Management ofAlexander Drilon MDThoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNon Small-CellLung CancersT...
Leading cause of cancerdeath• 7 out of 10 of patients will dieof disease• 220K cases/year in the US• 160K deaths/year• mor...
history
Lung Cancer: a 20th Century Epidemic• 20 year latency period• 1910: widespreadmanufacturing of cigarettes• 1930s: ↑ incide...
Doll and Hill:BritishDoctors Studycausal relationship establishedin the 1950s• 1964 Surgeon General’s Warning
SurgeonGeneral’sWarningBritishDoctor’sStudylung cancer mortality• ↓ in men• plateaued in women
etiology
Smoking accounts for 90% ofall lung cancers• risk associated with pack-year history and age ofinitiation• 10-15 years to r...
05101520253035Smoking +AsbestosSmoking Passive Smoke Asbestos RadonRelative Risk of Developing Lung Cancer
screeninglung CA
CXR and sputum cytology• Johns Hopkins• Memorial Sloan-Kettering• no mortality benefit
• n=31,567 patientsscreened• annual low-dose helicalchest CT scans• 484 patients diagnosed• 85% with Stage I disease• surv...
lead timelengthtime
overdiagnosis bias
• POPULATION• age 55 to 74• heavy smoker or formersmoker (quit within last15 years)• no prior cancer withinpast 5 years• 5...
histologyNSCLC
• Adenocarcinoma• Squamous Cell Carcinoma• Large Cell Carcinoma87%NSCLCSCLC
Adenocarcinoma• Most common histology (40%)• Least associated with smoking, butmajority who get it have been exposedto cig...
Squamous Cell• Second most common (30%)• most common histology until 1987• 90% associated with cigarettesmoking• P63 (p40)...
Large Cell• Least common subtype (11%)• associated with gynecomastia• advances in histopathologic technique: reclassificat...
stagingNSCLC
Stage Clinical Stage Pathologic StageIA 50 73IB 43 58IIA 36 46IIB 25 36IIIA 19 24IIIB 7 9IV 2 13International System for S...
Stage IIIb Stage IV
workup
Clinical Staging• PET/CT chest and upper abdomen, bone scan• MRI Brain: node-negative disease >3cm or node-positivedisease...
PET-positive lymphnodeslymph nodes largerthan 1 cm on CTregardless of FDGuptakeMediastinalEvaluation
Mediastinoscopy
Endoscopic Biopsy
Transbronchial Biopsy
managementNSCLCsurgery
Stage IaIbStage IIaIIbSURGERYSURGERY CHEMONSCLC Management: Stage I and II
Surgical ApproachWedge ResectionFVC < 1.5 L
Surgical ApproachLobectomyFVC at least 1.5 L
Surgical ApproachPneumonectomyFVC at least 2L
Preoperative EvaluationStereotactic Body RT>60 Gy, good local control ratespatients who are poorsurgical candidates
managementNSCLCsurgeryadjuvant chemo
Stage IaIbStage IIaIIbSURGERYSURGERY CHEMONSCLC Management: Stage I and II
RCTs: Adjuvant ChemoIALTLe Chevalier2003• Cisplatin + Etop/Vinor/Vinblas/Vindes• PORT allowed• Increased DFS, median OS, O...
Meta-Analyses: Adjuvant ChemoHottaJCO2004• Cisplatin-based chemo, Uracil-Tegafur• N= 5,716• Increased OS, HR 0.87LACEPigno...
SURGERY CHEMO4 Cycles of Therapy• Cisplatin + Vinorelbine• Cisplatin + Docetaxel• Cisplatin + Gemcitabine• Cisplatin + Pem...
managementNSCLCmodalitymultitherapy
Stage IIIaIIIbCHEMOCHEMORADIATIONSURGERYNSCLC ManagementRTsequence of treatments is variable
ChemoRT in Unresectable Stage IIIFuruse 1999 JCO
Stage IaIbStage IIaIIbStage IIIaIIIbStage IVSURGERYCHEMOCHEMORADIATIONSURGERY CHEMOSURGERYCHEMONSCLC ManagementRT
managementNSCLCchemotherapy
02468101214Median Overall Survival in Months
Systemic Therapy: Cisplatin Doublet2 drugs >1 drug• Lilenbaum Semin Onc 99• Lilenbaum ASCO 02• Sederholm Semin Onc 022 dru...
Systemic Therapy: Histology Matters• PEMETREXED: non-squamous histology• GEMCITABINE: squamous histology• PACLITAXEL, VINO...
Switch Maintenance• Increased PFS, Median OS 10.6  13.4 mos (2.8 mo)Ciuleneau Lancet 2009platinum-basedtherapy Pemetrexed...
managementNSCLCtargetedtherapy
Antiangiogenic Therapy
• BEVACIZUMABtill progressionof disease• Median OS 10.3 12.3 mos
Epidermal Growth Factor Receptor
Cetuximab• Monoclonal antibody to EGFR• 60-80% of lung cancers express EGFRon their surface (viaimmunohistochemistry)• FLE...
erlotinibgefitinibtyrosine kinase inhibitorscompetitive ATP inhibitors
POPULATION: IIIB or IVadenoCA, never or lightsmokers, Asian, untreatedRESPONSE RATE: gefitinib(43%) vs. chemo (32%)RESPONS...
RR 73% vs. 33% PFS 10.8 vs. 5.4 mos p < 0.001
conserved LREAmotifsmall in-framedeletions residues747-750pointmutationmissensemutationPFS 14.6monthsPFS 9.7months
TKI Resistance
EML4-ALK Inhibition
ALK-Rearranged Lung CancersSoda et al Nature 2007, Takeuchi CCR 2008, www.mycancergenome.orgCamidge et al Lancet Oncol 201...
crizotinib
ALK-Rearranged Lung Cancers
1999200420092012Timeline of Putative DriverEvent Discovery
LUNG CANCERSCarcinoidLarge CellLarge Cell Neuroendocrine5%
TISSUE IS THE ISSUELung cancer is NOT one disease.
Crizotinib in ROS1-Rearranged Lung Cancer
PI3K and MEK Inhibition in KRAS-Mutant Lung Cancer68/M former smoker with advanced KRAS G12D-mutant lung cancer– BKM120 (P...
Immune Checkpoint BlockadeRibas NEJM 2012, 366:2517-2519ipilimumab Nivolumab, MK-3475
• BMS-936558/Nivolumab• 122 advanced non-small cell lung carcinomas (total n=296)• heavily pre-treated patients• response ...
youthank
NSCLC housestaff
NSCLC housestaff
NSCLC housestaff
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NSCLC housestaff

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  • ALK – RTK, normal dev’t and function of the nervous systemIn the initial phase I trial, patients whose tumors harbored an ALK fusion displayed a 60.8% radiographic objective response rate to the dual ALK/MET tyrosine kinase inhibitor (TKI), crizotinib (Camidge et al. 2012). Median progression-free survival was demonstrated to be 9.7 months, and the probability of PFS at six months was estimated to be 87.9%. An international phase III trial randomizing patients with advanced lung cancer harboring ALK fusions to crizotinib vs. standard chemotherapy (docetaxel or pemetrexed) after disease progression on first-line treatment has recently been completed, and preliminary results support this survival benefit for crizotinib therapy (Shaw et al. 2012).Background Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) are associated with marked clinical responses to crizotinib, an orally available tyrosine kinase inhibitor targeting ALK. This global randomized phase III study compared the efficacy and safety of crizotinib (C) with standard chemotherapy (pemetrexed or docetaxel [P/D]) as 2nd-line therapy for patients (pts) with advanced ALK+ NSCLC.Methods Between Feb 2010 and Feb 2012, 347 pts with stage IIIB/IV ALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive C 250 mg PO BID (n = 173) or either P 500 mg/m2or D 75 mg/m2 IV q3w (n = 174; 58% P, 42% D). ALK was detected by FISH in a central lab. Pts with progressive disease on P/D were offered C on PROFILE 1005. The primary endpoint was progression-free survival (PFS) per independent radiologic review; secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes.Results The study met its primary objective by demonstrating the superiority of C over P/D in prolonging PFS (median 7.7 vs 3.0 mo; HR 0.49; 95% CI 0.37–0.64; P &lt; 0.0001). ORR was significantly higher in pts treated with C (65% vs 20%; P &lt; 0.0001). Interim analysis of OS (28% events) showed no statistically significant difference between C and P/D (preliminary median estimate 20.3 vs 22.8 mo; HR 1.02; 95% CI 0.68–1.5; P = 0.5394), but was not adjusted for crossover (108 pts [62%] crossed over to C). The most common treatment-related adverse events (TRAE) with C were visual disturbance (59%), diarrhea (53%), nausea (52%), vomiting (44%), and elevated transaminases (36%), and with P/D, nausea (35%), fatigue (29%), neutropenia (22%), decreased appetite (21%), and alopecia (20%). The incidence of grade 3/4 TRAE was the same for C vs P/D (31%). The incidence of TRAE leading to discontinuation was 6% for C vs 10% for P/D. Duration of treatment was longer for C vs P/D (median cycles started 11 vs 4).Conclusions C showed significant improvement in PFS and ORR compared with P/D and had an acceptable safety profile. These findings establish C as the standard of care for pts with previously treated advanced ALK+ NSCLC
  • ALK – RTK, normal dev’t and function of the nervous systemIn the initial phase I trial, patients whose tumors harbored an ALK fusion displayed a 60.8% radiographic objective response rate to the dual ALK/MET tyrosine kinase inhibitor (TKI), crizotinib (Camidge et al. 2012). Median progression-free survival was demonstrated to be 9.7 months, and the probability of PFS at six months was estimated to be 87.9%. An international phase III trial randomizing patients with advanced lung cancer harboring ALK fusions to crizotinib vs. standard chemotherapy (docetaxel or pemetrexed) after disease progression on first-line treatment has recently been completed, and preliminary results support this survival benefit for crizotinib therapy (Shaw et al. 2012).Background Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) are associated with marked clinical responses to crizotinib, an orally available tyrosine kinase inhibitor targeting ALK. This global randomized phase III study compared the efficacy and safety of crizotinib (C) with standard chemotherapy (pemetrexed or docetaxel [P/D]) as 2nd-line therapy for patients (pts) with advanced ALK+ NSCLC.Methods Between Feb 2010 and Feb 2012, 347 pts with stage IIIB/IV ALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive C 250 mg PO BID (n = 173) or either P 500 mg/m2or D 75 mg/m2 IV q3w (n = 174; 58% P, 42% D). ALK was detected by FISH in a central lab. Pts with progressive disease on P/D were offered C on PROFILE 1005. The primary endpoint was progression-free survival (PFS) per independent radiologic review; secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes.Results The study met its primary objective by demonstrating the superiority of C over P/D in prolonging PFS (median 7.7 vs 3.0 mo; HR 0.49; 95% CI 0.37–0.64; P &lt; 0.0001). ORR was significantly higher in pts treated with C (65% vs 20%; P &lt; 0.0001). Interim analysis of OS (28% events) showed no statistically significant difference between C and P/D (preliminary median estimate 20.3 vs 22.8 mo; HR 1.02; 95% CI 0.68–1.5; P = 0.5394), but was not adjusted for crossover (108 pts [62%] crossed over to C). The most common treatment-related adverse events (TRAE) with C were visual disturbance (59%), diarrhea (53%), nausea (52%), vomiting (44%), and elevated transaminases (36%), and with P/D, nausea (35%), fatigue (29%), neutropenia (22%), decreased appetite (21%), and alopecia (20%). The incidence of grade 3/4 TRAE was the same for C vs P/D (31%). The incidence of TRAE leading to discontinuation was 6% for C vs 10% for P/D. Duration of treatment was longer for C vs P/D (median cycles started 11 vs 4).Conclusions C showed significant improvement in PFS and ORR compared with P/D and had an acceptable safety profile. These findings establish C as the standard of care for pts with previously treated advanced ALK+ NSCLC
  • High PDL1 expression in placenta, endothelium, heart, lung, and liverPDL1 in ovarian, melanoma, renal cell, lung, pancreas, cervix, urothelialPDL2 on macrophages, dendritic cells, not common on non-lymphoid
  • NSCLC housestaff

    1. 1. Management ofAlexander Drilon MDThoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNon Small-CellLung CancersThe following material is intended for MSKCC internal medicine housestaff teaching purposesonly. The slides are courtesy of Dr. Anne Covey and were updated for the LibGuide in 2012-2013.
    2. 2. Leading cause of cancerdeath• 7 out of 10 of patients will dieof disease• 220K cases/year in the US• 160K deaths/year• more deaths than colorectaland breast cancers combined• majority with advanced diseaseat diagnosis• high recurrence rates in early-stage disease
    3. 3. history
    4. 4. Lung Cancer: a 20th Century Epidemic• 20 year latency period• 1910: widespreadmanufacturing of cigarettes• 1930s: ↑ incidence in men• 1960s: ↑ incidence inwomen after WW2
    5. 5. Doll and Hill:BritishDoctors Studycausal relationship establishedin the 1950s• 1964 Surgeon General’s Warning
    6. 6. SurgeonGeneral’sWarningBritishDoctor’sStudylung cancer mortality• ↓ in men• plateaued in women
    7. 7. etiology
    8. 8. Smoking accounts for 90% ofall lung cancers• risk associated with pack-year history and age ofinitiation• 10-15 years to reduce riskby 75% but neverapproaches zero• N-nitrosamines &polycyclic aromatichydrocarbonsOther causes• Radon, asbestos, nickel, radiation
    9. 9. 05101520253035Smoking +AsbestosSmoking Passive Smoke Asbestos RadonRelative Risk of Developing Lung Cancer
    10. 10. screeninglung CA
    11. 11. CXR and sputum cytology• Johns Hopkins• Memorial Sloan-Kettering• no mortality benefit
    12. 12. • n=31,567 patientsscreened• annual low-dose helicalchest CT scans• 484 patients diagnosed• 85% with Stage I disease• survival was 92% at 10years (stage I cancerresected within a month)• historical standard of 75%at 5 years
    13. 13. lead timelengthtime
    14. 14. overdiagnosis bias
    15. 15. • POPULATION• age 55 to 74• heavy smoker or formersmoker (quit within last15 years)• no prior cancer withinpast 5 years• 53,454 patientsrandomized• CXR vs. low dose helicalCT scan• annual imaging x 3• 3% of scans led to diagnosis oflung CA, NNS 288, falsepositive rate = 23 %National Lung Screening Trial20% reduction inlung cancermortality7% reductionin all causemortality
    16. 16. histologyNSCLC
    17. 17. • Adenocarcinoma• Squamous Cell Carcinoma• Large Cell Carcinoma87%NSCLCSCLC
    18. 18. Adenocarcinoma• Most common histology (40%)• Least associated with smoking, butmajority who get it have been exposedto cigarette smoke (70%)• TTF1-positive on IHCLocation• peripheral, scar tissuePresentation• frequently metastaticdisease• hypertrophicosteoarthropathy, Trosseau’s• BAC: multiple pulmonarynodules
    19. 19. Squamous Cell• Second most common (30%)• most common histology until 1987• 90% associated with cigarettesmoking• P63 (p40) positive on IHC• Presentation• centrally located mass  nowshifting• most common histology in Pancoasttumors• PTHrP: hypercalcemia
    20. 20. Large Cell• Least common subtype (11%)• associated with gynecomastia• advances in histopathologic technique: reclassification ofundifferentiated large cell tumors to adenoCA or SCC
    21. 21. stagingNSCLC
    22. 22. Stage Clinical Stage Pathologic StageIA 50 73IB 43 58IIA 36 46IIB 25 36IIIA 19 24IIIB 7 9IV 2 13International System for StagingPercent Surviving at 5 Years
    23. 23. Stage IIIb Stage IV
    24. 24. workup
    25. 25. Clinical Staging• PET/CT chest and upper abdomen, bone scan• MRI Brain: node-negative disease >3cm or node-positivedisease, brain metastases incidence 10-15%
    26. 26. PET-positive lymphnodeslymph nodes largerthan 1 cm on CTregardless of FDGuptakeMediastinalEvaluation
    27. 27. Mediastinoscopy
    28. 28. Endoscopic Biopsy
    29. 29. Transbronchial Biopsy
    30. 30. managementNSCLCsurgery
    31. 31. Stage IaIbStage IIaIIbSURGERYSURGERY CHEMONSCLC Management: Stage I and II
    32. 32. Surgical ApproachWedge ResectionFVC < 1.5 L
    33. 33. Surgical ApproachLobectomyFVC at least 1.5 L
    34. 34. Surgical ApproachPneumonectomyFVC at least 2L
    35. 35. Preoperative EvaluationStereotactic Body RT>60 Gy, good local control ratespatients who are poorsurgical candidates
    36. 36. managementNSCLCsurgeryadjuvant chemo
    37. 37. Stage IaIbStage IIaIIbSURGERYSURGERY CHEMONSCLC Management: Stage I and II
    38. 38. RCTs: Adjuvant ChemoIALTLe Chevalier2003• Cisplatin + Etop/Vinor/Vinblas/Vindes• PORT allowed• Increased DFS, median OS, OS at 5yr by 4%NCICWinstonNEJM 2005• Cisplatin + Vinorelbine• Median OS from 73  94 months (21 mos)• Increased OS at 5yr by 15%FranceDouilliardLancet Onc 2006• Cisplatin + Vinorelbine• Median OS from 43  65 months (12 mos)
    39. 39. Meta-Analyses: Adjuvant ChemoHottaJCO2004• Cisplatin-based chemo, Uracil-Tegafur• N= 5,716• Increased OS, HR 0.87LACEPignonJCO 2008• Cisplatin-based chemo• N=4,500• Stage IB HR 0.92, Stage II HR 0.83, Stage III HR 0.83
    40. 40. SURGERY CHEMO4 Cycles of Therapy• Cisplatin + Vinorelbine• Cisplatin + Docetaxel• Cisplatin + Gemcitabine• Cisplatin + PemetrexedAdjuvant Chemotherapy
    41. 41. managementNSCLCmodalitymultitherapy
    42. 42. Stage IIIaIIIbCHEMOCHEMORADIATIONSURGERYNSCLC ManagementRTsequence of treatments is variable
    43. 43. ChemoRT in Unresectable Stage IIIFuruse 1999 JCO
    44. 44. Stage IaIbStage IIaIIbStage IIIaIIIbStage IVSURGERYCHEMOCHEMORADIATIONSURGERY CHEMOSURGERYCHEMONSCLC ManagementRT
    45. 45. managementNSCLCchemotherapy
    46. 46. 02468101214Median Overall Survival in Months
    47. 47. Systemic Therapy: Cisplatin Doublet2 drugs >1 drug• Lilenbaum Semin Onc 99• Lilenbaum ASCO 02• Sederholm Semin Onc 022 drugs <3 drugs• Crimo JCO 99• Soguet Ann Onc 02• Greco Cancer 02Cisplatin >Carboplatin• Belani Semin Onc 01• Rosell Ann Onc 02• Ardizonni Meta JNCI 07• Hotta Meta JCO 04
    48. 48. Systemic Therapy: Histology Matters• PEMETREXED: non-squamous histology• GEMCITABINE: squamous histology• PACLITAXEL, VINORELBINE: any histology
    49. 49. Switch Maintenance• Increased PFS, Median OS 10.6  13.4 mos (2.8 mo)Ciuleneau Lancet 2009platinum-basedtherapy Pemetrexed• Increased PFS, Median OS 11  12 mos (2 mo)Cappuzzo Saturn Trialplatinum-basedtherapy Erlotinib
    50. 50. managementNSCLCtargetedtherapy
    51. 51. Antiangiogenic Therapy
    52. 52. • BEVACIZUMABtill progressionof disease• Median OS 10.3 12.3 mos
    53. 53. Epidermal Growth Factor Receptor
    54. 54. Cetuximab• Monoclonal antibody to EGFR• 60-80% of lung cancers express EGFRon their surface (viaimmunohistochemistry)• FLEX: Cis/Vin ± Cetuximab• ↑ benefit with H-score>300Increased OS by 13%HR 0.871Cetuximab 400mg
    55. 55. erlotinibgefitinibtyrosine kinase inhibitorscompetitive ATP inhibitors
    56. 56. POPULATION: IIIB or IVadenoCA, never or lightsmokers, Asian, untreatedRESPONSE RATE: gefitinib(43%) vs. chemo (32%)RESPONSE RATE (EGFRMutant): gefitinib (71%)vs. chemo (47%)QUALITY OF LIFE: better ingefitinib arm
    57. 57. RR 73% vs. 33% PFS 10.8 vs. 5.4 mos p < 0.001
    58. 58. conserved LREAmotifsmall in-framedeletions residues747-750pointmutationmissensemutationPFS 14.6monthsPFS 9.7months
    59. 59. TKI Resistance
    60. 60. EML4-ALK Inhibition
    61. 61. ALK-Rearranged Lung CancersSoda et al Nature 2007, Takeuchi CCR 2008, www.mycancergenome.orgCamidge et al Lancet Oncol 2012, Shaw et al Ann Oncol 2012
    62. 62. crizotinib
    63. 63. ALK-Rearranged Lung Cancers
    64. 64. 1999200420092012Timeline of Putative DriverEvent Discovery
    65. 65. LUNG CANCERSCarcinoidLarge CellLarge Cell Neuroendocrine5%
    66. 66. TISSUE IS THE ISSUELung cancer is NOT one disease.
    67. 67. Crizotinib in ROS1-Rearranged Lung Cancer
    68. 68. PI3K and MEK Inhibition in KRAS-Mutant Lung Cancer68/M former smoker with advanced KRAS G12D-mutant lung cancer– BKM120 (PI3K inhibitor) + MEK-162 (MEK inhibitor)– After 3 weeks: decreased perihilar mass and R-sided pulmonarynodules, complete resolution of pain/respiratory symptoms
    69. 69. Immune Checkpoint BlockadeRibas NEJM 2012, 366:2517-2519ipilimumab Nivolumab, MK-3475
    70. 70. • BMS-936558/Nivolumab• 122 advanced non-small cell lung carcinomas (total n=296)• heavily pre-treated patients• response rate: 16%
    71. 71. youthank

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