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- 1. Management of Alexander DrilonMD Thoracic Oncology Service Memorial Sloan Kettering Cancer Center Non Small-Cell Lung Cancers The following material is intended for MSKCC internal medicine housestaff teaching purposes only. The slides are courtesy of Dr. Anne Covey and were updated for the LibGuide in 2012-2013.
- 2. Leading cause ofcancer death • 7 out of 10 of patients will die of disease • 220K cases/year in the US • 160K deaths/year • more deaths than colorectal and breast cancers combined • majority with advanced disease at diagnosis • high recurrence rates in early- stage disease
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- 4. Lung Cancer: a20th Century Epidemic • 20 year latency period • 1910: widespread manufacturing of cigarettes • 1930s: ↑ incidence in men • 1960s: ↑ incidence in women after WW2
- 5. Doll and Hill: British DoctorsStudy causal relationship established in the 1950s • 1964 Surgeon General’s Warning
- 6. Surgeon General’s Warning British Doctor’s Study lung cancer mortality •↓ in men • plateaued in women
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- 8. Smoking accounts for90% of all lung cancers • risk associated with pack- year history and age of initiation • 10-15 years to reduce risk by 75% but never approaches zero • N-nitrosamines & polycyclic aromatic hydrocarbons Other causes • Radon, asbestos, nickel, ra diation
- 9. 0 5 10 15 20 25 30 35 Smoking + Asbestos Smoking PassiveSmoke Asbestos Radon Relative Risk of Developing Lung Cancer
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- 11. CXR and sputumcytology • Johns Hopkins • Memorial Sloan-Kettering • no mortality benefit
- 12. • n=31,567 patients screened •annual low-dose helical chest CT scans • 484 patients diagnosed • 85% with Stage I disease • survival was 92% at 10 years (stage I cancer resected within a month) • historical standard of 75% at 5 years
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- 15. • POPULATION • age55 to 74 • heavy smoker or former smoker (quit within last 15 years) • no prior cancer within past 5 years • 53,454 patients randomized • CXR vs. low dose helical CT scan • annual imaging x 3 • 3% of scans led to diagnosis of lung CA, NNS 288, false positive rate = 23 % National Lung Screening Trial 20% reduction in lung cancer mortality 7% reduction in all cause mortality
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- 17. • Adenocarcinoma • SquamousCell Carcinoma • Large Cell Carcinoma 87% NSCLC SCLC
- 18. Adenocarcinoma • Most commonhistology (40%) • Least associated with smoking, but majority who get it have been exposed to cigarette smoke (70%) • TTF1-positive on IHC Location • peripheral, scar tissue Presentation • frequently metastatic disease • hypertrophic osteoarthropathy, Trosseau’s • BAC: multiple pulmonary nodules
- 19. Squamous Cell • Secondmost common (30%) • most common histology until 1987 • 90% associated with cigarette smoking • P63 (p40) positive on IHC • Presentation • centrally located mass now shifting • most common histology in Pancoast tumors • PTHrP: hypercalcemia
- 20. Large Cell • Leastcommon subtype (11%) • associated with gynecomastia • advances in histopathologic technique: reclassification of undifferentiated large cell tumors to adenoCA or SCC
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- 22. Stage Clinical StagePathologic Stage IA 50 73 IB 43 58 IIA 36 46 IIB 25 36 IIIA 19 24 IIIB 7 9 IV 2 13 International System for Staging Percent Surviving at 5 Years
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- 26. Clinical Staging • PET/CTchest and upper abdomen, bone scan • MRI Brain: node-negative disease >3cm or node-positive disease, brain metastases incidence 10-15%
- 27. PET-positive lymph nodes lymph nodeslarger than 1 cm on CT regardless of FDG uptake Mediastinal Evaluation
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- 32. Stage Ia Ib Stage IIa IIb SURGERY SURGERYCHEMO NSCLC Management: Stage I and II
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- 34. Surgical Approach Lobectomy FVC atleast 1.5 L
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- 36. Preoperative Evaluation Stereotactic BodyRT >60 Gy, good local control rates patients who are poor surgical candidates
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- 38. Stage Ia Ib Stage IIa IIb SURGERY SURGERYCHEMO NSCLC Management: Stage I and II
- 39. RCTs: Adjuvant Chemo IALT LeChevalier 2003 • Cisplatin + Etop/Vinor/Vinblas/Vindes • PORT allowed • Increased DFS, median OS, OS at 5yr by 4% NCIC Winston NEJM 2005 • Cisplatin + Vinorelbine • Median OS from 73 94 months (21 mos) • Increased OS at 5yr by 15% France Douilliard Lancet Onc 2006 • Cisplatin + Vinorelbine • Median OS from 43 65 months (12 mos)
- 40. Meta-Analyses: Adjuvant Chemo Hotta JCO 2004 •Cisplatin-based chemo, Uracil-Tegafur • N= 5,716 • Increased OS, HR 0.87 LACE Pignon JCO 2008 • Cisplatin-based chemo • N=4,500 • Stage IB HR 0.92, Stage II HR 0.83, Stage III HR 0.83
- 41. SURGERY CHEMO 4 Cyclesof Therapy • Cisplatin + Vinorelbine • Cisplatin + Docetaxel • Cisplatin + Gemcitabine • Cisplatin + Pemetrexed Adjuvant Chemotherapy
- 42.
- 43. Stage IIIa IIIb CHEMO CHEMORADIATION SURGERY NSCLC Management RT sequenceof treatments is variable
- 44. ChemoRT in UnresectableStage III Furuse 1999 JCO
- 45. Stage Ia Ib Stage IIa IIb StageIIIa IIIb Stage IV SURGERY CHEMO CHEMORADIATION SURGERY CHEMO SURGERY CHEMO NSCLC Management RT
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- 48. Systemic Therapy: CisplatinDoublet 2 drugs > 1 drug • Lilenbaum Semin Onc 99 • Lilenbaum ASCO 02 • Sederholm Semin Onc 02 2 drugs < 3 drugs • Crimo JCO 99 • Soguet Ann Onc 02 • Greco Cancer 02 Cisplatin > Carboplatin • Belani Semin Onc 01 • Rosell Ann Onc 02 • Ardizonni Meta JNCI 07 • Hotta Meta JCO 04
- 49. Systemic Therapy: HistologyMatters • PEMETREXED: non-squamous histology • GEMCITABINE: squamous histology • PACLITAXEL, VINORELBINE: any histology
- 50. Switch Maintenance • IncreasedPFS, Median OS 10.6 13.4 mos (2.8 mo) Ciuleneau Lancet 2009 platinum- based therapy Pemetrexed • Increased PFS, Median OS 11 12 mos (2 mo) Cappuzzo Saturn Trial platinum- based therapy Erlotinib
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- 53. • BEVACIZUMAB till progression ofdisease • Median OS 10.3 12.3 mos
- 54. Epidermal Growth FactorReceptor
- 55. Cetuximab • Monoclonal antibodyto EGFR • 60-80% of lung cancers express EGFR on their surface (via immunohistochemistry) • FLEX: Cis/Vin ± Cetuximab • ↑ benefit with H-score>300 Increased OS by 13% HR 0.871 Cetuximab 400mg
- 56.
- 59. POPULATION: IIIB orIV adenoCA, never or light smokers, Asian, untreated RESPONSE RATE: gefitinib (43%) vs. chemo (32%) RESPONSE RATE (EGFR Mutant): gefitinib (71%) vs. chemo (47%) QUALITY OF LIFE: better in gefitinib arm
- 60. RR 73% vs.33% PFS 10.8 vs. 5.4 mos p < 0.001
- 61. conserved LREA motif small in-frame deletionsresidues 747-750 point mutation missense mutation PFS 14.6 months PFS 9.7 months
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- 64. ALK-Rearranged Lung Cancers Sodaet al Nature 2007, Takeuchi CCR 2008, www.mycancergenome.org Camidge et al Lancet Oncol 2012, Shaw et al Ann Oncol 2012
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- 67. 1999 2004 2009 2012 Timeline of PutativeDriver Event Discovery
- 68. LUNG CANCERS Carcinoid Large Cell LargeCell Neuroendocrine 5%
- 69. TISSUE IS THEISSUE Lung cancer is NOT one disease.
- 70. Crizotinib in ROS1-RearrangedLung Cancer
- 71. PI3K and MEKInhibition in KRAS-Mutant Lung Cancer 68/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 pulmonary nodules, complete resolution of pain/respiratory symptoms
- 72. Immune Checkpoint Blockade RibasNEJM 2012, 366:2517-2519 ipilimumab Nivolumab, MK-3475
- 73. • BMS-936558/Nivolumab • 122advanced non-small cell lung carcinomas (total n=296) • heavily pre-treated patients • response rate: 16%
- 74.
Editor's Notes
- #65 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 < 0.0001). ORR was significantly higher in pts treated with C (65% vs 20%; P < 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
- #67 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 < 0.0001). ORR was significantly higher in pts treated with C (65% vs 20%; P < 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
- #74 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