Dae Ho Lee, MD, PhD
Department of Oncology, University of Ulsan College of Medicine Asan Medical Center, Seoul, Korea
2017년 대한내과학회 혈액종양내과분과 연수강좌
Treatment of Advanced/Metastatic Lung Cancer
Stratified, Precision or Personalized
• We first classified small cell lung cancer (SCLC) ,
which is a different category due to its different
histopathological diagnosis, staging and treatment since 1960’s.
- Combination regimens were superior to single agent
chemotherapy in the 70’s and cisplatin-based combinations
in the 80’s.
- Combined chemo-radiotherapy treatment protocols were incorporated into the treatment of LD-SCLC in the 90’s.
- Prophylactic Cranial Irradiation?
If a stage IV patient was in front of you,
Prophylactic Cranial Irradiation!...?
Auperin A et al. B et al. N Engl J Med
1999
;341:476Subgroup Analysis
Prophylactic Cranial Irradiation?...!...?
ED SCLC
absence of brain metastases confirmed by MRI
PCI (n=113)
No PIC (n=111) Median OS, mo
(95% CI) 11.6
(9.5-13.3) 13.7 (10.2-16.4) HR (95% CI),
p value 1.27 (0.96-1.68)
P=0.094
Takahashi T et al. Lancet Oncol
2017
;18:663ED SCLC
Brain imaging was not part of standard staging and follow-up procedures
PCI
(n=143) No PIC (n=143)
Median OS, mo 6.7 5.4
HR (95% CI), p value
0.68 (0.52-0.88) P=0.003
Slotman B et al. N Engl J Med
2007
;357:664Cognitive function
“Precision” Cancer Medicine?
“ Stratified” Cancer Medicine!
One-Size Fits-All Medicine
Stratification
Stratified Medicine
• We did NOT have to differentiate (stratify) non-small cell lung cancer (NSCLC) further to several
subtypes including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma because however, their treatment outcomes were similar.
Schiller JH et al. N Engl J Med
2002
;346:92If a stage IV NSCLC patient was in front of you,
• Platinum-doublet therapy prolongs survival, improves symptom control, and yields superior quality of life compared to best supportive care but reached a plateau in overall response rates of 25~35%, time to
progression of 4~6 month s, median survival of
8~10 months, 1-year-survival rate of 30~40% and
2-year-survival rate of 10~15%.
• Unfit patients of any age ( performance status 3 or 4 ) do NOT benefit from cytotoxic chemotherapy.
• Response assessment
after1~2 cycles, then 2~4 cycles, to 4~6 in a total.
If Patient had NSCLC,
PS 0-2 Chemotherapy
PS 3-4 Best Supportive Care
Schiller JH et al. N Engl J Med
2002
;346:92However, if Patient has non-SQCC,
PS 0-2 Chemotherapy: Cisplatin/Gemcitabine vs Cisplatin/Pemetrexed
SQCC
Scagliotti et al. J Clin Oncol
2008
;26:354310.4
11.8
9.4 10.8HR 0.81 (95% CI, 0.70~0.94) HR 1.23 (95% CI, 1.00~1.51)
vs non-SQCC
Schiller JH et al. N Engl J Med
2002
;346:92If Patient has non-SQCC,
PS 0-2 Chemotherapy: Bevacizumab
Sandler A et al. N Engl J Med
2006
;355:2542• Bevacizumab/paclitaxel/carboplatin
improved median survival from 10.3 months to 12.3 months (p=0.003) with 1-YSR of 51% (vs 44%) and 2-YSR of 23%
(vs 15%) and improved median survival more in
adenocarcinoma patients from 14.2 months to 10.3 months.
• However, more toxicities was observed as
follows; G4 neutropenia 25.5% vs 16.8%; G5 hemoptysis 1.2% vs 0%; and G3 hypertension 6.8% vs 0.5%.
Therefore, bevacizumab should be given to patient without recent history of hemoptysis as well as non-SQCC.
• AVAiL Trial of
bevacizumab/gemcitabine/cisplatin did
NOT show improvement of survival outcome.
If Patient has non-SQCC,
PS 0-2 Chemotherapy: Maintenance Therapy
• Continuation Maintenance with Bev (E4599) improved OS from 10.3 mo to 12.3 mo.
• Continuation Maintenance with Pem (PARAMOUNT) improved OS from 14.0 mo to 16.9 mo.
• Continuation Maintenance with Bev/Pem
(POINTBREAK, bev/carbo/pem vs bev/carbo/pac) improved OS numerically from 12.6 mo to 13.4 mo
• Continuation Maintenance with Bev/Pem
(AVAPERL, bev/cis/pem followed by bev/pem vs bev) improved OS numerically from 13.2 mo to 17.1 mo.
Paz-Ares LG et al. J Clin Oncol
2013
;31:289516.9 14.0
Precision Medicine? Stratified Medicine?
One-Size Fits-All Medicine
Stratified
Stratified Medicine Precision Medicine
More Stratified
Precise?
What is Targeted Cancer Medicine?
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer .
Targeted cancer therapies are sometimes called
" molecularly targeted drugs ,"
" molecularly targeted therapies,"
"precision medicines ," or similar names.
Targeted therapies vs Standard chemotherapies
•Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard
chemotherapies act on all rapidly dividing normal and cancerous cells.
•Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard
chemotherapies were identified because they kill cells.
•Targeted therapies are a
cornerstone of precision cancer medicine
, a form of medicine that usesinformation about
a person’s tumor genes and
proteins
to prevent, diagnose, and treat disease.Genetic Testing
Adenocarcinoma
Large Cell Carcinoma
NSCLC, NOS
Squamous Cell Carcinoma
EGFR mutation testing
ALK FISH testing
Histologic Subtypes to Genetic Subtypes
If Patient has a tumor with Genetic Change,
Mok TS et al. N Engl J Med
2009
;361:947EGFRmutation-Positive EGFRmutation-Negative
ORR:
71.2% vs. 47.3%
p=0.0001
ORR:
1.1% vs . 23.5%
p=0.0013
If Patient has Tumor harboring EGFR activating mutation,
PS 0-4 EGFR TKI Therapy: Gefitinib, Erlotinib or Afatinib
Park K et al. Lancet Oncol
2016
;17:577EGFRmutation-Positive
HR, 0·73 (95% CI 0·57–0·95; p=0·017) afatinib: 11·0 mo (95% CI 10·6–12·9) vs gefitinib: 10·9 mo (95% CI 9·1–11·5)
ORR:
70% vs . 56%
p=0.0083
EGFR TKIs
Study Setting # of Pts ECOG PS Treatment RR (%) PFS (months,95% CI) OS (months, 95% CI)
TORCH
Gridelli G et al. (2012)
Caucasian
Unselected 760 0-1 Erlotinib vs
Cis/Gem
25.6 vs 8,7 (p<0.001)
2.2 vs 5.4
HR: 1.21 (1.04-1.42)
8.7 vs 11.6
HR: 1.24 (1.04-1.47) IPASS
Mok Tet al. (2009)
Asian
clinically selected 1217 0–2 Gefitinib vs CBDCA/Pac
43 vs 32.3 (p < 0.001)
5.7 vs 5.8,
HR: 0.74 (0.65-0.85)
18.6 vs 17.3
HR: 0.91, (0.76–1.10) First SIGNAL
Han JY et al. (2012)
Asian
clinically selected 309 0–2 Gefitinib vs Cis/Gem
55.4 vs 46.3 (p = 0.101)
5.8 vs 6.4,
HR: 1.198 (0.944-1.520)
22.3 vs 22.9
HR: 0.932 (0.716-1.213) WJTOG 3405
Mitsudomi T et al. (2010)
Asian
EGFR mutated 172 0–1 Gefitinib vs
Cis/Doc
62.1 vs 32.2 (p < 0.0001)
9.2 vs 6.3,
HR: 0.489 (0.34-0.71)
34.8 vs 37.3
HR: 1.252 (0.883-1.775) NEJ002
Inoue A et al. (2013)
Asian
EGFR mutated 230 0–2 Gefitinib vs
CBDCA/Pac
73.7 vs 30.7 (p < 0.001)
10.8 vs 5.4,
HR: 0.322 (0.236-0.438)
27.7 vs 26.6
HR: 0.887 (0.634-1.241) OPTIMAL
Zhou C et al. (2015)
Asian
EGFR mutated 165 0–2 Erlotinib vs
CBDCA/Gen
83 vs 36 (p < 0.0001)
13.1 vs 4.6,
HR: 0.16 (0.10-0.26)
22.8 vs 27.2
HR: 1.19 (0.83-1.71) EURTAC
Rosell R et al. (2012)
Caucasian
EGFR mutated 174 0–2 Erlotinib vs
platinum doublet
64 vs 18 (p < 0.0001)
9.7 vs 5.2,
HR: 0.37 (0.25-0.54)
19.3 vs 19.5
HR: 1.04 (0.65-1.68) ENSURE
Wu YL et al. (2015)
Asian
EGFR mutated 217 0-2 Erlotinib vs
Cis/Gem
62.7 vs 33.6 p
11.0 vs 5.5
HR: 0.34 (0.22-0.51)
26.3 vs25.5
HR 0.91 (0.63-1.31) LUX-LUNG 3
Sequist LV et al. (2013)
Worldwide
EGFR mutated 345 0–1 Afatinib vs
Pem/Cis
69.1 vs 44.3 (p < 0.001)
11.1 vs 6.9,
HR: 0.58 (0.43-0.78)
28.2 vs 28.2
HR: 0.88 (0.66-1.17) LUX-LUNG 6
Wu YL et al. (2013)
Asian
EGFR mutated 364 0–1 Afatinib vs
Gem/Cis
66.9 vs 23.0 (p < 0.0001)
11.0 vs 5.6,
HR: 0.28 (0.20-0.39)
23.1 vs 23.5
HR: 0.93 (0.72-1.22) LUX-LUNG7
Paz-Ares et al. (2016)
Worldwide
EGFR mutated 319 0-1 Afatinib vs
Gefitinib
73 vs 56 (p=0.002)
11.0 vs 10.9
HR 0.73 (0.57-0.95)
27.9 vs 24.5
HR 0.86 (0.66-1.12)
Inferior or Detrimental Not Superior
Superior!...?
Cross-over Effects
Camidge RD et al. Nat Rev Clin Oncol 2014;11:473
Acquired Resistance to 1 st or 2 nd EGFR TKIs
Maintenance Gefitinib?
mPFS
(95% CI)Pem/Cis/Gef
5.4
(4.5-5.7)Pem/Cis
5.4
(4.6-5.5)HR: 0.86 (95% CI, 0.65-1.13), p=0.27
Soria JC, et al. Lancet Oncol
2015
;16:990Median(months),
Gef vs Placebo HR (95% CI)
PFS 5.4 vs 5.4 0.86 (0.65-1.13)
OS 13.4 vs 19.5 1.44 (1.07-1.94)
T790 M(+)
PFS 4.6 vs 5.3 0.97
OS 10.8 vs 14.1 1.49 (1.02- 2.21)
T790M (-)
PFS 6.7 vs 5.4 0.67
OS 21.4 vs 22.5 1.15 (0.68-1.94)
Soria JC, et al.
2016
ESMO CongressDetrimental
Not Beneficial
ORR: 51%
(95% CI, 45~58%)
ORR for T790+:
61%
(95% CI, 52~70%)
ORR for T790-:
21%
(95% CI, 12~34%)
Median PFS: 8.2 months
(41% maturity [92 events in 222 patients])
mPFS: 9.6 mo
(95% CI, 8.3~NR; 30% maturity)
mPFS: 2.8 mo
(95% CI, 2.1 to 4.3; 71% maturity)
3 rd Generation EGFR TKI
Jänne PA, et al. N Engl J Med
2015
;372:1689T790M Negative!
REALLY?
mPFS
(95% CI)Pem/Cis/Gef
(n=133)
5.4
(4.5-5.7)Pem/Cis
(N=132) 5.4 (4.6-5.5)
HR: 0.86 (95% CI, 0.65-1.13), p=0.27
Soria JC, et al. Lancet Oncol
2015
;16:990mPFS
(95% CI)Osimertinib
(n=279)
10.1
(8.3-12.3)Pem/Platinum
(n=140) 4.4 (4.2-5.6)
HR: 0.30 (95% CI, 0.23-0.41), p<0.001
Mok TS, et al. N Engl J Med
2017
;376:6293 rd Generation EGFR TKI
PS 0-4 EGFR TKI Therapy Failure: Osimertinib
However, not reimbursed yet due to
financial toxicity (cost-effectiveness)
Shaw AT et al. N Engl J Med
2013
;368:2385ORR: 65% vs 20%
Median PFS: 7.7 mo vs 3.0 mo
If Patient has Tumor harboring ALK Translocation,
PS 0-4 ALK TKI Therapy: Crizotinib as second-line therapy
However, reimbursed since 2015 May due to
financial toxicity (cost-effectiveness)
Shaw AT et al. Lancet Oncol
2011
;12:1004Historical case-match analysis of survival in ALK-positive patients receiving crizotinib or standard therapy and ALK- negative, EGFR WT patients receiving standard therapy.
No Cross-over Effect: Crizotinib
Solomon BJ et al. N Engl J Med
2014
;371:2167Crossover effect:
70% received crizotinib while 12% platinum doublet
ORR: 74% vs 45%
Median : 10.9 mo vs 7.0 mo
If Patient has Tumor with an ALK Translocation,
PS 0-4 ALK TKI Therapy: Crizotinib as first-line therapy
However, reimbursed since 2017 January due to
financial toxicity (cost-effectiveness)
Camidge R et al. Nat Rev Clin Oncol
2012
; 9:268Acquired Resistance to 1 st ALK Inhibitor
Kim DW et al. Lancet Oncol
2016
;17:452ORR: 56%
ORR: 72%
ALK inhibitor-pretreated
Median PFS: 8.3 mo (5.6-8.7) ALK inhibitor-naïve
Median PFS: 18.4 mo (11.1-NE)
If Patient failed to 1 st ALK TKI,
PS 0-4 Crizotinib Failure: Ceritinib
reimbursed immediately since 2016 August
Kwak EL et al. N Engl J Med 2010;363:1693 Shaw AT et al. N Engl J Med 2014;371:1963
If Patient has Tumor with an ROS-1 Translocation,
Repurposing
based onDrug Targets
ORR:
72 %
mPFS
: 19.2 mo (95% CI, 14.4~NR)
ORR:
57 %
PFSR@6M
: 72%
Malignant Melanoma
ORR:
50% (95% CI, 42 to 57)
Hauschild A et al. Lancet 2012;380:358
Non-small Cell Lung Cancer
ORR:
33 % (26 out of 78)
mPFS
: 5.5 mo (95% CI, 3.4~7.3)
Planchard D et al. Lancet Oncol
2016
;17:642If Patient has Tumor with an BRAF mutation,
Repurposing
based onMolecular Targets
Non-small Cell Lung Cancer
ORR:
63.2 % (36 out of 57)
mPFS
: 9.7 mo (95% CI, 6.9~19.6)
Planchard D et al. Lancet Oncol
2016
;17:984If Patient has Tumor with an BRAF mutation,
Repurposing
based onMolecular Targets
RAF
MEK RAS
ERK
*
• Vemurafenib: 13.6 mo vs Dacarbazine: 9.7 mo HR 0.70 (0.57-0.87), p=0.0008
• Dabrafenib: 20.0 mo vs Dacarbazine: 15.6 mo HR 0.77 (0.52-1.13), p>0.05
• Trametinib: 81% @ 6M vs Chemotherapy: 67%
@ 6M
HR 0.54 (0.32-0.92), p=0.01
• Dabrafenib+Trametinib: 93% @ 6M vs Dabrafenib: 85% @ 6M
HR 0.63 (0.42-0.94), p=0.002
• Dabrafenib/Trametinib: 72% @ 12M vs Vemurafenib: 65% @ 12M
HR 0.69 (0.53-0.89), p=0.0005
• Vemurafenib/Cobimetinib: 81% @ 9 M vs Vemurafenib: 73% @ 9M
HR 0.65 (0.42-1.00), p=0.046
Change of Treatment of Melanoma
From Single BRAFi to Combo of BRAFi/MEKi
Dabrafenib/Trametinib
Precision Medicine
One-Size Fits-All Medicine
Stratification
Stratified Medicine Precision Medicine
More Stratified
More Precise
Precise Medicine
Genomics
Immune Checkpoint Inhibitor & PD-L1
Phase I Trial of Nivolumab or PD-1 Inhibitor
Topalian SL et al N Engl J Med
2012
;366:2443RR PDL-1
+
PDL-1 -
+ 9(36) 0 9(21)
- 16(64) 17(100) 33(79)
Total 25 17 42
P=0.006
• ORR
- Malignant Melanoma: 28%
(26/94)
- RCC: 27% (9/33)
- NSCLC: 18% (14/76)
Brahmer J et al. N Engl J Med
2015
;373:123ORR:
Nivolumab 20% [95% CI, 14 to 28] vs. Docetaxel 9% [95% CI, 5 to 15];
P=0.008
Nivolumab in SQCC of the Lung as 2
ndline therapy
If SQCC Patient failed to Platinum Doublet ,
Nivolumab (n = 292)
Docetaxel (n = 290)
mPFS, mo 2.3 4.2
HR = 0.92 (95% CI: 0.77, 1.11); P = 0.3932
Nivolumab (n = 292)
Docetaxel (n = 290)
mOS, mo 12.2 9.4
HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015
ORR:
Nivolumab 19% [95% CI, 15 to 24] vs. Docetaxel 12% [95% CI, 9 to 17];
P=0.0246
Nivolumab in non-SQCC of the Lung as 2
ndline therapy
Borghael H et al. N Engl J Med
2015
;373:1627If non-SQCC Patient failed to Platinum Doublet,
DOC PEM 2mg/kg PEM 10 mg/kg mPFS
(mo, 95% CI)
4.0 (3.1-4.3)
3.9 (3.1-4.1)
4.0 (2.7-4.3) HR
(95% CI, p value)
0.88 (0.74–1.05; 0.07)
0.79 (0.66–0.94; 0.004)
DOC PEM 2mg/kg PEM 10 mg/kg mOS
(mo, 95% CI)
8.5 (7.5-9.8)
10.4 (9.4-11.9)
12.7 (10.0-17.3) HR
(95% CI, p value)
0·71( 0.58–0.88; 0.0008)
0·61 (0.49–0.75; <0.0001) Herbst RS et al. Lancet
2016
;387:1540Pembrolizumab as 2
ndline therapy for PD-L1 positive NSCLC
If NSCLC Patient failed to Platinum Doublet but...
If Patient has PD-L1 (+) NSCLC,
Reck M et al. N Engl J Med
2016
;375:18236.0 10.3
70%
54%
HR: 0.50 (95% CI, 0.37-0.68) p<0.001
HR: 0.60 (95% CI, 0.41-0.89) p=0.005
PS 0-2 Nivolumab vs 2
ndline Chemotherapy (after platinum doublet),
PS 0-2 Pembrolizumab vs 2
ndline Chemotherapy (after platinum doublet ) but (+) PD-L1,
PS 0-1 Pembrolizumab vs 1
stline Chemotherapy but PD-L1 positive (TPS50%)
Stratified Medicine Again!
One-Size Fits-All Medicine
Stratification
Stratified Medicine Precision Medicine
Precise Medicine
Immunology +Genomics
Biomarker?
The Hallmarks of Cancer
Oncogene
Inhibitors Cyclin-dependent
Kinase Inhibitors
Anti-immune Checkpoint Antibodies
Telomerase Inhibitors
Selective anti- inflammatory Agents
HGF/c-MET inhibitors Anti-angiogenic
Antibodies PARP Inhibitors
Proapoptotic BH3 Mimetics Aerobic Glycolysis
Inhibitors
Hanahan and Weinberg. Cell 2011;144:646
Hanahan and Weinberg. Cell 2011;144:646