Lung Cancer Lecture PDF

Integrated Pharmacotherapy X: Hematology/Oncology PHRM 8110 Lung Cancer Anna Dushenkov, BS Pharm, PharmD, BCPS P3 Fall Semester September 30, 2024 1...

Integrated Pharmacotherapy X: Hematology/Oncology PHRM 8110 Lung Cancer Anna Dushenkov, BS Pharm, PharmD, BCPS P3 Fall Semester September 30, 2024 1  Discuss epidemiology and etiology of lung cancer Describe interventions to reduce the risk of lung cancer Identify treatment options for Objectives patients with different types and stages of the disease Recognize benefits and restrictions of antineoplastic agents used in the management of lung cancer September 30, 2024 2  Epidemiology and etiology September 30, 2024 3  Epidemiology Most frequent fatal malignancy in US Constitutes 25% of all cancer-related deaths in US Death rates are declining but still more from lung cancer than from breast, prostate, colorectal and brain combined Leading cause of cancer deaths in men and women 2/3 of cases - in 60 – 80 years of age September 30, 2024 4  Etiology Risk factors (RF): Smoking – 85 – 90% of lung cancers caused by cigarette smoking - cigarette smoke contains carcinogenic chemicals e.g., nitrosamines, benzo(a)pyrene diol epoxide - risk ↑with # of packs of cigarettes smoked per day and with the number of years spent smoking i.e., pack-years of smoking history - exposed nonsmokers ↑relative risk from second- hand smoke History of COPD, asthma (inflammatory conditions) Family history of lung or other cancers – mutations in never-smokers Exposure to environmental factors – increasing evidence e.g., asbestos; air pollution September 30, 2024 5  Risk reduction interventions September 30, 2024 6 Screening USPSTF = United States Preventive Services Task Force https://www.uspreventiveservicestaskforce.org/uspstf/ Population Recommendation Grade Adults 50 - 80 y.o Annual screening with low-dose computed tomography (LDCT) with 1. 20 pack-year Screening should be discontinued when: B (moderate smoking history certainty) and 1. Person has not smoked for 15 years 2. Currently smoke or have quit within or the past 15 years 2. Person develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery One pack-year = smoking ~20 cigarettes=1 pack/day for a year Rationale: “Screening high-risk persons with LDCT can reduce lung cancer mortality and may reduce all-cause mortality but also causes false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, increases in distress, and, rarely, radiation-induced cancers. The evidence for benefits comes from two RCTs that enrolled participants who were more likely to benefit than the U.S. screening-eligible population and that were mainly conducted at large academic centers, potentially limiting applicability to community-based practice” September 30, 2024 7  Avoidance of exposure Smoking cessation 5 “A’s” tool – Ask, Advise, Assess, Assist, Arrange Risk reduction American Cancer Society (ACS) has a guide how to quit smoking interventions Chemoprevention - unsuccessful β-carotene, glucocorticoids, vitamin E, NSAIDs, selenium, green tea extracts – unsuccessful Increase awareness about risk of developing secondary malignancies in former smokers September 30, 2024 8  Treatment options 9 September 30, 2024 Lung anatomy and cancer Most lung cancers are carcinomas – overgrowth of bronchial epithelial cells September 30, 2024 10 Classification Based on histological appearance Lung cancer NSCLC – Non-Small Cell SCLC – Small Cell Lung Cancer Lung cancer very aggressive 80% secrete autocrine growth factors Non-squamous Large cell carcinoma Squamous cell Adenocarcinoma carcinoma Undifferentiated tumor non-smokers male smokers diagnosis of exclusion increasing in frequency September 30, 2024 Further classified into subtypes 11 Clinical presentation Cough, hemoptysis, dyspnea, hoarseness, dysphagia Extrapulmonary symptoms - weight loss, malaise, change in mental status Paraneoplastic syndrome – symptoms that are not a result of the direct effects of the tumor; caused by the substances excreted by the tumor, occur in remote sites e.g., hypercalcemia, SIADH (hyponatremia), cardiovascular etc. Accidental findings on chest imaging – not often found More than 50% of lung cancers have distant metastases at the time of diagnosis September 30, 2024 12  Diagnosis Physical examination – patient’s PS -! Visualization of the tumor - images - status of the tumor Pathologic examination - tumor histology guides treatment approach - biopsy, sputum cytology - molecular diagnostics – drives pharmacotherapy PD-L1 testing Testing for EGFR, ALK, ROS1, BRAF/MEK mutations Testing is recommended for all patients September 30, 2024 13 Staging NSCLC Extent of the disease → prognosis, treatment TNM system for NSCLC - size of the tumor, extent of nodal involvement, presence of metastases Disease (clinical) grouping system into Stages from I to IV Stage I – early stage 5–year survival ~ 50% Stage IV – advanced disease 5-year survival is less than 10% In patients with metastatic disease eligible for targeted therapy or immunologics 5-year-survival can be up to 50% September 30, 2024 14 Goals of therapy Determined by tumor histology, stage of disease, and patient’s characteristics Early stage + good PS– cure with aggressive treatment Advanced stage + good PS– prolong survival with aggressive treatment Advanced stage + poor PS – alleviate symptoms Balance between aggressive treatment and quality of life Healthcare team + well-counseled patient make treatment decision September 30, 2024 15 Treatment of NSCLC Untreated patients will die within 3 to 12 months Surgery – the most potentially curative modality Adjuvant chemotherapy may provide additional benefit Radiation + chemotherapy = cure in small # of patients = palliation in most patients Chemoradiation can be sequential or concurrent In patients with advanced-stage disease, chemotherapy or targeted therapy offer modest improvements in PFS and sometimes OS Checkpoint inhibitors SS improve OS vs chemotherapy, although improvement is modest September 30, 2024 16  preferred NSCLC, non–small cell lung cancer; PD-L1, PD-1 targeting immunotherapy; EGFR, Epidermal Growth Factor Receptor; ALK, Anaplastic Lymphoma Kinase; MET, C-mesenchymal-epithelial transition factor; RET, rearranged during transfection Treatment algorithm is based on: 1. Tumor histology 2. Stage 3. Biomarkers: driver mutations, PD-L1 expression 4. September PS 30, 2024 17  Targeted therapy September 30, 2024 18  Presence of driver mutations September 30, 2024 19  Targeted therapy for mNSCLC Mutation status Pharmacology Generic name/Brand name Tyrosine kinase inhibitors (TKI) positive EGFR EGFR TKI Osimertinib/Tagrisso (preferred) EGFR mutations activate TK domain Erlotinib/Tarceva – oldest →sensitivity to TKI →sensitizing (± ramucirumab/bevacizumab) mutations afatinib, gefitinib, dacominitib Found in ~10% Caucasian, 50% Asian ALK ALK TKI Alectinib ALK (Anaplastic lymphoma kinase) Brigatinib gene rearrangements Ceritinib ROS1 ROS TKI Crizotinib ROS1 gene rearrangement (ROS proto-oncogene 1) Entrectinib BRAFV600E BRAF and MEK TKI Dabrafenib + Trametinib (See Skin CA) Point mutations in B-RAF proto- oncogene September 30, 2024 20  TKIs in patients with EGFR sensitizing mutation Efficacy Objective response ~80% ↑PFS in patients with EGFR mutations who receive TKI vs. platinum-based chemotherapy Improved quality of life Safety Grade 3-4 rash, diarrhea vs. neutropenia with platinum-based chemotherapy Administration Given until disease progression or intolerable toxicity Orally - COMPLIANCE Patient support programs September 30, 2024 21  Erlotinib (Tarceva) Indicated for patients - with EGFR mutation positive NSCLC Should not be used in combination with platinum-based chemotherapy Must be discontinued Interstitial lung disease Severe hepatic toxicity that does not improve in 3 wks Gastrointestinal perforation Corneal perforation or severe ulceration Severe bullous, blistering or exfoliating skin conditions September 30, 2024 22  Common side effects Seen within the first month of treatment Rash and other skin reactions - face, upper chest and back - pretreat with alcohol-free emollient cream - use sunscreen or avoid sun exposure Diarrhea - manage with loperamide September 30, 2024 23  Absorption Bioavailability is increased by food to ~100% Erlotinib solubility decreases as pH increases Erlotinib Metabolism CYP substrate - mostly 3A4 PK Inducers – e.g., phenytoin, carbamazepine, St. John’s Wort – decrease concentration Inhibitors – e.g., voriconazole, grapefruit juice, ciprofloxacin – increase concentration Cigarette smoking reduces erlotinib exposure September 30, 2024 24  Erlotinib dosing and administration Orally daily on an empty stomach Avoid use or adjust dosing with CYP3A4 inhibitors (e.g., ciprofloxacin) or inducers (e.g., St. John’s Wort) If concurrent cigarette smoking, increase the dose at 2- week intervals. Immediately reduce the dose upon cessation of smoking pH- altering drugs Avoid PPIs Separate erlotinib by 10 hours after H-2 antagonist and at least 2 hours prior No data in patients with renal impairment September 30, 2024 25 Osimertinib (Tagrisso) Resistance to EGFR TKIs develops in most patients in after ~ one year of treatment 60% of patients will have T790M mutation T790M mutation might occur in therapy-naïve pts Osimertinib – active against EGFR sensitizing mutations + T790M mutation Can be used as 1st line SS longer PFS, duration of response Penetrates BBB - responses observed in NSCLC patients with brain metastases Safety: QTc interval prolongation, cardiomyopathy, pneumonitis, keratitis (eye inflammation) September 30, 2024 26 Efficacy. OS September 30, 2024 27 Efficacy. PFS https://www.tagrissohcp.com/efficacy/metastatic-nsclc-efficacy.html#pfs Accessed Sep 2022 September 30, 2024 28 Safety. QTc interval prolongation Baseline QTc > 470 msec – exclusion criteria in clinical trials QTc > 500 msec occurred in 0.8% of patients on osimertinib Increase in QTc > 60 msec from baseline occurred in 3.1% of patients on osimertinib No QTc-related arrhythmias reported Periodic monitoring with ECGs and electrolytes in patients with CHF, electrolyte abnormalities, or those on medications known to prolong the QTc interval. Discontinue in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia September 30, 2024 29 Safety. Cardiomyopathy Cardiomyopathy = cardiac failure , chronic cardiac failure, congestive heart failure (CHF), pulmonary edema or decreased ejection fraction (EF) In clinical trials: cardiomyopathy and decreased LVEF ≥10 % from baseline and to < 50% LVEF occurred in 3% of patients treated with osimertinib 0.1% of cardiomyopathy cases were fatal Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment in patients with cardiac risk factors Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment Discontinue for symptomatic CHF September 30, 2024 30 Osimertinib dosing/administration Orally daily regardless of food Dose increase for strong CYP3A4 inducer PI “2.3 Administration to Patients Who Have Difficulty Swallowing Solids” Disperse tablet in 60 mL (2 ounces) of non- carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink.” September 30, 2024 31  Indicated for patients with ALK+ gene rearrangement mNSCLC Until disease progression or no longer tolerated by the patient Increase PFS to over a year or longer Alectinib - 1st line since better efficacy and ALK TKIs safety (vs. comparator = crizotinib) Fewer alectinib-treated patients had CNS metastatic progression vs. patients on comparator (crizotinib) Fewer Grade 3 -5 toxicities vs. comparator, although alectinib was given longer September 30, 2024 33  Hepatotoxicity Common very close monitoring first 2-3 months q2 weeks dose reduction, discontinuation in severe cases side Interstitial lung disease effects of Bradycardia Myalgia and creatine phosphokinase (CPK) ALK TKIs elevations – alectinib requires dose modifications September 30, 2024 34 BRAF and Dabrafenib + trametinib MEK TKIs See Skin cancers September 30, 2024 35  Immunotherapy targeting PD-1 September 30, 2024 36 Pembrolizumab (Keytruda) Indicated for the first-line treatment of patients with mNSCLC with no EGFR or ALK genomic tumor aberrations PD-L1 expression should be ≥ 1% (by FDA approved test) MOA: “monoclonal AB that binds to PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response” Monotherapy or in combination with traditional cytotoxics Better OS than chemotherapy with fewer toxicities Patients treated until disease progression or unacceptable toxicity, or for up to 24 months in patients without disease progression September 30, 2024 37 September 30, 2024 38 Nivolumab (Opdivo) Indicated for patients with mNSCLC who progressed after traditional cytotoxic chemotherapy or targeted therapy MOA: same as pembrolizumab No testing required for PD-L1 expression September 30, 2024 40  Indicated as first line treatment or subsequent therapy for mNSCLC Patients without EGFR or ALK genomic aberrations Atezolizumab MOA: PD-ligand 1 blocking antibody (Tecentriq) No required testing for PD-L1 expression Can be given as monotherapy or in combination with traditional cytotoxics September 30, 2024 41  Indicated in unresectable Stage III NSCLC, not progressed after platinum-based chemo and radiation No required testing for genomic aberrations Durvalumab MOA: PD-ligand 1 blocking antibody (Imfinzi) No required testing for PD-L1 expression Monotherapy for tumor response consolidation September 30, 2024 42 Common toxicities Most common SE – see Skin cancer lecture - immune-mediated reactions e.g., colitis, pneumonitis, nephritis, skin reactions, thyroid disorders, DM1 etc. Occur during treatment or long after stop Can initially present with “pseudoprogression” (inflammation within the tumor) - infusion reactions Supportive therapy – steroids Discontinue in severe cases September 30, 2024 45  Traditional cytotoxic therapy September 30, 2024 46  preferred NSCLC, non–small cell lung cancer; PD-L1, PD-1 targeting immunotherapy; EGFR, Epidermal Growth Factor Receptor; ALK, Anaplastic Lymphoma Kinase; MET, C-mesenchymal-epithelial transition factor; RET, rearranged during transfection Treatment algorithm is based on: 1. Tumor histology 2. Stage 3. Biomarkers: driver mutations, PD-L1 expression 4. September PS 30, 2024 47 Traditional chemotherapy for mNSCLC Platinum – based doublet: Cis/carbo-platin + docetaxel/paclitaxel, etoposide, gemcitabine, vinorelbine, PS 0 -1 pemetrexed for non-squamous only No (± immunotherapy) targetable PS 2 Platinum – based doublet: Carboplatin + mutations docetaxel/paclitaxel, etoposide, gemcitabine, vinorelbine, pemetrexed for non-squamous only or monotherapy (not platinum) PS 3-4 Best supportive care September 30, 2024 48 Traditional Platinum-based regimen – platinum- doublet cytotoxic + docetaxel/paclitaxel, gemcitabine, vinorelbine, etoposide, regimens pemetrexed (non-squamous only) Combination regimen in fit patients PS 0-2 – ORR 25 – 35% – time to progression – 4 – 6 months – 30- 40% 1-year survival rate 10 – 15% 2–year survival rate Single-agent therapy – reasonable alternative in the elderly or PS 2 September 30, 2024 49 Platinum-based regimens Effective combinations paclitaxel/docetaxel More toxic gemcitabine Cisplatin/carboplatin + vinorelbine pemetrexed Less toxic September 30, 2024 50 Platinum analogs side effects Cisplatin and carboplatin – both are highly toxic different toxicities profile Cisplatin Carboplatin (Platinol) (Paraplatin) Infusion related hypersensitivity reactions Both agents can cause, risk ↑ with repeated dosing Nephrotoxicity (Amifostine – chemoprotectant) SS* more !!!! Neurotoxicity (peripheral, ototoxicity) SS more Emetogenecity SS more Myelosuppression SS more Hypomagnesemia SS more !!!! *Statistically significant September 30, 2024 51 Carboplatin Carboplatin may be preferred in renal dysfunction dosing and Carboplatin dosing is based on PK administration Calvert formula: Total Dose (mg)= (target AUC) × (GFR + 25) Target AUC – usually 5 – 6 GFR = Clcr by C-G equation Use ABW – unless institution-specific protocol FDA Warning (10/2010): “The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used” Hydration 1–2 L of 0.9% NaCL before and after cisplatin administration Electrolyte(s) replenishment September 30, 2024 52 Medication safety issues Confusion cISplatin (Platinol) vs. cARBOplatin (Paraplatin) Inadvertent cisplatin overdose - if dose more than 100 mg/m2 – verify with prescriber Differentiate daily doses from total dose per cycle September 30, 2024 53 Taxanes Docetaxel Paclitaxel Nab-paclitaxel (Taxol) (Abraxane) Infusion-related reaction and fatal anaphylaxis – any taxane Premedicate: Dexamethasone, diphenhydramine, famotidine/ranitidine Formulation May contain alcohol Cremophor EL Albumin-bound (emulsifier) Hepatic Contraindicated Avoid or reduce the Dose reduction impairment dose Major Myelosuppression Peripheral neuropathy Neutropenia toxicity Severe fluid retention – premedicate Duration of ~1 hour Longest, >24hours ~ 30 minutes infusion Administrati Before platinum-based compounds – elimination is reduced if on September 30, 2024 platinum agent is given first 54 Etoposide Topoisomerase inhibitor II Dose-limiting myelosuppression Substrate CYP 3A4, 3A5 – drug interactions Available IV and PO (not for lung cancer) Hypotension – commonly seen with rapid infusion Preparation is driven by institution– specific protocol due to instability of solutions with concentration > 0.4 mg/mL – fast precipitation may occur Capsules require refrigeration September 30, 2024 55 Gemcitabine Antimetabolite – nucleoside metabolic inhibitor Exerts schedule-dependent toxicity Increased toxicity with infusion time > 60 minutes or dosing more frequently than once a week Infused over 30 minutes every 3 or 4 weeks September 30, 2024 56 Vinorelbine Microtubule inhibitor Potential drug interactions - CYP 3A4 substrate May cause serious GI toxicity: severe constipation, paralytic ileus, intestinal obstruction, necrosis, perforation IV ONLY – fatal if given intrathecally; administer in IV bag Can be given as IV push (syringe) – ↓risk of phlebitis and pain Vesicant – see Lecture “Management of oncologic emergencies” September 30, 2024 57 Pemetrexed Folate analog metabolic inhibitor (Alimta) Indicated in combo with cisplatin or as monotherapy in advanced non-squamous NSCLC Warnings and side effects: Myelosuppression – dose-limiting toxicity deaths associated with neutropenic sepsis Coadministration with NSAIDS – ↑ renal, GI toxicities – not recommended generally and especially in patients with renal impairment – NSAIDs should be stopped prior to and restarted a few days later September 30, 2024 58 Dosing and administration September 30, 2024 59 Dosing and administration (cont.) Dose modification schedule based on Absolute Neutrophil Count (ANC) Platelets’ nadir Should not begin a new cycle of treatment unless ANC ≥ 1,500 cells/mm3 Platelet count ≥ 100,000 cells/mm3 Clcr ≥ 45mL/min September 30, 2024 60 Summary: Lung cancer is the leading cause of death in both man and woman Currently there is no reliable screening technique; stopping smoking is the best intervention in high-risk patients Genetic testing and screening for PD1 are extremely important since their presence/absence determine the course of pharmacotherapy. PD1 inhibitors are very useful for patients without known mutations Targeted therapies are first line agents for patients with mNSCLC and corresponding genetic abnormalities Carboplatin and cisplatin show the most pronounced improvements in survival in patients with advanced stage NSCLC. Because of reduced neurotoxicity, nephrotoxicity, and GI toxicity, some clinicians may favor carboplatin over cisplatin. Patients should be monitored closely for toxicities not only with traditional cytotoxic therapies but also with oral agents and immunologics. September 30, 2024 62