두경부암의 정밀의료
국립암센터
윤 탁
Contents
1. Genomic Alteration in HNSCC
2. Molecular Targeted Tx. For HNSCC (EGFR, PI3K…)
3. Immunotherapy for HNSCC
4. Precision Medicine in HNSCC
CONTENTS
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.
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
Genomic Alteration in HPV(-)
TP53 mutation : 84%
CDKN2A/2B mutation/loss : 53%
PIK3CA/PTEN : 27%
CCND1 amplification : 26%, EGFR : 14% Annals of Oncology, 2015
Genomic Alterations in HPV(+) & HPV (-) HNSCC
JCO, 2015
HPV (+) HPV (-)
Contents
1. Genomic Alteration in HNSCC
2. Molecular Targeted Tx. For HNSCC
3. Immunotherapy for HNSCC
CONTENTS
Phase III Trials of EGFR MoAb in HNSCC
Response Rate by IHC Score
EJC, 2013
Survival Outcomes by
Different IHC Score Thresholds
EJC, 2013
OS by HPV Status (EXTREME)
Annals of Oncology 2014
PFS by HPV Status (EXTREME)
Annals of Oncology 2014
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
Potential Predictive
Biomarkers of Cetuximab
KRAS mutation BRAF mutation PIK3CA mutation
NRAS mutation
Negative Selection
Colorectal cancer
HNSCCKRAS mutation (X) BRAF mutation (X) NRAS mutation (?) PIK3CA mutation (?)
HPV status (?) EGFR IHC/FISH (?)
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
Afatinib vs MTX as 2nd-line R/M HNSCC
Lancet Oncol 2015
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%
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
Dacomitinib in R/M HNSCC
CCR, 2015
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
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
Overall Response Rate
Lancet Oncol 2017
Lancet Oncol 2017
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
Contents
1. Genomic Alteration in HNSCC
2. Molecular Targeted Tx. For HNSCC 3. Immunotherapy for HNSCC
4. Precision Medicine in HNSCC
CONTENTS
Gene Set Enrichment Analysis (n=280 HNSCC TCGA)
JCI, insight , 2017
Immune Landscape of HNSCC
JCI insight, 2017
JCI insight, 2017
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
Nivolumab vs Chemo in HNSCC (CheckMate-141)
NEJM, 2016
NEJM, 2016
Nivolumab vs Chemo in HNSCC :
Overall Survival in Subgroup
Nivolumab vs Chemo in HNSCC
PD-L1(+) >1% PD-L1 < 1%
NEJM, 2016
OS by PD-L1 Expression and p16 status
NEJM, 2016
Treatment-p16 Interaction
P16 (+) Tumors HR :0.56(0.32-0.99) p16 (-) Tumors HR: 0.73 (042-1.25)
NEJM, 2016
Adverse Event of Nivolumab
NEJM, 2016
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
Clinical Outcomes by HPV Status
JCO, 2017
Clinical Outcomes by PD-L1 Status : KEYNOTE 055 (Pembro. Single)
JCO, 2017
Potenti a l Therapeutic Targets in HNSCC
Cancer, April 1, 2017
• Hyperprogression {TGKR≥2} : 10/34 (29%)
• Pseudoprogression : None
Annals of Oncology,2017
Annals of Oncology,2017
PFS and OS of Hyperprogressors vs Non-hyperprogressors
PFS (RECIST) PFS (irRECIST)
OS
Annals of Oncology,2017
Contents
1. Genomic Alteration in HNSCC
2. Molecular Targeted Tx. For HNSCC 3. Immunotherapy for HNSCC
4. Precision Medicine in HNSCC
CONTENTS
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
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
MOSCATO 01 Trial- Study Flow
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.
MOSCATO 01 Trial-Results
PFS2/PFS1 ratio > 1.3
33% (63/193) ORR : 11% (22/194) OS : 11.9 months
MOSCATO 01 Trial-Results
Cancer Discovery, June 2017
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
정밀의료의 한계 (SHIVA)
Lancet Oncology 2015
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