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]
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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
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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 • QTc > 480 msec • Asymptomatic or neurologically stable brain metastases Wolf J, Seto T, Han JY, et al. N Engl J Med. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787 • ECOG 0 or 1
32 Wolf J, et al. N Engl J Med. 2020;383(10):944-957 33 Outcomes Measured Methods
Secondary Outcomes Primary Outcome Continue therapy until • Duration of response (DOR) • Overall response rate (ORR) disease progression • Progression-free survival (PFS) or unacceptable toxicity
Capmatinib 400 mg PO 364 patients twice daily
Wolf J, et al. N Engl J Med. 2020;383(10):944-957 34 Wolf J, et al. N Engl J Med. 2020;383(10):944-957 http://clipart-library.com/ 35
Results Safety
• 98% of patients experienced a treatment-related ADE of any grade Previously treated (n = 69) Previously untreated (n = 28) • Most common grade 3-4 adverse events Primary outcome • Peripheral edema (51%) ORR - % (95% CI) 41 (29-53) 68 (48-84) Secondary outcomes • Nausea (45%) Median DOR – mo. (95% CI) 9.7 (5.6-13) 12.6 (12.6 – could not be • Vomiting (28%) estimated) • Increased creatinine (24%) Median PFS – mo. (95% CI) 5.4 (4.2-7) 12.4 (8.2-could not be estimated) • Fatigue (21%)
Wolf J, et al. N Engl J Med. 2020;383(10):944-957 36 Wolf J, et al. N Engl J Med. 2020;383(10):944-957 37 Capmatinib: Place in Therapy
• Preferred first-line therapy for MET exon 14 skipping mutation discovered prior to initiation of first-line systemic therapy • Also preferred as subsequent therapy following disease progression on initial systemic therapy Selpercatinib • Other therapy option useful in certain circumstances: crizotinib • First-line therapy for MET exon skipping 14 mutation discovered during (Retevmo™) first-line systemic therapy • Other first-line therapy option: crizotinib
NCCN Guidelines. Non-Small Cell Lung Cancer (Version 6.2020). 38
Background Dosing and Drug Interactions
• FDA approved in May 2020 • Standard dosing (adults): 160 mg PO BID • Administer without regard to food; take with food if administering with a PPI • FDA approved indications • Dose reduce for weight < 50 kg, pre-existing hepatic impairment • Adults with metastatic RET fusion-positive NSCLC • Available formulations: 40 mg and 80 mg capsules • Adult and pediatric patients (12 and older) with advanced or metastatic RET-altered thyroid cancers • Drug Interactions • Mechanism of action: inhibits RET and VEGFR1 and VEGFR3 à blocks • Acid-reducing agents: Avoid if possible. If cannot be avoided, administer with proliferation of cancer cells food if coadministering with a PPI, or separate administration from H2RAs or antacids • Drug class: oral tyrosine kinase inhibitor • Strong and moderate CYP3A inducers and inhibitors: avoid if possible • CYP2C8 and CYP3A4 substrates: avoid if possible
Retevmo (selpercatinib) [package insert]. Eli Lilly and Company; Indianapolis, IN. 2020. 40 Retevmo (selpercatinib) [package insert]. Eli Lilly and Company; Indianapolis, IN. 2020. 41 Common Side Effects Precautions
• Dry mouth • Hepatotoxicity • Hypertension • Hypertension: do not initiate in patients with untreated hypertension • Diarrhea • QT interval prolongation • Constipation • Hemorrhagic events • Nausea/vomiting • Impaired wound healing: hold for at least 1 week prior to elective surgery. • Elevated AST and/or ALT Do not resume for at least 2 weeks following major surgery • Rash • Peripheral edema
Retevmo (selpercatinib) [package insert]. Eli Lilly and Company; Indianapolis, IN. 2020. 42 Retevmo (selpercatinib) [package insert]. Eli Lilly and Company; Indianapolis, IN. 2020. 43
Eligibility
Inclusion Criteria Exclusion Criteria • Age > 12 • Major surgery within 4 weeks of study enrollment • Advanced RET fusion-positive Efficacy of selpercatinib in RET fusion-positive non- NSCLC • Myocardial infarction within 6 months small cell lung cancer • Previously untreated or previously received platinum-based • Use of PPIs within 14 days chemotherapy Drilon A, Oxnard GR, Tan DSW, et al. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653 • QT interval > 470 msec • ECOG 0-2 • Asymptomatic or neurologically stable brain metastases
44 Drilon A, et al. N Engl J Med. 2020;383(9):813-824 45 Outcomes Measured Methods
Secondary Outcomes Primary Outcome • Duration of response (DOR) Continue therapy until • Objective response rate (ORR) • Progression-free survival (PFS) 105 patients previously treated with disease progression or platinum-based chemotherapy unacceptable toxicities
Selpercatinib 160 mg PO twice daily
39 previously untreated patients
Drilon A, et al. N Engl J Med. 2020;383(9):813-824 46 Drilon A, et al. N Engl J Med. 2020;383(9):813-824 http://clipart-library.com/ 47
Results Safety
Previously platinum-based Previously untreated • 91% of patients experienced a treatment-related ADE of any grade treatment (N = 105) (N = 39) Primary outcome • Most common grade 3-4 adverse effects ORR - % (95% CI) 64 (54-73) 85 (70-94) • Hypertension (9%) Secondary outcomes • Elevated AST and/or ALT (8%; 5%) Median DOR – mo. 17.5 NE* Median PFS – mo. 16.5 NE*
*Unable to assess at the time of interim analysis
Drilon A, et al. N Engl J Med. 2020;383(9):813-824 48 Drilon A, et al. N Engl J Med. 2020;383(9):813-824 49 Patient Assistance Programs for Oral Selpercatinib: Place in Therapy Tyrosine Kinase Inhibitors • Preferred first-line therapy RET-rearrangement positive NSCLC • Other treatment options: cabozantinib or vandetanib Entrectinib Capmatinib Selpercatinib Standard dose 600 mg PO daily 400 mg PO BID 160 mg PO BID • Preferred as subsequent therapy for RET-rearrangement positive Estimated price per dose $672 $384 $412 NSCLC following progression on other systemic therapy Estimated price per $18,816 $21,504 $23,072 treatment cycle • Other treatment options: cabozantinib or vandetanib
NCCN Guidelines. Non-Small Cell Lung Cancer (Version 6.2020). 50 Lexicomp Online, Lexi-Drugs. online.lexi.com 51
Patient Assistance Programs for Oral Tyrosine Kinase Inhibitors
• Manufacturer-issued co-pay assistance cards • Independent co-pay assistance foundations • Free drug programs through the manufacturer Lurbinectedin Helpful resources • Manufacturer website (Zepzelca™)
52 57 Background Dosing and Administration
• FDA approved in June 2020 • Standard dosing: 3.2 mg/m2 IV every 21 days • FDA approved indication: metastatic SCLC with disease progression on or • Consider premedicating with corticosteroids and a serotonin receptor after platinum-based chemotherapy antagonist for antiemetic prophylaxis • Mechanism of action: binds to guanine residues in DNA and affects DNA • Administer over 60 minutes through a central or peripheral line transcription and repair pathways à cell death • Available as a 4 mg lyophilized powder • Drug class: alkylating agent
Zepzelca (lurbinectedin) [package insert]. Jazz Pharmaceuticals Inc; Palo Alto, CA. 2020. 58 Zepzelca (lurbinectedin) [package insert]. Jazz Pharmaceuticals Inc; Palo Alto, CA. 2020. 59
Drug Interactions and Precautions Common Side Effects
• Drug interactions: CYP3A4 inhibitors • Fatigue • Avoid coadministration with a strong or moderate CYP3A4 inhibitor • Nausea/vomiting • Consider dose reduction if cannot avoid moderate CYP3A4 inhibitors • Constipation • Precautions • Diarrhea • Myelosuppression • Musculoskeletal pain • Hepatotoxicity
Zepzelca (lurbinectedin) [package insert]. Jazz Pharmaceuticals Inc; Palo Alto, CA. 2020. 60 Zepzelca (lurbinectedin) [package insert]. Jazz Pharmaceuticals Inc; Palo Alto, CA. 2020. 61 Preparation
• Inject 8 mL sterile water for injection into the vial of lurbinectedin powder. Shake until fully dissolved • For central line administration, withdraw the appropriate amount of reconstituted solution and add to an infusion container of at least 100 mL Lurbinectedin as second-line treatment for patients of 0.9% sodium chloride or 5% dextrose with small-cell lung cancer: a single-arm, open-label, • For peripheral line administration, withdraw the appropriate amount of phase 2 basket trial reconstituted solution and add to an infusion container of at least 250 mL of 0.9% sodium chloride or 5% dextrose Trigo J, Subbiah V, Besse B, et al. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1 • The final product is stable for 24 hours after reconstitution either stored at room temperature or refrigerated
Zepzelca (lurbinectedin) [package insert]. Jazz Pharmaceuticals Inc; Palo Alto, CA. 2020. 62 63
Eligibility Outcomes Measured
Inclusion Criteria Exclusion Criteria • Age > 18 • Previously treated with Secondary Outcomes lurbinectedin or trabectedin • SCLC with documented Primary Outcome • Duration of response (DOR) progression • Known CNS involvement • Overall response rate (ORR) • Progression-free survival (PFS) • Previously treated with one • Concomitant serious or unstable chemotherapy-containing treatment medical condition within the past • Overall survival (OS) line year • ECOG 0-2
Trigo J, et al. Lancet Oncol. 2020;21(5):645-654. 64 Trigo J, et al. Lancet Oncol. 2020;21(5):645-654. 65 Methods Results
Primary Outcome • ORR: 35.2% (CI 26.2-45.2)
Continue therapy until Secondary Outcomes disease progression or unacceptable • Median DOR: 5.3 months (4.1-6.4) toxicity 2 • Median PFS: 3.5 months (2.6-4.3) 105 patients Lurbinectedin 3.2 mg/m IV once every 3 weeks • Median OS: 9.3 months (6.3-11.8)
Trigo J, et al. Lancet Oncol. 2020;21(5):645-654. 66 Trigo J, et al. Lancet Oncol. 2020;21(5):645-654. 67
Safety Subsequent Systemic Therapy for SCLC Relapse < 6 months; PS 0-2 • Most common grade 3-4 adverse effects Preferred regimens Other recommended regimens • Neutropenia (21%) • Topotecan IV or PO • Nivolumab • Temozolomide • Lurbinectedin • Pembrolizumab • PO etoposide • Leukopenia (19%) • Clinical trial • Paclitaxel • Vinorelbine • Anemia (9%) • Docetaxel • Gemcitabine • Irinotecan • Bendamustine • Fatigue (7%) • Cyclophosphamide/doxorubicin/ vincristine Relapse > 6 months Preferred regimen • Original regimen* Other recommended regimen • Lurbinectedin
*Do not retreat with immunotherapy if included in original regimen
Trigo J, et al. Lancet Oncol. 2020;21(5):645-654. 68 NCCN Guidelines. Small Cell Lung Cancer (Version 1.2021). 69 Summary A Breath of Fresh Air:
• New FDA drug approvals for NSCLC and SCLC are changing the face of first-line and New Drugs in Lung Cancer subsequent therapy and providing survival benefit to patients • For patients with metastatic NSCLC, identification of tumor mutations can lead to use of oral targeted therapy • Lurbinectedin is a new treatment option for metastatic SCLC that has progressed on a platinum-based chemotherapy regimen • Recent FDA approvals for NSCLC (entrectinib, capmatinib, selpercatinib) and SCLC (lurbinectedin) demonstrated acceptable objective response and/or survival benefit in preliminary data from clinical trials Jaelyn R. Westfield, PharmD • These agents were all granted accelerated approval from the FDA and final approved PGY-2 Hematology/Oncology Pharmacy Resident indications are subject to change pending final study results Huntsman Cancer Institute [email protected]
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