13. Mutational signature
analysis revealed age-
and gender-related
mutagenesis mechanisms,
characterized by high
prevalence of APOBEC
mutational signature in
younger females and
over-representation of
environmental
carcinogen-like
mutational signatures in
older females.
Cell, 2020
20. Biomedicine & Pharmacotherapy 61 (2007) 515-519
Tumor markers ?
Despite extensive studies, most results still remain controversial.
None of the above described biomarkers is mature enough to be
routinely used in the clinic as a diagnostic, therapeutic or prognostic tool
31. The current evidence does not
support screening for lung cancer
with chest radiography or sputum
cytology.
Cochrane Database Syst Rev. 2013 Jun; 2013(6):
35. • 族群 : aged 55 to 74
years with 30 pack-
years of smoking and
who quit 15 years prior
to entry if ex-smokers
• LDCT : HR 0.80, 95% CI
(0.70 to 0.92)
2014 , cochrane review
在特定族群裡, 使用Low dose CT (LDCT)和常規使用CXR
診斷及追蹤相比, 可以明顯降低 20% 肺癌死亡率
64. SCC
P+D : 13.2m
• D : Docetaxel (Taxotere)
• T : Paclitaxel
• V : Vinorelbin
• G : Gemcitabin
• P : Platinum (Cisplatin or
Carboplatin
D - Docetaxel (Taxotere)歐洲紫杉醇
加上鉑金治療可能有最佳overall survival(OS)
69. FDA 允許用於末期非小細胞肺癌的抗血
管新生藥物
• Bevacizumab (Avastin®) 癌思停
– Recombinant humanised anti-VEGF
monoclonal antibody
• Ramucirumab (Cyramza®) 欣銳擇
– Fully human IgG1 monoclonal antibody to
VEGF Receptor-2
70. Bevacizumab (Avastin®) 是一種單株抗體, 結合上血清中的
VEGF(血管內皮生長因子) , 使它沒有辦法跟接受器結合而
去抑制血管新生
70
Bevacizumab
VEGF receptor
VEGF
1. Avastin Summary of Product Characteristics; 2. Presta, et al. Cancer Res 1997; 3. Avastin prescribing information,
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf
• Bevacizumab prevents binding of VEGF to receptors1,2
• Bevacizumab has a long elimination half life (approximately 20 days) which may contribute
to continuous tumour control3
71. Avastin(Bevacizumab) 癌思停
1. Baluk, et al. Curr Opin Genet Dev 2005; 2. Willett, et al. Nat Med 2004; 3. O’Connor, et al. Clin Cancer Res 2009; 4. Hurwitz, et al. NEJM 2004; 5. Sandler, et al. NEJM 2006 6. Escudier, et al. Lancet 2007; 7. Miller,
et al. NEJM 2007; 8. Mabuchi, et al. Clin Cancer Res 2008; 9. Wild, et al. Int J Cancer 2004; 10. Gerber, Ferrara. Cancer Res 2005 11. Prager, et al. Mol Oncol 2010; 12. Yanagisawa, et al. Anti-Cancer Drugs
2010; 13. Dickson, et al. Clin Cancer Res 2007; 14. Hu, et al. Am J Pathol 2002
15. Ribeiro, et al. Respirology 2009; 16. Watanabe, et al. Hum Gene Ther 2009; 17. Mesiano, et al. Am J Pathol 1998; 18. Bellati, et al. Invest New Drugs 2010
19. Huynh, et al. J Hepatol 2008; 20. Ninomiya, et al. J Surg Res 2009
讓肺癌既有的血管萎縮 抑制新生的血管
增加治療反應率
持續控制腫瘤生長
減少肋膜積水及腹水
減少血管通透性
74. Ramucirumab (Cyramza®) 欣銳擇
• High affinity to
human VEGFR-2.
• Ramucirumab
potently blocks
binding of VEGF-A to
VEGFR-2
• Ramucirumab blocks
binding of VEGF-C
and VEGF-D to
VEGFR-23
1. Lu et al. J Biol Chem 2003;278(44):43496-507.
2. Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.
3. Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.
76. Study Design Phase 3, randomized, multi-site study of ramucirumab or placebo plus docetaxel following
progression on or after a platinum-based regimen
Primary endpoint Overall survival
Secondary endpoints Progression-free survival, overall response rate, safety, patient-reported outcomes
REVEL: Study Design1,2
1. http://clinicaltrials.gov/ct2/show/NCT01168973.
2. Garon et al. Lancet 2014;384(9944):665-73.
89. • Erlotinib, gefitinib, afatinib and icotinib are all active agents in
EGFR M+ NSCLC patients, and demonstrate an increased
tumour response rate and prolonged PFS compared to
cytotoxic chemotherapy.
• We found a beneficial effect of the TKI compared to cytotoxic
chemotherapy in adverse effect and health-related quality of
life. We found limited evidence for increased OS for the TKI
when compared with standard chemotherapy
• Single agent-TKI remains the standard of care.
Cochrane Database Syst Rev. 2021 Mar 18;3(3):CD010383.
108. AURA3 study design1,2
1. Mok TS, et al. N Engl J Med. 2017; 376:629-640.
Key eligibility criteria
• ≥18 years (≥20 years in Japan)
• Locally advanced or metastatic NSCLC
• Evidence of disease progression following first-
line EGFR-TKI therapy
• Documented EGFRm and central confirmation
of tumor EGFR T790M mutation after first-line
EGFR-TKI treatment
• WHO performance status 0 or 1
• No more than one prior line of treatment for
advanced NSCLC
• No prior neo-adjuvant or adjuvant
chemotherapy treatment within 6 months prior
to starting first EGFR-TKI treatment
• Stablea asymptomatic CNS metastases allowed
R
2:1
Osimertinib (n=279)
80 mg orally
QD
Platinum-pemetrexed (n=140)
Pemetrexed 500 mg/m2 +
carboplatin AUC5 or
cisplatin 75 mg/m2
Q3W for up to 6 cycles
+ optional maintenance
pemetrexedb
Optional crossover: Protocol amendment
allowed patients on chemotherapy to begin post-
BICR confirmed progression open-label
osimertinib treatment
Endpoints Primary:
• PFS by investigator assessment (RECISTv1.1)
Secondary and exploratory:
• OS
• ORR
• DoR
• DCR
• Tumor shrinkage
• BICR-assessed PFS
• PROs
• Safety and tolerability
• Patients were stratified at randomisation based on ethnicity (Asian/Non-Asian)
• RECISTv1.1 assessments performed every 6 weeks until objective disease progression; patients could receive study treatment beyond RECISTv1.1 defined
progression as long as they experienced clinical benefit
108
帶有EGFR T790M 的第二線治療
有 enroll Brain Metastases 的病人
Primary Endpoint : PFS
Main Secondary Endpoint : OS
允許 Chemo Arm Progression 後
Crossover 使用 Osimertinib
For internal training only
對於第一線用標靶藥物產生抗藥性而又證實產生
T790M mutation的病患
113. Taiwan national health insurance cover Osimertinib in 1st and 2nd line use
.
• To maximum the benefit of Osimertinib in first line
use, NHI limited patient eligibilities into subgroup
of EGFR exon 19 Del without CNS metastasis.
Soria JC et al. N Engl J Med. 2018;378:113-125.
FLAURA PFS
FLAURA OS
Osimertininb 泰格莎2020.4開始有條件健保給付
113
114. 既然被證實在產生T790M抗藥性族群有效, 那
如果把泰格莎放在第一線治療呢?
- FLAURA study
Stratification by
mutation status
(Ex19del / L858R)
and race
(Asian /
non-Asian)
Crossover was allowed for patients in the SoC
EGFR-TKI arm, who could receive open-label
osimertinib upon EGFR T790M positivity and central
confirmation of progression
Patients with locally advanced or
metastatic NSCLC (n=556)
Key inclusion criteria
• ≥18 years (≥20 years in Japan)
• WHO performance status 0 / 1
• Ex19del / L858R (enrollment by locala
or centralb EGFR testing)
• No prior systemic anti-cancer /
EGFR-TKI therapy
• Stable CNS metastases allowed
Randomised 1:1d
RECIST v1.1 assessment
every
6 weekse until objective
progressive disease
SoC EGFR-TKIc
Gefitinib (250 mg po qd)
or
Erlotinib (150 mg po qd)
(n=277)
Osimertinib
(80 mg po qd)
(n=279)
Follow-up
for post-
progression
outcomes and OS
every 6 weekse
Endpoints
• Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1)
• The study had a 90% power to detect a hazard ratio of 0.71 (representing an improvement in median PFS from 10 months to 14.1 months) at a two-sided alpha-level
of 5%
• Secondary endpoints: Objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported outcomes, safety
• Exploratory endpoints: post-progression efficacy
FLAURA data cut-off: 12 June 2017; NCT02296125.
a With central laboratory assessment performed for sensitivity. bcobas EGFR Mutation Test (Roche Molecular Systems). cSites to select either gefitinib or erlotinib as the sole comparator prior to site initiation. dPatients received randomized treatment until objective
disease progression or as long as they were continuing to show clinical benefit, as judged by the Investigator eEvery 12 weeks after 18 months.
CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; po, orally; RECIST 1.1, Response Evaluation Criteria In Solid Tumors version 1.1; QD, once daily; TKI, tyrosine kinase inhibitor; WHO,
World Health Organization.
1. Soria JC, et al. N Engl J Med. 2018;378(2):113-125. 2. Planchard D et al. Presented at: European Lung Cancer Congress; 11-14 April 2018; Geneva, Switzerland.
For internal training only
115. Osimertinib Significantly Improves PFS vs EGFR-TKI Comparator in
First-Line EGFRm NSCLC
.
1.0
Probability
of
PFS
0.2
0.4
0.6
0.8
0
0 3 6 9 12 15 18 21 24 27
Time from randomization (months)
279
277
262
239
233
197
210
152
178
107
139
78
71
37
26
10
4
2
0
0
No. at risk
Osimertinib
EGFR-TKI
comparator
Osimertinib
EGFR-TKI comparator
Median PFS, months (95% CI)
Osimertinib: 18.9 (15.2-21.4)
EGFR-TKI comparator: 10.2 (9.6-11.1)
HR (95% CI) 0.46 (0.37-0.57)
p<0.001
342 events in 556 patients at DCO: 62% maturity; osimertinib: 136 events (49%), EGFR-TKI comparator: 206 events (74%)
Soria JC et al. N Engl J Med. 2018;378:113-125.
1
1
5
116. Osimertinib Significantly Improves OS vs EGFR-TKI Comparator,with
.
HR (95% CI) 0.8 (0.64-1.00)
p=0.046
0 21 27 33 36 48 54
45 51
42
39
30
24
18
15
12
9
6
3
No. at risk
Osimertinib
EGFR-TKI
comparator
Osimertinib
mOS 38.6 months
(95% CI: 34.5-41.8)
EGFR-TKI comparator
mOS 31.8 months
(95% CI: 26.6-36.0)
0.2
0.4
0.6
0.8
1.0
0.0
Probability
of
OS
Time from randomization (months)
0.1
0.3
0.5
0.7
0.9
276
263
245
219
17
17
0
0
236
205
254
239
270
252
279
277
217
182
204
165
193
148
180
138
166
131
153
121
138
110
123
101
86
72
50
40
2
2
Osimertinib
EGFR-TKI comparator
62% of patients in the
FLAURA trial were Asian
DCO: June 25, 2019.
Ramalingam SS et al. Presented at: ESMO 2019 LBA5 ; Ramalingam et al. N Engl J Med.2020;382:41-50.
Soria JC et al. N Engl J Med. 2018;378:113-125. ; Lan KG and DeMets DL. Biometrika.1983;70:659-666
1
1
6
118. EML4-ALK 基因重組 檢測方式
Fluorescence
in situ
hybridization
(FISH)1
Immunohisto-
chemistry
(IHC)2
Polymerase
chain reaction
(PCR)/reverse
transcription
(RT)-PCR3
Next-generation
sequencing
(NGS)4,a
• Fluorescent probes
are used to label
and detect specific
regions on a gene
• Samples are
visualized under a
microscope
• Antibodies are used
to detect specific
proteins expressed
by cells
• Chemicals are
added so that cells
will change color
when visualized
under a microscope
• Relatively large
numbers of copies
of DNA are
produced from
minute quantities of
DNA (PCR) or RNA
(RT-PCR) material
• Faster and
massively parallel
alternative to
Sanger sequencing
FDA approved VENTANA ALK
(D5F3) CDx Assay
120. Median
OS
(
months)
Median OS in first line EGFR mut +
gefitinib erlotinib afatinib
ALKi
ALK陽性的族群治療效果應該是目前標靶
藥物中最佳 , 五年存活率可以高達50%
121. Treatment Landscape in ALK+ NSCLC Is Evolving
Lorlatinib
accelerated
approval
(post-2G
+/– crizotinib)
2018
Crizotinib
conditional
approval
(≥2L)
2012
Ceritinib
conditional
approval
(post-
crizotinib)
2015
Crizotinib 1L
label extension
2015
Alectinib
conditional
approval
(post-
crizotinib)
2017
Ceritinib
1L approval
2017
EML4-ALK
identified as driver
oncogene in
NSCLC
P L A T I N U M D O U B L E T S A L K - T A R G E T E D A G E N T S
US milestones
EU milestones
Alectinib
accelerated
approval
(post-
crizotinib)
2015
Crizotinib
regular
approval
(any line)
2013
Alectinib
1L approval
2017
Ceritinib
1L approval
2017
Crizotinib
accelerated
approval
(any line of therapy)
2011
Brigatinib
accelerated
approval
(post-crizotinib)
2017
Alectinib
1L approval
2017
Brigatinib
full approval
(post-crizotinib)
2018
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
Ceritinib
accelerated
approval
(post-crizotinib)
2014
1L, first-line; 2L, second-line; 2G, second-generation; ALK, anaplastic lymphoma kinase; EML4, echinoderm microtubule-associated protein-like 4; NSCLC, non-small cell lung cancer.
144. 高雄醫學大學
Kaohsiung Medical University
Study KN024
ESMO 2020
KN042
WCLC2021
CM026 IM110
ESMO2019
Mystic
EMPOWER
Lung 1
WCLC2021
patients(n) 305 1274 423 205 488 563
Regimen Pembro vs chemo
Pembro vs
chemo
Nivolumab vs
chemo
Atezolizumab vs
chemo
Durvalumab vs
chemo
Cemiplimab vs
chemo
PDL-1 TPS ≧ 50% TPS ≧1% TPS>5% TC3 or IC3 All comer TPS≧ 50%
mOS m
(IO vs CT)
26.3 vs 13.4
HR 0.62* (5 yr)
16.4 vs 12.1
HR 0.80*
14.4 vs 13.2 ;
HR 1.02
20.2 vs 13.1
HR 0.59*
16.3vs 12.9;
HR 0.76
22.1 vs 14.3
HR 0.68*
OS rate
(12m)
70.3% vs 54.8% 57% vs 50% 58% vs 54% 64.9 vs 50.6% N/A NA
mPFS
(IO vs CT)
7.7 vs 5.5m
HR 0.5*
5.4 vs 6.6m
HR 1.05
4.2 vs 5.9m
HR 1.15
8.1 vs 5.0m
HR 0.63*
4.7 vs 5.4m
HR 0.87
6.2 vs 5.6
HR 0.59*
ORR(%) 46.1% vs 36.1% 27.2 vs 26.5 24 vs 33 38.3 vs 28.6 35.6 vs 37.7 36.5 vs 20.6
DoR(m) 29.1 vs 6.3 20.2 vs 8.4 12.1 vs 5.7m NE vs 6.7 NA 21.0 vs 6.0
TRAEs Grade 3-
4 (DC%)
31.2(13.6%) vs
53.3(10.7)
17.8(9.0%) vs
41.0(9.4%) %
13 (8%) vs
16(6%)
31.8(6.3%) vs
53.6(16.3%)
NA 37.2 vs 48.5
1st line monotherapy of IO
148. 高雄醫學大學
Kaohsiung Medical University
Study KN189
WCLC 2020
KN407
ECLL 2021
CM227
ASCO2021
CM9LA
ASCO2021
IM130
ESMO 2018
POSEIDON
WCLC2021
Pathology type NSQ SQ NSQ & SQ NSQ & SQ NSQ; M(+) NSQ & SQ
Regimen
Pembro +
Peme+Plat vs PP
Pembro + Pacli +
Carbo + PC
Nivo+Ipi
vs chem
Nivo + Ipi + chem
vs chem
Atezo+Carbo
+nab-paclitaxel vs
CP
Durva + CT
vs CT
Dura+Trem+CT
vs CT
Patients 616 559 1189 719 723 137 vs 81 130 vs 81
PDL-1 All comer All comer All comer All comer All comer All comer All comer
mOS
22.0 vs 10.6
HR 0.60*
17.2 vs 11.6
HR 0.71*
17.1 vs 14.9
HR 0.79*
(>1%)
15.8 vs 11
HR 0.66*
18.6 vs 13.9
HR0.79*
13.3 vs 11.7 HR
0.86
14.0 vs 11.7
HR0.77*
OS rate 12m 70 vs 48.1% 64.7 vs 49.6% 62.6 vs 56.2% 63 vs 47% 63.1 vs 55.5 - -
mPFS(m)
9.0 vs 4.9
HR 0.50*
8.0 vs 5.1
HR 0.59*
11.0 vs 6.7
HR 0.65*
6.7 vs 5.3
HR 0.67*
7.0 vs 5.5
HR 0.64*
5.5 vs 4.8m
HR 0.74*
6.2 vs 4.8m
HR 0.72*
ORR(%) 48.3 vs 19.9 62.6 vs 38.8 35.9 vs 30.0 38 vs 25 49.2 vs 31.9 41.5 vs 24.4 38.8 vs 24.4
DoR(m) 11.2 vs 7.8 9.0 vs 4.9
23.2 vs 6.7
(>1%)
13.0 vs 5.6 8.4 vs 6.1 7.0 vs 5.1 9.5 vs 5.1
TRAEs Grade 3-
4 (DC%)
67.2 (27.7%)
Vs 65.8 (14.9%)
69.8 (23.4%) vs
68.2(11.8%)
31.2 (17.4%)
vs 36.1(8.9%)
47 (19%) vs 38(7%)
73.2 (26.4%) vs
60.3(22%)
44.6 (14.1%) vs
44.4(9.9%)
51.8 (15.5%) vs
44.4(9.9%)
1st line combined IO + Chemo or IO + IO
