Lung Cancer Study Guide

Lung Cancer Dr. Leiva Lung Cancer Screening • Have a 20 pack-year or more smoking history and • Smoke now or have quit within the past 15 years and • Are between 50 and 80Isyears old – A pack-year is smoking an average of one pack of cigarettes per day for one year • Example: person could have a 20 pack-year history by smoking one pack a day for 20 years or two packs a day for 10 years When Should Screening Stop? __ • Yearly lung cancer screening stop when the person being screened— – Turns 81 years old, or – Has not smoked in 15 or more years, or – Develops a health problem and is unable to have surgery if lung cancer is found NCCN(National Comprehensive Cancer Network) Guidelines • Two major subtypes: – Small Cell Lung Cancer (SCLC) – Non-Small Cell Lung Cancer (NSCLC) ECOG Performance Status Eastern Cooperative Oncology Group Measurement of Performance Status ECOG Score Description 0 Asymptomatic 1 Symptomatic, fully ambulatory 2 Symptomatic, in bed <50% of day 3 Symptomatic, in bed >50% of day, but not bedridden 4 Bedridden 5 Dead Pathology Small Cell Lung Cancer (SCLC – 13%) • Rapid proliferation; most aggressive of all lung cancers • Paraneoplastic syndromes common • Systemic disease at diagnosis • 60-70% patients present with metastases • Clear relationship to smoking Non-Small Cell Lung Cancer (NSCLC –84%) • Slower growing • 40% of patients present with metastases Non-Small Cell Lung Cancer (NSCLC) • 84% of lung cancers • Slower growing • Surgery is treatment of choice in early stages • Lower sensitivity to chemotherapy Small Cell Lung Cancer (SCLC) • 13% of all lung cancers • Very aggressive • 60-70% present with metastatic disease • Death occurs in 2-4 months w/o treatment • Very chemo and radiation sensitive Major Genetic Mutations Involved in Pathogenesis of Lung Cancer, AKA “Driver Mutations” Enola Geffre Ms K-ras and EGFR EML4-ALK ROS1-Rearragement BRAF V600E Mutation PD-L1 Expression • Not a mutation, but PD-L1 positivity correlates with known alterations in NSCLC oncogenic tumor drivers PD-L1 Expression and Testing Does measuring for the presence of PD-L1 in tumor tissues help to identify patients who are most likely to respond to PD-L1/PD1 inhibitor immunotherapies? Tumors overexpressing PD-L1 may have improved outcomes, but tumors with low levels may also exhibit robust responses 4 PD-L1 assays registered with the FDA, using four different PDL1 antibodies and each has its own scoring system PD-L1 Expression and Testing • PD-L1 testing recommendations depend on the drug being considered for use, the malignancy, and the stage of cancer in question – CPS (Combined Positive Score) • PD-L1 expression determined by the # of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, x 100 – Several interpretive scoring systems available, including the tumor proportion score (TPS), and tumor-infiltrating immune cell (IC) staining assessments SCLC: Histologic Subtypes • Classical small cell carcinomacomprises the vast majority of SCLCs • Large cell neuroendrocrine cancer • Combined small cell carcinoma (predominately SCLC with occasional NSCLC) SCLC Staging • Limited disease • Disease confined to one hemithorax and regional lymph nodes can be contained in a tolerable radiation port • Extensive disease • Any disease beyond limited disease sites Limited Stage: 30-40% of all SCLC SCLC Staging • • • • Curative intent 5 year survival 10-13% Median survival 15-20 months Cure rate = 20% Extensive Stage: 60-70% of all SCLC • • • • Survival without treatment: 5 weeks Rarely curable Median survival with treatment 8-13 months 5 year survival 1-2% Overall 5 year survival of all SCLC is 5% Distant MetastasisSCLC • Liver, bones, retroperitoneal lymph nodes, adrenal glands, and brain • CNS preferential site (10% at presentation) • CNS symptoms (headache, double vision) Highly sensitive to radiation therapy and chemotherapy Treatment of Small Cell Lung Cancer Surgery generally not recommended for SCLC Negative prognostic factors • Poor performance status • Extensive stage disease • Weight loss • Excessive bulky disease Use in combination with chemotherapy to decrease incidence and delay onset of local tumor recurrences. This is called chemoradiation Radiation Therapy in SCLC Concurrent (vs. sequential) with chemotherapy is more favorable in limited stage Used for palliation of symptoms in extensive stage Prophylactic Cranial Irradiation - recommended if achieve complete response to chemoradiation Shown to improve 3 yr survival (15% vs 21%) Not recommended in patients with advanced age or poor performance status Chemotherapy in Limited Stage SCLC • Chemotherapy is given with a curative intent; the associated cure rate is 20% • Treatment: concurrent chemoradiotherapy: • Cisplatin-etoposide with concurrent radiation has the best supporting clinical data (NCCN category 1) • If a patient is not able to tolerate cisplatin-based therapy (e.g. poor renal function, inability to tolerate fluids) carboplatin may be substituted for cisplatin. • Chemotherapy should be given for 4 to 6 cycles • No benefit in maintenance therapy SCLC Limited Stage Treatment Cisplatin 60 mg/m2 IV D1, etoposide 120 mg/m2 IV D1-3 Q21 days x 4 – 6 cycles OR Cisplatin 75 mg/m2 IV D1, etoposide 100 mg/m2 IV D1-3 Q21 days x 4 – 6 cycles OR Cisplatin 25 mg/m2 IV D1-3, etoposide 100 mg/m2 D1-3 Q21 days x 4 – 6 cycles WITH radiation (NCCN® category 1) Etoposide-carboplatin (EC) q 4 weeks SCLC Limited Stage Treatment Carboplatin AUC=6 on Day 1 Etoposide 100mg/m2 Days 1-3 With concurrent radiation Used for cisplatin-intolerant patients, but not preferred • Etoposide (VP-16) Epipodophyllotoxin: Derived from mayapple or mandrake plant – Forms complexes with topoisomerase II and DNA to inhibit strand rejoining after breakage – Important points: •r Hypotension occurs with rapid infusion (need to give over at least 60 minutes) •z Secondary malignancies may develop 5-8 years later s • Has concentration dependent stability – Solutions prepared at < 0.4mg/mL are stable for 24 hours – Solutions > 0.4mg/mL are very unstable and may precipitate within a few minutes – Solubilized in Polysorbate 80 which may leach plastic. Must use low sorbing tubing Chemotherapy in Extensive Stage SCLC • Median survival without treatment: 5 weeks • Rarely curable • Treatment: Cisplatin- or carboplatin-based combination chemotherapy for 4-6 cycles • Unlike limited stage where cisplatin is preferred, in extensive stage, there is no difference in disease response between cisplatin and carboplatin • Cisplatin or carboplatin can be combined with either etoposide or irinotecan (“platinum doublets”) NCCN Preferred Regimens for SCLC Extensive Stage Treatment Carboplatin AUC 5 Day 1, Etoposide 100mg/m2 Days 1-3, and atezolizumab 1200mg Day 1 q21 days x 4 cycles, followed by maintenance atezolizumab 1200mg Day 1 every 21 days Carboplatin AUC 5-6 Day 1, Etoposide 80-100 mg /m2 Days 13, durvalumab 1500mg Day 1 q21 days x 4 cycles, followed by maintenance durvalumab 1500mg Day 1 q 28 days Cisplatin 75-80mg/m2 Day 1, Etoposide 8-100mg/m2 Days 1-3, durvalumab 1500mg Day 1 q21 days x 4 cycles followed by maintenance durvalumab 1500mg day 1 q28 days Adding immunotherapy to chemotherapy in SCLC increases OS by 2-3 months Treatment Summary SCLC • Limited Stage • Chemoradiation  5 yr survival 10-13% • Extensive Stage • Chemotherapy  5 yr survival 1-2% • • • • No role for surgery in SCLC No added benefit from adding a third chemotherapeutic drug to a platinum doublet Prolonged chemotherapy (after 4-6 cycles) has not been associated with improved results Immunotherapy with chemo followed by maintenance immunotherapy is beneficial NSCLC: Histologic Subtypes Adenocarcinoma (37 – 47%) • Most common type in non-smokers Squamous Cell carcinoma (25 – 32%) • • • • Slower growing Clear relationship with smoking 8 Go than adenocarcinoma Better prognosis Increased incidence of bleeding Large Cell Carcinoma (10 – 18% incidence) Non-Small Cell Lung Cancer Staging • Based on TNM Staging System – T=Tumor size – N=Nodal Involvement – M=Metastasis – TNM Staging System Predicts Survival NSCLC Prognosis 5 year survival by Stage • IA >70% • IB 60% • IIA 50% • IIB 30-40% • IIIA 10-30% • IIIB < 10% • IV < 5% The overall lung cancer five-year survival rate is 18.6 % Only 16 % of lung cancer cases are diagnosed at an early stage More than half of people with lung cancer die within one year of being diagnosed Distant MetastasisNSCLC Less likely than SCLC for developing distant metastasis early Metastasis to bone, brain, liver, adrenal glands Role of Surgery for NSCLC • Treatment of choice for NSCLC stages I or II, and some stage III disease • Treat with curative intent • Offers the best opportunity for long tem survival • Important prognostic factors: size of tumor, lymph node involvement, residual tumor in surgical margins • 5-yr survival following surgical resection • Stage I > 50% • Stage II > 35% • Stage IIIA ~ 20% Radiation Therapy in NSCLC • In medically inoperable patients, can be used with curative intent • Use for non-resectable tumor - fixed major blood vessel, trachea, esophagus • Adjuvant radiation in stage IIIA may confer a modest benefit. • May be used for palliation in advanced stage NSCLC Treatment for Early Stage (Stage I) NSCLC Surgical resection (pneumonectomy or lobectomy) is treatment of choice and provides best chance for cure Chemotherapy, platinum based, with or without radiation is usually not recommended Treat with curative intent Surgical Procedures for NSCLC Lobectomy: Removal of 1 lobe of the lung Pneumonectomy: Removal of whole lung http://www.meb.uni-bonn.de/cancer.gov Treatment dependent on ability to resect tumor and surgical margins Treatment of Locally Advanced NSCLC (Stage II, III) May utilize neoadjuvant or adjuvant chemotherapy and/or radiation If unresectable  chemoradiation Chemotherapy in Locally Advanced NSCLC Stage II - III • Adjuvant cisplatin-based chemotherapy is the standard of care in resected Stage II and IIIA NSCLC • Improves 5 year overall survival • Data from a large meta-analysis were inadequate to establish the • • • • • optimal cisplatin regimen NCCN recommended platinum doublets include: Pemetrexed/Cisplatin q 21 days (for nonsquamous) x 4 cycles • Pemetrexed 500mg/m2 IV on Day 1 • Cisplatin 75 mg/m2 IV Day 1 Cisplatin/Docetaxel q 21 days x 4 cycles (for squamous) • Cisplatin 75 mg/m2 IV Days 1 • Docetaxel 75 mg/m2 IV Day 1 A choice among these agents depends on the side effect profile and patient and provider preferences. All regimens can be used with sequential radiation therapy Summary of Cancer Care Ontario and ASCO Recommendations for Adjuvant Treatment of NSCLC Stage Chemotherapy Radiotherapy* IA Not recommended Not recommended IB Not recommended Not recommended IIA Cisplatin-based regimen Not recommended IIB Cisplatin-based regimen Not recommended IIIA Cisplatin-based regimen Not recommended-clinical trials ongoing *Radiotherapy will be recommended for patients with positive margins after resection. J Clin Oncol 35:2960-2974. 2017 by ASCO (American Society of Clinical Oncology) Cisplatin vs Carboplatin in NSCLC Carboplatin is often substituted for cisplatin in combination regimens for patients with advanced NSCLC due to its more favorable toxicity profile Evidence suggests cisplatin gives a higher objective response rate than carboplatin, although the survival benefit is small and may not be clinically meaningful Carboplatin appropriate for majority of patients with advanced disease, for whom quality of life is an important consideration Carboplatin valuable in patients with metastatic NSCLC in whom cisplatin is likely to be poorly tolerated (elderly patients, those with poor performance status, and those with significant comorbidities) Chemo Regimens for NSCLC Platinum based chemotherapy + radiation, with goal of downstaging the tumor for resection Treatment of NSCLC Stage IIIB (Unresectable): Duration of therapy should not exceed 8 cycles Concurrent versus sequential chemoradiation improved survival, but it is more toxic than sequential therapy Systemic Therapy for Advanced or Metastatic Disease • Drug regimen with highest likelihood of benefit with acceptable toxicity should be given as initial therapy • Two drug regimens are preferred; a third cytotoxic drug increases response rate but not survival • Maintenance Therapy • Therapy changes in the presence of driver mutations and elevated PD-L1 expression Stage IV 1st line Treatment Guiding Principles Targeted therapy is preferred first line treatment for patients who are found to have driver mutations, such as EGFR and ALK If no actionable mutations are found, then evaluate PD-L1 status for consideration of immunotherapy single-agent or in combination with systemic chemotherapy Patients who have contraindications to immunotherapy should receive chemotherapy without immunotherapy in the first line setting Major Genetic Mutations Involved in Pathogenesis of Lung Cancer, AKA “Driver Mutations” K-ras and EGFR EML4-ALK ROS1-Rearragement BRAF V600E Mutation PD-L1 Expression • Not a mutation, but PD-L1 positivity correlates with known alterations in NSCLC oncogenic tumor drivers. First Line Therapy Options for Stage IV Metastatic NSCLC Single agent pembrolizumab • PD-L1 expression ≥ 50%, negative results for EGFR mutations, BRAF V600E mutations, ALK and ROS1 rearrangements Pembrolizumab in combination with chemotherapy • FDA approved and NCCN Category 1 recommendation for pembrolizumab in combination with either carboplatin or cisplatin and pemetrexed for nonsquamous histologies irrespective of PD-L1 status • For squamous histology pembrolizumab +platinum + albumin bound paclitaxel Atezolizumab is also used first line in combination with chemotherapy Initial systemic therapy for non-small cell lung cancer Chemotherapy in Advanced Disease (Stage IV-Patients w/ No Driver Mutation) Not curable and not resectable if disseminated Chemotherapy increases overall survival & cost savings compared to best supportive care • Survival advantage 6-8 weeks • Improved quality of life • Improved time to progression Performance status predicts response/survival • PS 3-4, no benefit from chemotherapy Platinum based regimen should be given for 4 to 6 cycles Stage IV NSCLC Platinum Doublets • Cisplatin-based combination therapy • • • • Cisplatin + docetaxel Cisplatin + paclitaxel Cisplatin + pemetrexed Cisplatin + vinorelbine • Carboplatin-based combination therapy • • • • Carboplatin + nanoparticle albumin-bound paclitaxel Carboplatin + paclitaxel (± bevacizumab) Carboplatin + pemetrexed Carboplatin + docetaxel J Clin Oncol 35: 3484-3515 2017 by ASCO Stage IV- NSCLC • Vinorelbine (Navelbine) – often given with Cisplatin but can substitute with Carboplatin – Administration: • Vesicant, Not given intrathecally, Max dose 30 mg IV – Nadir: 18-23 Days; recovery by day 39 – Dose Modifications: • Hepatic only – Monitoring: • CBC w/diff, LFTs, Serum bilirubin – ADRs: BM suppression, peripheral neuropathy, severe constipation/ileus, fatigue Important Points to Remember in NSCLC Treatment • Primary treatment is with Platinum Doublets-no advantage to adding a third cytotoxic agent. • Optimal platinum-based regimen remains unclear, optimal duration of therapy is 46 cycles. • Treatment is for PS 0-2. Patients with PS 3-4 derive no benefit from therapy (some exceptions with targeted therapies) • Meta-analyses demonstrate survival advantage for chemotherapy compared to best supportive care (6-8 wk gain). One year survival increased by a mean of 16% (up to 40%) • Pay your taxes first! – Always infuse the taxane before the platinum (decreases toxicity, primarily myelosuppression and neurotoxicity) Maintenance Therapy Delivered following 4-6 cycles of chemotherapy in patients showing a response or those with stable disease Continuation maintenance = continuing at least one of the agents used in first line therapy, e.g., bevacizumab, pemetrexed or pembrolizumab or atezolizumab to progression or poor tolerability. Switch maintenance = initiation of a different agent such as pemetrexed or docetaxel Role of Pemetrexed (Alimta®) Multi-targeted antifolate • Inhibits at least 4 enzymes in folate metabolism and DNA synthesis (thymidine synthesis) issue Reallyabig go SE: Rash, myelosuppression, stomatitis, N/V, fatigue • Patients must receive at least 350 mcg p.o. daily of folic acid, and 1mg IM vitamin B12 q 9 weeks while on pemetrexed to reduce hematologic toxicity • Dexamethasone 4mg p.o. bid x 3 days starting day before chemo Day 1 to minimize skin toxicity. • Avoid aspirin and NSAIDS: Inhibit renal excretion of pemetrexed, resulting in ↑ toxicity FDA Approved Indications for Pemetrexed Use • Treatment of locally advanced or metastatic nonsquamous NSCLC as initial treatment in combination with cisplatin • Use as a single agent maintenance treatment after 4 cycles of platinum based doublet therapy • Use as second line agent • NOT indicated for squamous cell NSCLC – Pemetrexed has been proven to have inferior overall survival compared to other chemotherapy options in patients with squamous histology Curr Oncol. 2012 Feb; 19(1): e9–e15. Bevacizumab (Avastin®) • Bevacizumab is a recombinant humanized monoclonal antibody • MOA: Binds vascular endothelial growth factor (VEGF) and prevents it from binding to the VEGF receptors expressed on endothelial cells • SE: Hypertension, proteinuria, hemorrhage, GI perforation, wound healing complications • Impact of VEGF inhibition – Prevents angiogenesis – Decreases likelihood of metastasis • VEGF over expression is found in many cancers, including lung cancer Ncc firstline guideline Bevatplatiumbasedcoiskeybd ApthasECOOPI my Role of Bevacizumab in NSCLC Gosinglesmaintannaafter Chef • NCCN guidelines recommend bevacizumab in combination with platinum based doublet as first line therapy for advanced nonsquamous cell NSCLC, in patients with ECOG PS 0-1 • May also be used as single agent maintenance therapy after completion of chemotherapy • FDA indicated as first line therapy for Isunresectable, locally advanced, recurrent or metastatic non-squamous cell NSCLC in combination with carboplatin and paclitaxel • NOT indicated in the adjuvant setting Contraindications for Bevacizumab Squamous cell NSCLC – may cause hemoptysis Presence of untreated CNS metastasis Uncontrolled hypertension Severe proteinuria History of hemoptysis Poor wound healing Measure BP and check for proteinuria prior to each dose Treatment Summary NSCLC w/o Driver Mutations • Stage I • Surgical resection ±Chemotherapy (not recommended)  5yr survival: • • • • • • • • 60-70% Stage II Surgical resection Chemotherapy ± Radiation (not recommended) 5yr survival: 30-50% Stage III –Resectable Neoadjuvant chemo surgery ± Radiation + Chemotherapy  5yr survival 10-30% Stage III unresectable Chemoradiation 5 yr survival: 10% Stage IV Chemotherapy ± Immunotherapy x 4-6 cycles Maintenance therapy  5 year survival < 5% Platinum Agents • Mechanism of action similar to alkylating agents – Formation of intrastrand cross links with DNA or RNA • Agents – Cisplatin – Carboplatin – Oxaliplatin-not indicated in lung cancer Platinum Toxicities & Dosing • Cisplatin – – – – – – – – Nephrotoxicity Electrolyte wasting Nausea & vomiting (delayed) Ototoxicity Neuropathy Myelosuppression Dosed based on BSA Dose should generally never exceed 50mg/m2/week (low dose vs. high dose) • Carboplatin – – – – Thrombocytopenia Neutropenia Nausea & vomiting Hypersensitivity-delayed (7-8 doses) – Nephrotoxicity – Dose based on Calvert equation: Dose = (CrCl + 25) x target AUC – A single dose should generally not exceed 900mg • Dose higher in pediatric patients • Rarely some adult protocols call for AUC 7 or 8 Platinum Toxicities Toxicity Cis Carbo Delayed Hypersens X Myelosuppression X Nephrotoxicity X Neurotoxicity X Ototoxicity X Nausea & vomiting XXX Oxali X X XX XX 58 Carboplatin Delayed Hypersensitivity Reaction (HSR) • Incidence of carboplatin induced HSR have been reported widely ranging from 1% to 35% depending upon the severity and grade • Usually occurs after the 7th or 8th exposure to the drug • These reactions could be acute, which manifests within a couple of minutes or delayed, which happens after a couple of hours or days after receiving the drug • Pattern of hypersensitivity constitutes a broad spectrum, which may be varied from mild to severe life-threatening reactions – Mild: Flushing, rash, itching, diaphoresis, facial edema, fever, chills. – Serious/life threatening: hypertension/hypotension, tachycardia, breathlessness, chest pain, palpitation, altered sensorium, wheezing, stridor, laryngeal edema, shock Carboplatin Delayed Hypersensitivity Reaction (HSR) • Exact mechanism of carboplatin induced hypersensitivity is yet to be elucidated • Repeated exposure to low dose free platinum metal, which is present as impurity or contaminant in the drug is the likely culprit • This analogy holds true from allergic manifestation in platinum mining workers and explains why allergic manifestation develop after median seven cycles of carboplatin due to gradual exposure to low metal concentration. • If treatment with carboplatin is crucial, desensitization may be attempted using slow infusions of dilutions of the clinical formulation: 1:1000, then 1:100, then 1:10, and lower dilutions as tolerated until infusion is complete • This approach is successful in up to 50% of patients Hypersensitivity reactions to carboplatin.Markman M Gynecol Oncol. 2002 Feb; 84(2):353-4. Lenz, HJ. Management and Preparedness for infusion and hypersensitivity reactions. Oncologist 2007; 12: 601 -609. Example Carboplatin Desensitization Protocol • Desensitization Protocol Premedication: – Dexamethasone: 8–12 mg (i.v.) single dose immediately before the infusion of carboplatin – Ondansetron hydrochloride: 24 mg (i.v.) single dose immediately before the infusion of carboplatin • Carboplatin—each solution diluted in 150 mL D5W (Total dose=500mg) – – – – 1/1000 (0.5mg) of the total dose—in 150 mL D5W over 1.5 hrs. If tolerated: 1/100 (5mg) of the total dose—in 150 mL D5W over 1.5 hrs. If tolerated: 1/10 (50mg) of the total dose in—150 mL D5W over 1.5 hrs. If tolerated: The remainder of the dose (444.5mg) in—150 mL D5W over 1.5 hrs. • 0.5mg+5mg+50mg=55.5mg • 500mg-55.5mg=444.5mg Cancer 2005;104:640 –3. © 2005 American Cancer Society . Cisplatin Induced Ototoxicity Reports demonstrate some degree of hearing loss in 75–100% of cisplatin-treated patients This makes ototoxicity the most common dose-limiting side effect of cisplatin behind N/V without prophylaxis Several areas of the cochlea are damaged, resulting in hearing impairment The mechanisms appear to involve the production of reactive oxygen species (ROS), which can trigger cell death Baseline audiology exam and periodic evaluations during therapy are recommended Cisplatin is contraindicated in patients with pre-existing hearing deficit Hear Res. 2007 Apr;226(1-2):157-67. Epub 2006 Nov 17. Cisplatin Induced Neurotoxicity Usually seen in the form of peripheral sensory neuropathy Paresthesias and numbness occur in a classic stocking-glove pattern Tends to occur after several cycles of therapy and risk increases with cumulative doses May be irreversible The platinum drugs appear to effect the axons, myelin sheath, neuronal cell body and the glial structures of the neurons At the cellular level, the chemotherapy interferes with DNA replication and metabolic function of the neurons Platinum-based agents have the propensity to enter the dorsal root ganglia and peripheral nerves as opposed to the brain, as these drugs have poor penetration through the blood-brain barrier Mol Cancer Ther. 2009 Jan; 8(1): 10–16. Cisplatin Induced Nephrotoxicity • Dose limiting toxicity in 35-40% of patients • Dose related, and usually seen 10-20 days after therapy • Electrolyte abnormalities are common: – Hypomagnesemia – Hypokalemia • Optimal administration requires concurrent saline hydration and mannitol (this is still controversial) diuresis to minimize the likelihood of potentially lethal damage to the kidneys • Cisplatin, Mannitol, K+ and Mg++ may all be mixed in the same bag of NS • Multiple mechanisms contribute to cisplatin nephrotoxicity, but concentrations within the kidney exceed those in blood suggesting an accumulation of drug by renal parenchymal cells via active transport mechanisms Toxins (Basel). 2010 Nov; 2(11): 2490–2518. Treatment in the Presence of Driver Mutations K-ras and EGFR (Epidermal Growth Factor Receptor) Mutations • K-ras (Kirsten rat sarcoma) mutations in adenocarcinoma exclusive to smokers – Overall frequency in NSCLC = 10-30% – Predicts primary resistance to EGFR tyrosine kinase inhibitors – Prognostic of poor survival • EGFR mutations (exon 19 deletions or exon 21 substitution mutations) activate the tyrosine kinase pathway, leading to increased cell proliferation, motility, and invasion. – Overall frequency in NSCLC = 10-15% – The T790M mutation has been found in approximately 50% of patients who develop resistance to erlotinib and it may also occur without tyrosine kinase inhibitor-based therapy – 32% of Asian patients with NSCLC have an EGFR mutation vs. 7% in patients of all other ethnicities – Often non-smokers, female • K-ras and EGFR mutations are mutually exclusive Treatment in the Presence of Driver Mutations EGFR mutation positive — Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as single agents is indicated for the initial management of patients whose tumors contain an activating mutation in EGFR, regardless of PS In this setting, first-line treatment with an EGFR TKI improves progression-free survival compared with standard platinum-based chemotherapy. In the absence of significant toxicity, treatment with an EGFR TKI is continued until there is evidence of progression. Treatment may be used for PS 0-4 EGFR TKI for NSCLC Treatment Eon Drug Trade Name Dose Associated Facts Afatinib Gilotrif 40mg p.o. daily Highest incidence of diarrhea e Erlotinib Tarceva 150mg p.o. daily Avoid use with as PPIs/H2 blockers Gefitinib Iressa 250mg p.o. daily Avoid use with PPIs/H2 blockers Osimertinib* Tagrisso 80mg p.o. daily Confirm T790M EGFR mutation status in pretreated Dacomitinib Vizimpro 45mg p.o. daily Severe & fatal diarrhea has occurred D *All agents are considered first line by NCCN, but osimertintib is preferred The T790M EGFR mutation is associated with acquired resistance to EGFR TKI therapy This resistance occurs in approximately 60% of patients who initially respond to therapy EGFR TKI Class Side Effects A papulopustular rash that erupts most often on the face but can also be seen on the chest, back, trunk, and limbs. Diarrhea (May be severe) Drug interactions with CYP3A4 inhibitors/inducers requiring dose adjustments Avoid PPIs/H2 blockers with some agents Acneiform Rash Induced by EGFR Inhibitors The acneiform rash is characterized by erythematous papules and pustules that develop on the face, scalp, and upper trunk within the first month in > 90% of patients Not only does the rash have a cosmetic impact, but it is frequently associated with pain, infections, and pruritus The mechanism of rash development is primarily inflammatory, but approximately 30% of patients develop secondary bacterial infections, with hallmarks such as purulent discharge and yellow crusting http://www.ascopost.com/issues/may-15-2013/prevention-and-treatment-of-acneiform-rash-caused-by-egfr-inhibitors/ Acneiform Rash Induced by EGFR Inhibitors • Prevention of acneiform rash caused by EGFR inhibitors includes topical corticosteroids: – Hydrocortisone 2.5% – Alclometasone 0.05% • Oral antibiotics: – – – – Minocycline Doxycycline Other antibiotics covering skin flora Taken twice daily for at least the first 6 weeks of EGFR therapy • This results in a reduction of grade 2 and greater skin toxicities by more than 50% • In addition, these measures lessen the need to modify the dose of the EGFR inhibitor http://www.ascopost.com/issues/may-15-2013/prevention-and-treatment-of-acneiform-rash-caused-by-egfr-inhibitors/ Has NCCN recommendation for continuation of therapy in asymptomatic disease progression e Erlotinib Dose adjustment for concomitant smoking: • If smoking is unavoidable, increase dose at 2 week intervals in 50mg increments to max dose of 300mg. GE • Reduce dose to recommended starting dose upon smoking cessation EML4-ALK Mutation: • Mutation causes fusion oncogene EMLA4-ALK, which drives cancer cell growth and proliferation independently in 4-8% of NSCLC patients • Clinical features include – adenocarcinoma histology (97%), no/light smoking history, younger age (median age of ALK + patients = 52 years) • ALK inhibitors selectively inhibit ALK (Anaplastic lymphoma kinase) tyrosine kinase, which reduces proliferation of cells expressing this genetic alteration EML4-ALK Mutation Positive (ALK positive disease) • For patients with advanced NSCLC whose tumors contain the anaplastic lymphoma kinase (ALK) fusion oncogene, treatment with an ALK TKI is the preferred treatment • NCCN recommends the following agents as first line therapy in patients with the ALK mutation: • • • • • Alectinib (Alecensa®)* Brigatinib (Alunbrig®)* Lorlatinib (Lorbrena®)* Ceritinib (Zykadia®) Crizotinib (Xalkori®) EDNUQ • Class side effects of ALK inhibitors: Edema, diarrhea, nausea, vision disorders, QTc prolongation • Treatment is for patients with PS 0-4 Treatment in ROS1 Rearrangement NSCLC •Crizotinib(Xalkori®) •Ceritinib (Zykadia®) •Entrectinib (Rozlytrek®) •Treat regardless of PS Treatment in ROS1 Rearrangement NSCLC • Crizotinib (Xalkori) – Moderate emetogen – Administration – With or without food – Drug Interactions – CYP3A4 substrate and inhibitor – Monitoring – CBC w/diff, EKG, HR and BP, ocular toxicity – ADRS – EDEMA, bradycardia, neutropenia, diarrhea, constipation, hypophosphatemia, blurred vision, cardiac arrhythmia, PE, fever, and hepatotoxicity PD-L1 Expression • Programmed cell death ligand 1(PD-L1), the primary ligand of PD-1, is upregulated in different types of tumors, including NSCLC • PD-1 is a key immune checkpoint receptor expressed on the surface of activated T, B and NK cells and plays a crucial role in tumor immune escape • PD-L1 expression is an unfavorable prognostic factor for nonsmall cell lung cancer • PD-1 and PD-L1 inhibitors are also referred to as “checkpoint inhibitors” www.nature.com/articles/s41598-017-10925-7 Immune Therapy in NSCLC • PD-1 Inhibitors approved in NSCLC: – Pembrolizumab – Nivolumab (+/- Ipilimumab) – PD-L1 Inhibitors approved in NSCLC: – Atezolizumab – Durvalumab – In general, if there is no contraindication to the use of immune therapy, then checkpoint inhibitors are used front line regardless of PD-L1 expression status*: • If PD-L1 expression ≥ 50%, pembrolizumab alone • If PD-L1 expression 1-49% immune therapy + chemo *May include active or previously documented autoimmune disease and/or current use of immunosuppressive agents or presence of an oncogene which would predict lack of benefit. PD-L1 Expression • High PD-L1 expression — For patients with at least 50 % tumor cell staining for PD-L1 and without contraindications to immunotherapy (e.g., connective tissue, rheumatologic, or interstitial lung disease), first-line treatment should begin with: • Pembrolizumab(Keytruda®) as monotherapy, and should be continued until progression or intolerable toxicity occurs. Class Effects of PD-1 and PDL1 inhibitors • Despite important clinical benefits, checkpoint inhibition is • • • • associated with a unique spectrum of side effects termed immunerelated adverse events (irAEs): These drugs cause “Anything-itis” 2Diarrhea/Colitis It'Iflammationoflargeintestine 3Pneumonitis KDinflamation a Endocrinopathies –s Hyper, hypothryroidism (no steroids for this) –G Type I Diabetes –7 Adrenal insufficiency – Treatment is with high dose steroids tapered over 4-6 weeks Durvalumab (Imfinzi®) • Monoclonal antibody PD-L1 inhibitor • NCCN recommends as consolidation therapy for unresectable, locally advanced NSCLC beginning within 6 weeks of chemoradiotherapy in patients who had concurrent chemotherapy and radiation as their initial treatment • The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months with placebo • Note: no measurement of PD-L1 expression is necessary N Engl J Med 2017; 377:1919-1929 November 16, 2017 Immunotherapy for no previous IO or chemo for previous IO Wrap Up • • • • • • Epidemiology – Small cell and Non-small cell Molecular Markers Clinical Presentation and Diagnosis Small Cell Lung Cancer – Less common – More aggressive – Traditional chemotherapy w/wout XRT Earlier Stages – surgery, RT w/wout chemo Advanced/Metastatic – determine molecular markers and if appropriate for targeted therapy