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(1)

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

(2)

• 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,

(3)

Prophylactic Cranial Irradiation!...?

Auperin A et al. B et al. N Engl J Med

1999

;341:476

Subgroup Analysis

(4)

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

;18:663

ED 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

;357:664

Cognitive function

(5)

“Precision” Cancer Medicine?

“ Stratified” Cancer Medicine!

One-Size Fits-All Medicine

Stratification

Stratified Medicine

(6)

• 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

;346:92

If a stage IV NSCLC patient was in front of you,

(7)

• 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

after

1~2 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

;346:92

(8)

However, if Patient has non-SQCC,

PS 0-2  Chemotherapy: Cisplatin/Gemcitabine vs Cisplatin/Pemetrexed

SQCC

Scagliotti et al. J Clin Oncol

2008

;26:3543

10.4

11.8

9.4 10.8

HR 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

;346:92

(9)

If 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.

(10)

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

;31:2895

16.9 14.0

(11)

Precision Medicine? Stratified Medicine?

One-Size Fits-All Medicine

Stratified

Stratified Medicine Precision Medicine

More Stratified

Precise?

(12)

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 uses

information about

a person’s tumor genes and

proteins

to prevent, diagnose, and treat disease.

(13)

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,

(14)

Mok TS et al. N Engl J Med

2009

;361:947

EGFRmutation-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

;17:577

EGFRmutation-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

(15)

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

(16)

Camidge RD et al. Nat Rev Clin Oncol 2014;11:473

Acquired Resistance to 1 st or 2 nd EGFR TKIs

(17)

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

;16:990

Median(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 Congress

Detrimental

Not Beneficial

(18)

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

;372:1689

T790M Negative!

REALLY?

(19)

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

;16:990

mPFS

(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

;376:629

3 rd Generation EGFR TKI

PS 0-4  EGFR TKI Therapy Failure: Osimertinib

However, not reimbursed yet due to

financial toxicity (cost-effectiveness)

(20)

Shaw AT et al. N Engl J Med

2013

;368:2385

ORR: 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)

(21)

Shaw AT et al. Lancet Oncol

2011

;12:1004

Historical 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

(22)

Solomon BJ et al. N Engl J Med

2014

;371:2167

Crossover 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)

(23)

Camidge R et al. Nat Rev Clin Oncol

2012

; 9:268

Acquired Resistance to 1 st ALK Inhibitor

(24)

Kim DW et al. Lancet Oncol

2016

;17:452

ORR: 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

(25)

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 on

Drug Targets

ORR:

72 %

mPFS

: 19.2 mo (95% CI, 14.4~NR)

ORR:

57 %

PFSR@6M

: 72%

(26)

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

;17:642

If Patient has Tumor with an BRAF mutation,

Repurposing

based on

Molecular Targets

(27)

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

;17:984

If Patient has Tumor with an BRAF mutation,

Repurposing

based on

Molecular 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

(28)

Precision Medicine

One-Size Fits-All Medicine

Stratification

Stratified Medicine Precision Medicine

More Stratified

More Precise

Precise Medicine

Genomics

(29)
(30)

Immune Checkpoint Inhibitor & PD-L1

Phase I Trial of Nivolumab or PD-1 Inhibitor

Topalian SL et al N Engl J Med

2012

;366:2443

RR 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)

(31)

Brahmer J et al. N Engl J Med

2015

;373:123

ORR:

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

nd

line therapy

If SQCC Patient failed to Platinum Doublet ,

(32)

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

nd

line therapy

Borghael H et al. N Engl J Med

2015

;373:1627

If non-SQCC Patient failed to Platinum Doublet,

(33)

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

;387:1540

Pembrolizumab as 2

nd

line therapy for PD-L1 positive NSCLC

If NSCLC Patient failed to Platinum Doublet but...

(34)

If Patient has PD-L1 (+) NSCLC,

Reck M et al. N Engl J Med

2016

;375:1823

6.0 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

nd

line Chemotherapy (after platinum doublet),

PS 0-2  Pembrolizumab vs 2

nd

line Chemotherapy (after platinum doublet ) but (+) PD-L1,

PS 0-1  Pembrolizumab vs 1

st

line Chemotherapy but PD-L1 positive (TPS50%)

(35)
(36)

Stratified Medicine Again!

One-Size Fits-All Medicine

Stratification

Stratified Medicine Precision Medicine

Precise Medicine

Immunology +Genomics

Biomarker?

(37)

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

(38)

Hanahan and Weinberg. Cell 2011;144:646

Personalized Medicine?

(39)

The FATE of Lung Cancer

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