Lung Cancer Presentation

Lung Cancer Gauri Sabnis, PhD 2ndmostcommoncoder intros Reading: Katzung et al, Basic and Clinical Pharmacology, Chapter 54 Goodman and Gilman’s Pharmacological Basis of Therapeutics, Chapter 37 Dipiro et al, Pharmacotherapy: A pathophysiologic Approach, Chapter 106 Epidemiology ✥Death rates for lung cancer declining Em ✥Incidence rates have declined significantly ❊Awareness about smoking risks ✥Risk factors ❊Smoking Jong⇥ Passive smoking ❊Environmental exposure ⇥ Occupational ❊Age ❊Familial predisposition Cancer Facts and Figures, ACS 2020 4 Smoking and lung cancer ✥⅓rd of all cancer deaths are related to smoking; ~80% of lung cancer deaths ✥Duration and quantity of cigarettes smoked ❊ After 45, 30 and 15 years annual incidence rate 0.5%, 1% and 0.01% ❊ Risk continues at the same rate when smoking ceases ✥Cigarette smoke contains may chemicals that can act as carcinogens, procarcinogens and tumor promoters ❊ Solid phase (particles) and gas phase ❊ Benzo[a]pyrene (polycyclic aromatic hydrocarbon), formaldehyde, benzene ✥Passive smoking ❊ Risk 30% higher in non-smokers living with smokers ✥~20% of smokers develop lung cancer e ❊ additional risk factors - first degree relatives ❊ Epigenetics? 5 Radon (Rn 86) ✥Odorless, tasteless, colorless noble gas that is decay Indo product of radium which is decay product of uranium ❊Radiation half-life of 3.8 days for Rn ✥Building material, rocks, soil etc. ❊Indoor air contaminant - radiation source ❊Gets trapped in attics, basements ❊Heavier than air ✥Thought to be second leading cause of lung cancer after smoking ❊Leading cause of lung cancer among non-smokers ✥Higher risk in smokers who are also exposed to Radon 6 Classification ✥Most common types are non small cell lung cancers (NSCLCs) which include I ❊Squamous cell carcinoma – more association w/ smoking, more common in men, tends to bleed t more 2❊Adenocarcinoma – generally “never smokers” ❊Bronchioalveolar carcinoma (BAC) ✥Large cell carcinoma (LCLC) ✥Small cell carcinoma (SCLC) ✥Other – mesotheliomas, soft tissue tumors and mixed (adenosquamous etc.) SCLC LCLC NSCLC 8 StagingisBasedon Clinical Presentation MNGT Angkindofmetastisis isstaged ✥Patients usually are diagnosed due to worsening symptoms ❊ Due to local tumor growth and intra-thoracic spread coughing godfront ⇥ Cough, wheeze, hemoptysis, signs of airway obstruction such as dyspnea, SOB pneumonitis, fever yngoraivaeys ⇥ Intra-thoracic spread - mediastinal spread - poorly localized chest pain, compression or invasion of the esophagus, hoarseness due to entrapment of laryngeal nerve - dysphasia for solids and liquids leading to frequent aspiration ⇥ Pericardial tamponade, superior vena cava obstruction ❊ Due to distant metastasis ⇥ Most frequent sites are CNS, bones, liver and adrenal glands ❊ Non-specific systemic symptoms ⇥ Weight loss with/without anorexia (½ patients), fatigue (⅓) ❊ Paraneoplastic syndrome ⇥ Non-specific systemic symptoms that are not a result of local presence of cancer Excessive ⇥ SIADH - syndrome of inappropriate secretion of ADH - hyponatremia, hypo-osmolarity waterand retention ⇥ Syndrome of ectopic ACTH (Cushing’s), hypercalcemia of malignancy, ↑ incidences of cowgodiam thromboembolism 9 Stages of NSC Lung Cancer ✥Most frequent sites are CNS, bones, liver and adrenal sign so glands ❊IVa - other lung ❊IVb – thoracic im no ❊Ivc – extra-thoracic ✥5-year survival for ❊IVa - 10% ❊IVb is <1% 13 ma small celllatino Clinical Staging - SCLC wayaggressive ✥For treatment purposes ✥Only 2 stages are used ❊Limited ⇥Only 1 side of the lungs, radiation + chemo ⇥Small enough to be treated with radiation therapy with single port it ❊2Extensive ⇥Both lungs, throughout the lung or other parts of the body 14 Screening and Prevention ✥Tobacco cessation Thereisnon ✥Chemopreventionwe ❊ NSAIDs, green tea, retinoids, inhaled GCs, vit. E, selenium - failed e ❊ β-carotene supplements - older smokers who took supplements – ⇥ ↑ risk of mortality ✥Screening ❊ 20% risk reduction in moderate to high-risk pts. HJ de Koning et al. N Engl J Med 2020;382:503-513. ❊ LD-CT 16 Screening IpockHowmany ✥Low dose CT (LDCT) years ❊ Current or former (quit within last 15 years) smokers ❊ At least 20 “pack years” ✥ Other risk factors ❊ Contact with radon, asbestos or other carcinogens ❊ Family history O ❊ Other chronic lung diseases (such as COPD) https://www.youtube.com/watch?v=wE4jrFNmigQ ✥Should not be used as a substitute for quitting smoking canidatefor Low Me dogs 17 Treatment choices - NSCLC p no ✥Surgery - Stage Ia and IB ly❊Re-resection for positive margins; chemo and radiation ❊IIa and IIb surgery + adjuvant chemo z ✥Chemotherapy ❊Platinum doublet 3 ✥Targeted therapy ❊VEGF targeted therapy ❊EGFR targeted therapy ⇥ EGFR wild-type or mutated ⇥ B-RAF mutations ❊ALK/ROS1 targeted therapy a ✥Immunotherapy ❊Immune checkpoint inhibitors 18 Chemotherapy regimens for NSCLC Ms ✥Platinum doublet Ingham Notplatinum ❊2 drug combination containing a platinum agent; shows 851 superiority ⇥ Cisplatin or carboplatin ❊Taxane (paclitaxel) or vinca (vinorelbine) for any histology ❊Pemetrexed for non-squamous cell cancer ❊Gemcitabine for squamous cell ❊Patients with good performance score, add bevacizumab ⇥ Not for pts. with hemoptysis, risk of thrombocytopenia or bleeding ✥Elderly and poor performance status (≥2) single agent ℞ with palliative intent 19 3 Organometallic compounds ✥Contain electron deficient metal atom - acts as a magnet for electron rich DNA nucleophiles ✥Bifunctional and can accept electrons from 2 DNA nucleophiles ❊ Intrastrand crosslinks G-G (~65%) or G-A (~25%) ❊ Interstrand crosslinking G-A (<3%) ✥All current agents, platinum (Pt II) with square planar geometry ❊ Pt inherently electron deficient but net charge on the molecule is neutral ❊ 2 / 4 ligands bound to the parent Pt, contribute electrons to the Pt ❊ Chloride is generally the leaving group ✥Effects similar to alkylating agents and radiation ✥React with aluminum — needles Cisplatin 20 Platinum Compounds hd this ✥Before reacting with DNA, electron donating ligands are displaced through nucleophilic attack by gwater. ❊ When displaced ions are Cl-, the low Cl- environment of tumor cell facilitates it ❊ Drives generation of active cytotoxic hydrated form ❊ Ligands left with their negative charge, so a net positive charge is left on the Pt ❊ Hydrated platinum readily attacked by the DNA nucleophiles ⇥ N7 of adjacent guanines ❊ DNA bases become coordinated with the platinum ❊ NH2 is bound strongly with Pt w/ coordinate bonds - can’t be displaced by DNA nucleophiles ❊ In the cis configuration, DNA repair machinery can recognize but not correct the distortion ❊ Cell cycle arrest and apoptosis - damage repaired with NER and MMR pathways – moa of resistance 21 Cisplatin 22 Cisplatin ✥Highly reactive - Chloride leaving group ❊Must be compounded in NS ✥Light sensitive - protect from light ✥Myelosuppression, nephrotoxicity and ototoxicity ✥Highly emetogenic ❊Pretreatment required ✥Plasma protein bound, penetrates tissues and slowly excreted unchanged in the urine (t½ ~ 1 hour initially and then >24 hrs) 23 Cisplatin ✥Highly nephrotoxic ❊Aggressive hydration required ⇥ Chloride containing ⇥ Saline or mannitol diuresis • Toxicity not overcome by dialysis ✥Amifostine to ameliorate toxicity ❊Required to be activated by alkaline phosphatase (only expressed in healthy cells) ❊Made only in NS 24 Carboplatin ✥2nd generation platinum compound, better tolerated ❊Same planar geometry — forms same hydrated intermediate ⇥ Slower (10X) rate of formation — 20-40X less potent ⇥ Similar anti-tumor efficacy as cisplatin but much less toxicity ✥Less protein binding – t½ 2-4 hours ✥Toxicity: ❊Nephro-, neuro- and ototoxicity are low ❊N/V milder than cisplatin 000 ❊DLT – thrombocytopenia and leucopenia (less than cisplatin) ✥Reduce dose in renal impairment (CrCL < 60 mL/min) ❊Calvert formula - Dose = AUC×(GFR+ 25) 25 Oxaliplatin ✥Platinum complex that loses oxalate dianion in vivo to form mono and dihydrated diaminocyclohexane (DACH) ❊ Trans-DACH serves as a carrier for the cytotoxic hydrated platinum ❊ Extends into the major groove of DNA ❊ DNA platinum complex forms with inter strand crosslinks of G-G, G-A and G-X-G DACH Oy's wit Oxaliplatin Oxaliplatin diaquo form (active) ✥Adduct formed is distinct from cisplatin/carboplatin ❊ Due to stearic impact of DACH carrier, cis-NH2 moieties hydrogen bond with O6 of guanine ❊ Much less likely to be recognized by the MMR proteins ⇥ Activity significantly different than cisplatin, also active in cisplatin resistant population 26 Oxaliplatin ✥Significantly less nephrotoxic, ototoxic and mutagenic than cisplatin ❊ Nausea is well controlled with 5HT3 RA ✥Oxalate loss is essential step in activation of oxaliplatin ❊ Rate of oxalate loss can be increased by solutions containing chloride ⇥ Should NOT be diluted in NS - D5W only! ❊ Oxalate based chelation of Ca2+ causing inhibition of voltage gated Na+ channels ❊ Peripheral sensory neuropathy ⇥ Acute with cold exposure (treatment of mucositis with ice chips, cold compress for extravasation can exacerbateWoo this) pyo ⇥ Infusion of Ca and Mg salts to attenuate neuropathy without affecting efficacy ❊ QT prolongation ✥Hematologic toxicity rare ✥Acute allergic reaction with urticaria, hypotension and bronchospasms (anaphylaxis —BBW) 27 Microtubule 5 Damaging Agents ✥Cell cycle specific ❊M- phase ❊Chromosomes fail to move apart ❊Cell cycle arrest and apoptosis ✥Vinca alkaloids ❊Vincristine ❊Vinblastine ❊Vinorelbine ✥Taxanes ❊Paclitaxel ❊Docetaxel 28 Vinca alkaloids ✥Several alkaloids found naturally in Catharanthus Roseaus (periwinkle, Vinca rosea) if❊ Halt cell division by inhibiting polymerization of microtubules ❊ Bind to the +ve end of growing microtubule and attenuate GTPase activity of β- tubulin ❊ Stabilization of protofilament preventing elongation of microtubule ⇥ Cause disruption of mitotic spindles ⇥ Can interfere with cytoskeletal functioning ❊ 1-2% occupation of high-affinity sites leads to blockade of 50% microtubule assembly ❊ At higher concentration, low-affinity sites are also occupied and microtubular depolymerization is stimulated - leading to exposure of more binding sites ⇥ Chromosomal clumping ➜ cell death ✥TP53 mutation is associated with vinca resistance ✥All vinca alkaloids undergo hepatobilliary excretion ❊ Caution with hepatic insufficiency 29 Vinca Administration ✥All vinca alkaloids are severe vesicants ❊ Inadvertent injection into CSF can lead to irreversible coma and seizures - Death ❊ Extravasation during IV – necrosis, cellulitis and phlebitis ❊ Hyaluronidase and warm compress to disperse the drug ⇥ Cold exacerbates tissue destruction ✥Should NEVER be administered IT ✥Label must clearly state: #NCCNJustBagIt ❊ “For IV use only — Fatal if given by any other route” 30 Vincristine ✥Tolerated better by children than adults a ✥NOT myelosuppressive at therapeutic doses ✥DLT: peripheral neuropathy (CNS) prominent with vincristine axonal microtubules targeted as ❊ Numbness, painful paresthesias in the extremities ❊ Progress to muscle pain, severe weakness, loss of coordination ❊ Constipation secondary to intestinal neuropathy - progressing to paralytic ileus ⇥ Severe constipation causing colicky abdominal pain - laxatives ✥Other toxicities: Alopecia, ANS dysfunction with orthostatic hypotension, urinary retention, paralytic ileus; inappropriate secretion of ADH (SIDH) ✥AA patients with CYP3A5A*1 allele have lower risk than Caucasians 31 Vinca alkaloids ✥Vinblastine ❊Toxicity: neurotoxicity and alopecia less severe; ❊Bone marrow depression is more prominent with vinblastine than vincristine ✥Vinorelbine ❊Semisynthetic derivative of vinblastine ⇥PO bioavailability 10 ❊Toxicity: myelosuppression w/ neutropenia, N/V, transient increase in LFTs, neurotoxicity ⇥Fatal interstitial pulmonary changes - symptoms of respiratory distress ❊Inappropriate secretion of ADH (SIADH) - observed with all vinca (rare) 32 4 Topoisomerase Poisons ✥Topoisomerase enzymes ❊ Control the degree of DNA supercoiling to maintain proper DNA structure during replication and transcription ❊ Through trans-esterification of tyrosine residues and then reverse transesterification they repair their own damage ✥Topoisomerase I ❊ Reduces DNA supercoiling by inducing ss breaks, re-ligates the DNA ✥Topoisomerase II ❊ Reduces DNA supercoiling by inducing ds breaks and religates the breaks ✥Topoisomerase poisons allow the breaking of the DNA strand, but prevent the re-ligation step leaving DNA strand(s) broken — so i irreversible DNA damage ✥Topo-I inhibitors – Camptothecins  Topotecan, irinotecan ✥Topo-II inhibitors – Epipodophyllotoxins  Etoposide, teniposide 33 Gaia 2 e 35J Targeting Angiogenesis 35 Bevacizumab (Avastin™) ✥Humanized monoclonal antibody against VEGF ❊ Prevents its binding to VEGF ✥NSCLC (with non-squamous histology) with carboplatin and paclitaxel ❊ Standard of care for pts. with good performance score ✥ADRs: ❊ Hypertension, thromboembolic events (MI, stroke) ❊ CNS (fatigue, pain, headaches, dizziness); ❊ Respiratory (dyspnea, URTIs); contraindication – hemoptysis ✥BBW: gastric perforations, surgery and wound healing complications and hemorrhage ❊ Hold for 28 days before and after surgery ❊ Proteinuria (grade ≥3) ✥Prepare in NS ❊ Do not mix in dextrose containing solution Sandler et al., N Engl J Med 2006;355:2542-50. 36 Angiogenesis Targeting Agents ✥Antibodies against VEGF e ❊Bevacizumab (Avastin, Mvasi) ❊Ramucirumab ✥Tyrosine Kinase inhibitors ❊Sunitinib ❊Sorafenib Multi-kinase inhibitors ❊Regorafenib 37 ✥Transmembrane receptor tyrosine kinase – ligand EGFR in Lung Cancers dependent ✥Proto-oncogene – mutations that lead to overexpression associated with several cancers including lung adenocarcinoma ❊ In-frame deletions in exon 19 or point mutations in exon 21  resulting in arginine replacing leucine at codon 858 (L858R) ⇥ Leading to constitutive activation of EGFR ❊ Amplification (gene copy number) also observed – not associated with better response EGF, TGFα Epiregulin etc. No Ligands Neuregulins P P P P Her-1 EGFR ErbB-1 P P P P P P Her-2 ErbB-2 Neuregulin (NRG-1) Her-3 ErbB-3 P P Her-4 ErbB-4 Extracellular: Ligand Binding Domain Intracellular: Tyrosine Kinase Domain 38 EGFR Targeting Antibodies ✥Cetuximab (Erbitux) ❊ Monoclonal antibody against extracellular domain of EGFR ❊ G1 type antibody - also elicits anti-tumor immune response 095 ⇥ No longer preferred in NCCN guidelines for LC ⇥ Grade 4 neutropenia ❊ BBW: infusion site reactions (premedicate with H1RA - IV 30-60 min before 1st dose) B ✥Only approved for use in patients with wild-type K-RAS ❊ K-Ras mutations are associated w/ smoking, asbestos exposure and females ✥ADRs: ❊ Dermatologic toxicity (acneiform rash) ❊ Electrolyte abnormality (hypomagnesemia) ⇥ Cardiopulmonary arrest (BBW) 0 Is ⇥ Monitor Mg, Ca and K during Rx and at least 8 weeks Varghese AM, Sima CS, Cha3 JE, et al. J Thorac Oncol. 2013;8(1):123-5. after ✥Panitumumab (Vectibix) ✥Necitumumab (Portrazza) ❊ BBW – hypo-Mg 39 Growth Factor Receptor PI(4,5)P2 PI(3,4,5)P3 PI3-K Shc Grb2 SHP-2 Akt PTEN SHP-2 P P P P SOS RAS-GDP RAS-GTP mTOR RAF 4E-BP1 S6K elF-4E p90RSK Ribosomal Synthesis mRNA Translation Nucleus DNA Polymerase MAPK MEK Cyclin D1 Cell proliferation Suppress apoptosis TRANSCRIPTION 40 ✥Small molecule tyrosine kinase inhibitors binding to Tyrosine Kinase Inhibitors the hydrophobic hinge region (ATP binding domain) of the receptors ❊ Type I - Compete with ATP and bind to active enzyme ❊ Type II – bind to inactive enzyme ❊ Type III – allosteric binding near ATP binding site ❊ Type IV – allosteric binding distant from ATP binding site ✥TKIs contain 4-anilinoquinazoline pharmacophore CYP (R ≠ H) ❊ Metabolized by CYP enzymes to aniline  p- hydroxyaniline  quinoneimine (hepatotoxic) Aniline moiety ✥Most TKIs exhibit (structure associated) ❊ Hepatotoxicity CYP Tyrosine kinase inhibitor ⇥ Baseline LFT ⇥ Monitoring of LFTs routine CYP Quinoneimine (Hepatotoxic) Diabetic ⇥ Dose adjustment no ❊ DDI/DFI requiring dosage adjustments w/ CYP3A4 Affection p-hydroxyaniline moiety inhibitors/inducers ❊ Interstitial lung disease (ILD), pneumonitis ❊ Diarrhea ✥Other ADRs related to EGFR pathway inhibition ❊ Rash – EGFR mediated ❊ Cardiotoxicity – Her-2 mediated ❊ Neutropenia – DNA damage mechanisms 41 Key Points Related to TKIs o ✥DDIs/DFIs WN ❊CYP3A4 mediated metabolism and active metabolites ⇥ Inducers and inhibitors of CYP3A4 z ⇥ Dose adjustment required in hepatic insufficiency ✥Metabolism forms a hepatotoxic quinoneimine ❊Baseline and routine monitoring required 3 ✥pH dependent solubility and absorption ❊Administration with or without food; high fat foods g❊Co-administration of PPIs should be avoided – separate by 2 hours ✥5All TKIs excreted predominantly through feces ❊GI toxicity, diarrhea 42 ✥Small molecule tyrosine kinase inhibitors EGFR targeting agents ❊ Erlotinib (Tarceva): EGFR kinase inhibitor ⇥ Erlotinib levels lower in smokers ⇥ Avoid with PPIs EGFR mutant versus wild type ❊ Gefitinib (Iressa): Dual EGFR-Her-2 inhibitor ⇥ Higher binding affinity for Mutant EGFR w/ L858R and exon 19 deletion than wt ❊ Afatinib (Gilotriff): Her-1, 2 and 4 inhibitor ⇥ Mutant EGFR w/ T790M, L858R and exon 19 deletion and wt EGFR ❊ Osimertinib (Tagrisso): Mutant EGFR onIan K-RAS mutant versus wild type FEI L858R and exon 19 deletion or w/ T790M (after previous ℞), ⇥ Less active against wt EGFR ⇥ Hyper Mg, QT prolongation, cardiomyopathy ❊ Dacomitinib ✥EGFR targeting agents will not work in patients with K-Ras mutations ✥EGFR Rash ❊ May predict response to treatment David A. Eberhard, et al. J Clin Onco. 2005;23(25):5990-09 43 ✥Antibodies targeting extra cellular domain of EGFR targeting agents EGFR – wild-type EGFR ✥TKIs targeting intracellular domain of EGFR ❊Mutated EGFR (exon 19 deletion or exon 21 L858R Cetuximab Panitumumab Necitumumab EGF, TGFα Epiregulin etc. substitution) but must have wt K-Ras ❊Must have wt. B-Raf Neuregulin No Ligands NRG-1 (NRG-1) Extracellular: Ligand Binding Domain Intracellular: P P P P Her-1 EGFR ErbB-1 P P P P P P Her-2 ErbB-2 Erlotinib Afatinib Gefitinib Osimertinib Her-3 ErbB-3 P P Tyrosine Kinase Domain Her-4 ErbB-4 44 Erlotinib ✥Metabolized by CYP3A4 and CYP1A1 ❊O-dealkylation – forms active Alcohol dehydrogenase Aldehyde dehydrogenase desmethyl metabolite ❊Smoking increases clearance of erlotinib ⇥ AUC and t½ ↓ and dose↑ needed ✥Hepatotoxicity due to O-dealkylation CYP3A4/1A1/1A2 quinoneimine metabolite ✥Other ADRs: ❊Rash – EGFR inhibition Aromatic hydroxylation CYP3A4 p-hydroxyaniline moiety Erlotinib ❊GI tox – diarrhea Quinoneimine (Hepatotoxic) 45 EGFR targeting TKis Lapa4nib Afatinib Erlotinib Gefitinib Osmertinib GotMost common used 46 B-RAF mutations ✥BRAF (encodes B-Raf protein) is a proto-oncogene ❊ Serine/threonine kinase ✥More than 30 mutations have been identified in various cancers ❊ V600E mutation is most common, found in melanoma (~60 – 80%) and NSCLC, allows ⇥ Dimeric and monomeric activation ⇥ Inhibits negative feedback from pMEK • Addictively activate the MAPK pathway – promote malignant transformation and cell proliferation ⇥ Associated with Lynch syndrome ✥Drugs targeting B-Raf ❊ Dabrafenib ❊ Vemurafenib ❊ Encorafenib • Must possess the activating mutation – may activate wt B-Raf 47 B-Raf inhibitors ✥BRAF inhibitors ❊ Dabrafenib ❊ Vemurafenib ❊ Encorafenib Vemurafenib ✥Inhibition of mutated B-Raf (V600E) allows activation of wild-type B-Raf and turns the MAPK pathway on again a ❊ Dual inhibition of B-Raf and MEK ✥ADRs: Cardiotoxicity (QT prolongation, HTN, ↓ LVEF), dermatologic toxicity Dabrafenib ✥Paradoxical activation of C-Raf and wt B-Raf leading to secondary skin cancers ❊ Squamous cell carcinoma (SCC) ✥CYP3A4 mediated metabolism Encorafenib ❊ DDI 48 ✥MEK is the kinase that activates MAPK MEK inhibitors (ERK) ✥Dual specificity kinase – Y and S/T kinase ✥MEK inhibitors ❊ Trametinib ❊ Cobimetinib ❊ Binimetinib ✥Given with B-Raf inhibitors for a stepwise inhibition of the pathway ✥ADRs: Cobimetinib Trame0nib ❊ CV – HTN, cardiomyopathy (↓LVEF) ❊ ↑ CPK, rhabdomyolysis ❊ Derm – photosensitivity, PPE, xeroderma including secondary skin cancers Binimetinib ❊ GI – diarrhea, stomatitis, ulcers ❊ Ocular – retinal detachment, visual sons as impairment, retinopathy ✥B-RAF testing is required 49 ALK/ROS1 ✥Anaplastic Lymphoma Kinase (ALK) belongs to insulin receptor superfamily ❊Proto-oncogene ❊Critical for embryonic development; absent in adults ❊ALK fuses with (EML4) gene and encodes EML4-ALK fusion protein ⇥ ~3-5% of NSCLC ❊Exclusive from EGFR expression ❊Younger and non-smokers ✥Oncogene ROS1 – Encodes cros - gene rearrangement ✥℞ targeting ALK fusion gene and ROS1 ⇥ Requires testing to confirm presence of these on the tumors 50 ALK/ROS1 Targeting Agents ✥All metabolized by CYP3A4 to active or less active metabolite ✥Crizotinibnotmoreotent ❊ Bradycardia, QT prolongation ❊ PPI co-admin not C/I ✥Ceritinib Crizotinib ❊ 20X more potent than crizotinib, active against crizotinib resistant tumors and not a substrate for PgP  able to accumulate in CSF CYP3A4 ✥Alectinib ❊ 2nd generation, similar to critinib – not a substrate Crizotinib lactam (less active) for PgP ✥Brigatinib ❊ Active against ALKi-resistant tumors – 3rd generation ❊ Hypertension, ↑ CPK, bradycardia ✥ ADRs: ❊ GI tox, Hepatotoxicity, ocular, pulmonary (ILD), Quinoneimine (Hepatotoxic) p-hydroxyaniline moiety bradycardia, QT prolongation (torsades) ❊ DDI/DFI ⇥ CYP4A4 mediated ⇥ Bradycardia related 51 Immune Checkpoints ✥Inhibitory pathways ❊ Maintain self-tolerance ❊ Modulate duration of immune response ✥Expression of immune checkpoint proteins is dysregulated by tumors – imp immune resistance mechanism ✥T – cells: ability to recognize peptides from all cellular compartments so ❊ Ability to recognize and kill antigen expressing cells – CD8+ T cells – CTL ❊ Ability to orchestrate diverse immune response – helper T cells – integrate adaptive and innate immunity ✥Inhibitory ligands – regulate effector functions of T cells – commonly overexpressed on tumors/tumor microenvironment ✥Antibodies targeting these pathways target not only the tumor cells but the lymphocyte receptor or their ligands ❊ Enhance endogenous anti-tumor immunity ✥2 immune checkpoints – utilized for anticancer drug therapy ❊ CTLA – 4 (CD 152) Cytotoxic T Lymphocyte associated antigen 4 ❊ PD – 1 (CD 279) – Programed cell Death 1 ✥Both inhibitory receptors, regulate immune response at different levels and mechanisms 52 07 38 Progression-free Survival, According to PD-L1 Tumor Proportion Score. L Gandhi et al. N Engl J Med 2018;378:2078-2092. 60 Anti-PD-L1 ✥Antibodies against the PD-L1 that is expressed on the tumors ✥Block the same pathway but the target in the ligand (PD-L1 instead of the receptor (PD-1) Antonia SJ et al. N Engl J Med 2017;377:1919-1929. ❊Atezolizumab (Tecentriq) ❊Durvalumab (Imfinzi) ❊Avelumab (Bavencio) ⇥ Not indicated for NSCLC (not yet at least) 61 Naming of Antibodies ✥Antibodies name end with – ab ✥Monoclonal antibodies - mab ✥Humanized antibodies - zumab ✥Human antibodies - umab ✥Chimeric antibodies - ximab ❊ Antibodies that target ⇥ Circulatory system – ci ⇥ Tumors – tu OR t ⇥ Immune system – li OR l ⇥ Interleukin – ki OR k ⇥ Bone – os ❊ Other targets for antibodies: ⇥ Virus - vir ⇥ Bacteria - bac ⇥ Toxin - to OR tox ⇥ Growth factors - gr 62 Rx of SCLC ✥Most patients present with extensive disease (60-70% of cases) ⇥ Paraneoplastic syndrome ❊Median survival is 14-20 months for limited and 9-11 months for extensive disease ❊Chemo ± radiation ✥Platinum based - etoposide and cisplatin is standard ✥Relapse ≤ 6 months - irinotecan, topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine single agent ✥Relapse ≥ 6 months - repeat EP regimen ✥Rx usually restricted to ECOG score of 0 and 1 ❊Patient age, renal status and patients’ desire to receive Rx 63