discuss the role of patient assistance programs for selpercatinib, capmatinib, and entrectinib Introduction to Lung 3. Recognize which new medications used in lung cancer treatment are oral and which are intravenous Cancer 6 7 US Statistics 2017 US Statistics 2017 US Top 5 Cancers by Rates of New Cancer Cases Per 100,000 People 2017 US Top 5 Cancers by Rates of Cancer Deaths Per 100,000 People 2017 Female breast 125.1 Lung and bronchus 36.7 Pr ost at e 106.5 Female breast 19.9 Lung and bronchus 55.2 Pr ostat e 18.9 Colon and rectum 36.8 Colon and rectum 13.5 Corpus and Uterus, NOS 27.2 Pancr eas 11.1 0 20 40 60 80 10 0 12 0 14 0 0 5 10 15 20 25 30 35 40 U.S. Cancer Statistics Data Visualizations Tool. https://gis.cdc.gov/cancer/USCS/DataViz.html 8 U.S. Cancer Statistics Data Visualizations Tool. https://gis.cdc.gov/cancer/USCS/DataViz.html 9 US Lung Cancer Statistics 2020 Types of Lung Cancer Non-Small Cell Lung Cancer (NSCLC) Small Cell Lung Cancer (SCLC) Estimated new cases in 2020 228,820 • 85% of lung cancer diagnoses • 15% of lung cancer diagnoses Percentage of all new cancer cases 12.7% 5-year survival rate • Primary risk factor: smoking • Primary risk factor: smoking • 15% of cases in never smokers • 5% of cases in never smokers • Other risk factors: exposure to known • High rate of proliferation and rapid Estimated deaths in 2020 135,720 hazards (radon, asbestos, secondhand doubling time 2010-2016 smoke), family history Percentage of all cancer deaths 22.4% • Slower rate of proliferation compared to SCLC Seer Stat Fact Sheets: Lung and Bronchus Cancer. https://seer.cancer.gov/statFacts/html/lungb.html 10 NCCN Guidelines. Small Cell Lung Cancer (Version 1.2021). NCCN Guidelines. Non-Small Cell Lung Cancer (Version 6.2020). 11 Principles of First-line Therapy: Principles of First-line Therapy: Metastatic NSCLC Extensive-Stage SCLC EGFR mutations Metastatic NSCLC ALK rearrangements Molecular target(s) Atezolizumab + carboplatin + etoposide à identified and targeted ROS1 rearrangements treatment initiated followed by atezolizumab maintenance therapy BRAF V600E mutation Durvalumab + carboplatin + etoposide à Histology identified Extensive-stage Chemotherapy NTRK alterations followed by durvalumab maintenance therapy • Adenocarcinoma Molecular testing SCLC plus immunotherapy • Squamous carcinoma RET rearrangements • Large cell carcinoma Durvalumab + cisplatin + etoposide à followed • Mixed carcinoma MET exon 14 skipping by durvalumab maintenance therapy mutation No molecular target(s) identified PD-L1 Initiate systemic chemotherapy + immunotherapy NCCN Guidelines. Non-Small Cell Lung Cancer (Version 6.2020). 12 NCCN Guidelines. Small Cell Lung Cancer (Version 1.2021). 13 Recent Evolution of Lung Cancer Treatment Dacomitinib Entrectinib Lurbinectedin (Vizimpro®) (Rozlytrek®) (Zepzelca™) April November May September Entrectinib 2017 2018 2020 2020 ® September August June 2018 2019 2020 (Rozlytrek ) Capmatinib (Tabrecta™) Brigatinib Lorlatinib Selpercatinib Pralsetinib ® (Alunbrig ) (Lorbrena®) (Retevmo™) (Graveto®) NSCLC SCLC U.S. Food and Drug Administration Center for Drug Evaluation and Research (CDER). Novel Drug Approvals. https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new- therapeutic-biological-products 14 Background Dosing and Drug Interactions • FDA approved in August 2019 • Standard dosing: 600 mg PO once daily • FDA approved indications • Take with or without food • Adults with metastatic ROS1-positive NSCLC • Available formulations: 100 mg and 200 mg capsules • Adult and pediatric patients (12 and older) with NTRK-mutated solid tumors and no other suitable treatment options • Drug Interactions • Mechanism of action: inhibition of malignant cells bearing ROS1 or NTRK • Moderate and strong CYP3A inhibitors: dose reductions required fusion genes à blocks tumor cell division, cell survival • Moderate CYP3A inhibitors: 200 mg PO once daily • Drug class: oral tyrosine kinase inhibitor • Strong CYP3A inhibitors: 100 mg PO once daily • Moderate and strong CYP3A inducers: avoid coadministration Rozlytrek (entrectinib) [package insert]. Genentech, Inc; South San Francisco, CA. 2019 16 Rozlytrek (entrectinib) [package insert]. Genentech, Inc; South San Francisco, CA. 2019 17 Common Side Effects Precautions • Fatigue • New or worsening congestive heart • Vison Changes failure • Constipation or diarrhea • Hyperuricemia • QT interval prolongation • Edema • Hepatotoxicity • Central nervous system (CNS) • Nausea effects • Increased risk for fractures • Taste disturbances • Dizziness • Muscle pain • Weight gain Rozlytrek (entrectinib) [package insert]. Genentech, Inc; South San Francisco, CA. 2019 18 Rozlytrek (entrectinib) [package insert]. Genentech, Inc; South San Francisco, CA. 2019 19 Eligibility Inclusion Criteria Exclusion Criteria • Age > 18 • History of other malignancy or • Locally advanced or metastatic currently active secondary Entrectinib in ROS1 fusion-positive non-small-cell ROS1 fusion-positive NSCLC malignancy lung cancer: integrated analysis of three phase 1-2 • Not previously treated with a ROS1 • Prolonged QTc interval > 450 msec trials tyrosine kinase inhibitor • Active gastrointestinal disease or • Eastern Cooperative Oncology other malabsorption syndromes Drilon A, Siena S, Dziadziuszko R, et al. Lancet Oncol. 2020;21(2):261-270. doi:10.1016/S1470-2045(19)30690-4 Group (ECOG) performance status of 0-2 • Asymptomatic or previously treated and controlled brain metastases 20 Drilon A, et al. Lancet Oncol. 2020;21(2):261-270 21 Outcomes Measured Methods Primary Outcomes Secondary Outcomes Continue therapy until • Objective response rate (ORR) • Progression-free survival (PFS) disease progression • Duration of response (DOR) • Overall survival (OS) or unacceptable toxicity 53 patients included Entrectinib 600 mg in efficacy analysis PO daily Drilon A, et al. Lancet Oncol. 2020;21(2):261-270 Drilon A, et al. Lancet Oncol. 2020;21(2):261-270 22 http://clipart-library.com/ 23 Results Safety Primary Outcomes • 100% of patients experienced a treatment-related ADE of any grade • ORR: 77% (64-88) • Most common grade 3-4 adverse effects • Median DOR: 24.6 months (11.4-34.8) • Weight increase (7%) • Neutropenia (4%) Secondary Outcomes • Elevated LFTs (4%) • Median PFS: 19 months (12.2-36.6) • Median OS: unable to assess at time of interim analysis • 85% of patients alive at 12 months • 82% of patients alive at 18 months Drilon A, et al. Lancet Oncol. 2020;21(2):261-270 24 Drilon A, et al. Lancet Oncol. 2020;21(2):261-270 25 Entrectinib: Place in Therapy • Preferred first-line therapy for ROS1 positive NSCLC, for rearrangements discovered prior to or during first-line systemic therapy • Other preferred treatment option: crizotinib Capmatinib • Preferred first-line therapy for NTRK gene fusion-positive metastatic NSCLC, for rearrangements discovered prior to or during first-line systemic therapy (Tabrecta™) • Other preferred first-line therapy option: larotrectinib NCCN Guidelines. Non-Small Cell Lung Cancer (Version 6.2020). 26 Background Dosing and Drug Interactions • FDA approved in May 2020 • Standard dosing: 400 mg PO BID • FDA approved indication: treatment of adult patients with metastatic • Take with or without food NSCLC with MET exon 14 skipping mutation • Available formulations: 150 mg and 200 mg tablets • Mechanism of action: inhibits MET phosphorylation and MET-mediated phosphorylation of downstream signaling proteins à blocks proliferation • Drug interactions and survival of MET-dependent cancer cells • Moderate and strong CYP3A inducers: avoid concomitant use • Drug class: oral tyrosine kinase inhibitor Tabrecta (capmatinib) [package insert]. Novartis Pharmaceutical Corp; East Hanover, NJ. 2020. 28 Tabrecta (capmatinib) [package insert]. Novartis Pharmaceutical Corp; East Hanover, NJ. 2020. 29 Common Side Effects Precautions • Peripheral edema • Interstitial lung disease/pneumonitis: monitor for new or worsening pulmonary symptoms • Nausea/vomiting • Hepatotoxicity: monitor liver function tests • Fatigue • Photosensitivity: limit direct UV exposure • Constipation • Diarrhea Tabrecta (capmatinib) [package insert]. Novartis Pharmaceutical Corp; East Hanover, NJ. 2020. 30 Tabrecta (capmatinib) [package insert]. Novartis Pharmaceutical Corp; East Hanover, NJ. 2020. 31 Eligibility Inclusion Criteria Exclusion Criteria • Age > 18 • Previously treated with a MET inhibitor • Stage IIIB or IV NSCLC with a MET Capmatinib in MET exon 14-mutated or MET- exon 14 skipping mutation or MET • Uncontrolled heart disease amplification amplified non-small cell lung caner