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두경부암의 정밀의료

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(1)

두경부암의 정밀의료

국립암센터

윤 탁

(2)

Contents

1. Genomic Alteration in HNSCC

2. Molecular Targeted Tx. For HNSCC (EGFR, PI3K…)

3. Immunotherapy for HNSCC

4. Precision Medicine in HNSCC

CONTENTS

(3)

Genomic Characterization of HNSCC (TCGA Network)

HPV(-) HNSCC

•HER pathway 20%

•FGFR pathway 14%

•PIK3CA pathway 34%

•Cell cycle pathway 31%

HPV(+) HNSCC

•HER pathway 9%

•FGFR pathway 11%

•PIK3CA pathway 56%

•Cell cycle pathway 3%

Nature 2015: 517, 576-582.

(4)

Genomic Alteration in HPV(+)

Materials : TCGA : 279 cases + 252 HNSCC FFPE tissue

 PIK3CA (37%), PTEN (11%) , SOX2 (16%), RB1 mutation/loss (12%), Notch1 mutation (11%)

 TP53 mutation : 8% Annals of Oncology, 2015

(5)

Genomic Alteration in HPV(-)

 TP53 mutation : 84%

 CDKN2A/2B mutation/loss : 53%

 PIK3CA/PTEN : 27%

 CCND1 amplification : 26%, EGFR : 14% Annals of Oncology, 2015

(6)

Genomic Alterations in HPV(+) & HPV (-) HNSCC

JCO, 2015

HPV (+) HPV (-)

(7)

Contents

1. Genomic Alteration in HNSCC

2. Molecular Targeted Tx. For HNSCC

3. Immunotherapy for HNSCC

CONTENTS

(8)

Phase III Trials of EGFR MoAb in HNSCC

(9)

Response Rate by IHC Score

EJC, 2013

(10)

Survival Outcomes by

Different IHC Score Thresholds

EJC, 2013

(11)

OS by HPV Status (EXTREME)

Annals of Oncology 2014

(12)

PFS by HPV Status (EXTREME)

Annals of Oncology 2014

(13)

HPV and Cetuximab Efficacy

(Biomarker Analysis in EXTREME)

• P16 and HPV status have prognostic value in R/M SCCHN

• Survival benefits of cetuximab+chemo vs

chemo. alone are independent of tumor p16 and HPV status

(no biomarker –treatment interaction)

Annals of Oncology 2014

(14)

Potential Predictive

Biomarkers of Cetuximab

KRAS mutation BRAF mutation PIK3CA mutation

NRAS mutation

Negative Selection

Colorectal cancer

HNSCC

KRAS mutation (X) BRAF mutation (X) NRAS mutation (?) PIK3CA mutation (?)

HPV status (?) EGFR IHC/FISH (?)

(15)

Afatinib vs MTX as 2nd-line R/M HNSCC (LUX-Head&Neck1)

 R/M HNSCC

pretreated platinum

 Cetuximab allowed

 ECOG PS: 0-1 n=483

Afatinib 40mg (n=322)

Methotrexate 40mg/m2 weekly i.v. (n=161)

Stratification factors

1. Previous EGFR-therapy 2. ECOG PS

Primary endpoint : PFS (ICIRC)

Lancet Oncol 2015

(16)

Afatinib vs MTX as 2nd-line R/M HNSCC

Lancet Oncol 2015

(17)

Afatinib vs MTX as 2nd-line R/M HNSCC PFS by p16 Status

P16 (-) HNSCC p16 (+) HNSCC

Lancet Oncol 2015

HPV(-) HNSCC from TCGA

HER pathway 20%

FGFR pathway 14%

PIK3CA pathway 34%

Cell cycle pathway 31%

(18)

Dacomitinib in R/M HNSCC

 R/M HNSCC

 ECOG PS: 0-2

 PD after platinum- based chemo

 Previous cetuximab allowed

 (n=48)

 Dacomitinib 45mg qd

CR :0 (0%)

PR: 10 (20.8%) SD : 31(64.6%) PD : 6(12.5%)

ORR =20.8% (10.5-35.0)

CCR, 2015

(19)

Dacomitinib in R/M HNSCC

CCR, 2015

(20)

Buparlisib+Paclitaxel vs Paclitaxel+Placebo (RCT, phase 2 ; BERIL-1)

 R/M HNSCC

pretreated platinum

 Cetuximab allowed

 ECOG PS: 0-1

Paclitaxel 80mg/m2 D1,8,15,22 Buparlisib 100mg po qd

Paclitaxel 80mg/m2 D1,8,15,22 Placebo

Stratification factors

1. number of previous therapy 2. Site

Primary endpoint : PFS

Lancet Oncol 2017

(21)

Buparlisib+Paclitaxel vs Paclitaxel+Placebo (RCT, phase 2 ; BERIL-1)

PFS OS

Median PFS: 4.6 months (95% CI; 3.5-5.3) Median PFS: 3.5 months (95% CI; 2.2-3.7) HR : 0.65 (95% CI; 0.45-0.95)

Median OS: 10.4 months (95% CI; 7.3-12.8) Median OS: 6.5 months (95% CI; 5.3-8.8) HR : 0.72 (95% CI; 0.49-1.04)

Lancet Oncol 2017

(22)

Overall Response Rate

Lancet Oncol 2017

(23)

Lancet Oncol 2017

(24)

Biomarkers of Buparlisib

 HPV (-) tumors PIK3CA/PTEN : 27%

 HPV (+) tumors PIK3CA/PTEN : 48%

From TCGA, FM, Chicago

But, more benefit in HPV (-) patients

Small sample size of PI3K pathway activated tumors in this study Incidence of PI3K pathway alteration

(25)

Contents

1. Genomic Alteration in HNSCC

2. Molecular Targeted Tx. For HNSCC 3. Immunotherapy for HNSCC

4. Precision Medicine in HNSCC

CONTENTS

(26)

Gene Set Enrichment Analysis (n=280 HNSCC TCGA)

JCI, insight , 2017

(27)

Immune Landscape of HNSCC

JCI insight, 2017

(28)
(29)

JCI insight, 2017

(30)
(31)
(32)

Nivolumab vs Chemo in HNSCC (CheckMate-141)

Recurrent HNSCC had progressed within

6 months after platinum- based chemotherapy ECOG PS: 0-1

(June 2014-Aug 2015)

Nivolumab 3mg/kg q 2weeks (n=240)

Single agent chemotherapy (MTX, docetaxel, or cetuximab)

(n=121)

Primary endpoint : OS

NEJM, 2016 Stratified by previous cetuximab

(33)

Nivolumab vs Chemo in HNSCC (CheckMate-141)

NEJM, 2016

(34)

NEJM, 2016

Nivolumab vs Chemo in HNSCC :

Overall Survival in Subgroup

(35)

Nivolumab vs Chemo in HNSCC

PD-L1(+) >1% PD-L1 < 1%

NEJM, 2016

(36)

OS by PD-L1 Expression and p16 status

NEJM, 2016

(37)

Treatment-p16 Interaction

P16 (+) Tumors HR :0.56(0.32-0.99) p16 (-) Tumors HR: 0.73 (042-1.25)

NEJM, 2016

(38)

Adverse Event of Nivolumab

NEJM, 2016

(39)

Pembrolizumab in Platinum-and Cetuximab- Refractory HNSCC (KEYNOTE-055)

 R/M HNSCC

 Resistant to both platinum and cetuximab

 Measurable Ds.

 ECOG PS: 0,1 (n=171)

 PD-L1 (+) =82%

 HPV(+) =22%

 Prior systemic therapies median 2 (range 1-6)

 ORR=16% (11%-23%)

 Median duration of response : 8months (2+ to12+ months)

 Median PFS= 2.1 months

 Median OS=8 months

JCO, 2017

(40)

Clinical Outcomes by HPV Status

JCO, 2017

(41)

Clinical Outcomes by PD-L1 Status : KEYNOTE 055 (Pembro. Single)

JCO, 2017

(42)

Potenti a l Therapeutic Targets in HNSCC

Cancer, April 1, 2017

(43)

• Hyperprogression {TGKR≥2} : 10/34 (29%)

• Pseudoprogression : None

Annals of Oncology,2017

(44)

Annals of Oncology,2017

(45)

PFS and OS of Hyperprogressors vs Non-hyperprogressors

PFS (RECIST) PFS (irRECIST)

OS

Annals of Oncology,2017

(46)

Contents

1. Genomic Alteration in HNSCC

2. Molecular Targeted Tx. For HNSCC 3. Immunotherapy for HNSCC

4. Precision Medicine in HNSCC

CONTENTS

(47)

정밀의료(1) NCI-MATCH

• 미국 주도로 2015년 8월 시작

• 대상: 표준항암화학요법에 실패한 모든 고형암 환자

• 6개 제약회사 참여 NGS

반응 없음 반응 있음

약물 유지 Actionable mutation 발견

고형암 3000명, 림프종 1000명 스크리닝 목표

임상시험연구약물 투여

질병진행 actionable 다른

mutation 확인

다시 생검

Yes

Actionable mutation

없음

No

연구참여종료

(48)

정밀의료(2) MOSCATO

• 프랑스 주도로 2011년 시작,

• 유전자 기반 항암치료에 따른 효과를 연구

2016년 11월까지 1,110명 등록

948명에서 암조직 생검 시행 (111명이 두경부암)

739명에서 NGS+/CGH결과를 얻음

411명에서

actionable target에 따른 치료군 배정 199(19%)명에서 치료 시행

• 암환자 1,100명 등록 목표

• 2014년부터 WES+RNAseq

105 종류의 actionable mutation 중 78%를 차지한 most common 27 mutations

PIK3CA mut

FGF4 Amp

FGF3 Amp KRASmut

FGFR1 PIK3CAAmp Amp

(49)

MOSCATO 01 Trial- Study Flow

(50)

MOSCATO 01 Trial- Study Flow

Cancer Discovery, June 2017

HNSCC:

111명 조직검사 

15명(13.5%)이 matched Tx.

전체948명 조직검사 

199명 (21%)이 matched Tx.

(51)

MOSCATO 01 Trial-Results

PFS2/PFS1 ratio > 1.3

33% (63/193) ORR : 11% (22/194) OS : 11.9 months

(52)

MOSCATO 01 Trial-Results

Cancer Discovery, June 2017

(53)
(54)

재발성/전이성 두경부암 우산형임상시험 (암정복과제:2016-2020)

암조직 유전체분석 유전체결과해석 및 적합한 임상시험약 선택을 위한

Molecular tumor board meeting

두경부암

PathwayEGFR (15%)

PathwayFGFR (10%)

PathwayPI3K (30%)

Cell Cycle Pathway 20% in HPV(-)

Immune pathway

Poziotinib Nintedanib BYL719 Abemaciclib Durvalumab+

tremelimumab

After 1st line chemotherapy

유전자변이발견된

표적치료제

2상임상시험에서 총 약 200명의 환자 등록, 표적항암제의 유효성과 안전성 검증

연구책임자 윤환중 교수님

(55)

정밀의료의 한계 (SHIVA)

Lancet Oncology 2015

(56)

Summary

1. Many genomic differences btw HPV(+) and HPV(-) HNSCC

2. FDA approved targeted drugs in HNSCC : cetuximab, nivolumab, pembrolizumab

3. HPV (+) : higher immune cells infiltration,

(CD8 T cell, Treg, NK-cell, memory T cell…)

HPV (-) : lower immune cells infiltration, high mutations burden,

molecular tobacco signature (immunosuppression)

 Strategy of Immunotherapy may be different

4. Precision medicine in HNSCC: not dream, it’s reality

(57)

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