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NSCLC housestaff
1. Management of
Alexander Drilon MD
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 of cancer
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
4. Lung Cancer: a 20th Century Epidemic
• 20 year latency period
• 1910: widespread
manufacturing of cigarettes
• 1930s: ↑ incidence in men
• 1960s: ↑ incidence in
women after WW2
8. Smoking accounts for 90% 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
11. CXR and sputum cytology
• 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
15. • POPULATION
• age 55 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
18. Adenocarcinoma
• Most common histology (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
• Second most 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
• Least common subtype (11%)
• associated with gynecomastia
• advances in histopathologic technique: reclassification of
undifferentiated large cell tumors to adenoCA or SCC
39. RCTs: Adjuvant Chemo
IALT
Le Chevalier
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)
50. Switch Maintenance
• Increased PFS, 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
59. POPULATION: IIIB or IV
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
64. ALK-Rearranged Lung Cancers
Soda et al Nature 2007, Takeuchi CCR 2008, www.mycancergenome.org
Camidge et al Lancet Oncol 2012, Shaw et al Ann Oncol 2012
71. PI3K and MEK Inhibition 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
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
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
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