Sun Young RHAYonsei Cancer Center

Yonsei University College of Medicine

ESMO GI preceptorship 2019

Biological targeted agents for mGC

Disclosures

• Research grants and research support: MSD, BMS, GSK, Eli Lilly, Boehringer Ingelheim

• Consultation/advisory role: MSD, Celltrion, Ipsen, Daiichi Sankyo, Eisai

• Speaker bureau: Eli Lilly, Ipsen

Agenda

• Molecular subgrouping

• Her-2 +

• Angiogenesis

• Others

5-fluorouracil/platinum(+/- docetaxel) 5-7 Mo

Paclitaxel or Irinotecan (3-5 Mo)

+ Trastuzumab in Her-2 + + Ramucirumab

Current treatment of metastatic GC (median 16-18m)

90 % 60-65% 30-40%

Supportive2nd line Tx (3rd - 4th line Tx)1st line Tx

Chemotherapy

Apatinib?

Pembrolizumab in MSI-H/dMMR

� Asians vs westerns

� Chemotherapy is the main treatment

� Doublet vs triplet

� Various doublets are similar

� Sequential treatment improved survival

� Angiogenesis inhibitor showed benefit in 2nd line and more

� Role of molecular targeted agents?

� IO showed the potential benefit in subgroup

� New strategy: Conversion surgery, IP chemotherapy

Nivolumab, Pembrolizumab in PD-L1 +

Multiple combination

with next generation

precision medicine

1970s 1980s 1990s 2000s 2015s~2010s

Surgery/

Radiotherapy

Combination

Chemotherapy

Targeted

Agents

Various

combinations

Targeted

Agents

Precision medicine

with targeted

agents

Immunotherapy

Trastuzumab

in Her-2+ GCRamucirumab

in 2nd line GC

GCNivolumab

Pembrolizumab

Lung ca

mOS 6months ----------------------------------------------------- ---------------------------� 38-52months

mOS 6months ----------------------------------------------------- ---------------------------� 16 months

Different treatment development and outcome in Lung Ca and Gastric Ca

1) Development of high-technology2) Genomic dissection3) Understanding biology4) Translating into clinical/patient biology : Dependency?

-> novel targets-> novel drugs

5) Clinical feasibility: heterogeneity-> proper patient selection : Biomarker!!

Genomic Dissection -> Improving Treatment Outcome

Beyond histological classification

1) Deng N, Goh LK et al, GUT 2012:61:673, 2) Wang K , Yuen ST et al. Nature Genetics 2014;46; 573, 3) T CGA Nature 2014:513:202, 4) Cristescu R, Lee J et a l, Nat Med 2015: 21:449

Singapore HK

TCGAACRG

� Many negative trials • Bevacizumab• Cetuximab• Panitumumab• Lapatinib• Everolimus (mTORi)• Rilotumumab• Onartuzumab• AMG337(Met i)• AZ4547 (FGFRi)• MK2206 (AKTi)• Etc ..

Deng N, Goh LK et al, GUT 2012:61:673

� Not a genomic-driven disease?� Hit the proper target with proper biomarker/assay for patient

enrichment?

� Heterogeneity and genomic evolution? � Immunogenic tumor? Role of IO Tx?

Adding molecular targeted agents-> Genomics and precision medicine in mGC

Adding trastuzumab in Her-2 + patients(1st line): 2010

Gastric cancerLung ca

NRAS 1%

US Lung Cancer Mutation Consortium(N = 733 for 10 genes)

EGFR(sensitizing)

17%

HER2 3%

ALK 8%MEK1 <1%

MET 1%

Mut >1 gene 3%

No oncogenicdriver detected

36%

PIK3CA 1%

KRAS 25%

EGFR (other)4%

BRAF 2%

Oncogenic driver 466/733 (64%)

TCGA 30.6% -> real world <10% Her-2 10%

• Utility of molecular subtype in clinical practice: ~20%

So many differences among tumor types

� Different genomic dependency� More heterogeneity and genomic evolution? � Different TMEs� Etc …

Genomic dissection of Gastric cancer did not transl ate to the clinical practice

Therapy Target molecule Compound Study

1st line HER2 Trastuzumab ToGA （Bang et al., 2010 ）

VEGF Bevacizumab AVAGAST （Ohtsu et al., 2011 ）

HER2 Lapatinib LOGiC （Hecht et al., 2013 ）

EGFR Panitumumab REAL 3 （Waddell et al., 2013 ）

EGFR Cetuximab EXPAND （Lordick et al., 2013 ）

VEGF Bevacizumab AVATAR （Shen et al., 2015 ）

HGF Rilotumumab RILOMET-1 （Cunningham et al., 2015 ）

Met Onarutuzumab MET Gastric （Shah et al., 2015 ）

HER2 Perutuzumab JACOB （Tabernero et al., ESMO2017 ）

2nd , 3rd line HER2 Lapatinib TyTAN （Bang et al., 2012 ）

mTOR Everolimus GRANITE-1 （Ohtsu et al., 2013 ）

HER2 TDM-1 GATSBY （Kang YK, et al., ASCO-GI 2016 ）

PARP Olaparib GOLD （Yung-Jue Bang et al., ESMO 2016 ）

STAT3 BBI-608 BRIGHTHER

EGFR Nimotuxumab ENRICH

VEGFR Ramucirumab REGARD, RAINBOW

VEGFR Apatinib Li et al, ASCO 2015Revised from Lordick F, et al: Cancer Treatment Reviews 40:692-700, 2014 Table2

positive

negative

positive

Trials with molecular targeted agents in mGC

• Ethnic difference?

– LOGiC trial (lapatinib, Her-2 +)

• Preplanned exploratory analysis: OS↑ in Asian (16.5 vs 10.9 months, HR 0.68, P=0.026), younger patients (12.9 vs 9.0 months, HR 0.69, P=0.014)

– AVAGAST trial (bevacizumab)

• Reduced chemotherapy d/t toxicity

– REAL-3(panitumumab+ EOX): ↓ starting dose of xeloda/oxaliplatin (20-23%)

• Negative interaction of targeted agent & CTx

– Panitumumab & oxaliplatin

• Not properly enriched due to variability of biomarkers

– MET inhibitors, FGFR inhibitor (AZD4547)

• Monotherapy in late line of GC with less genomic dependency?

Better drugs, better assay, better design!

Possible causes of Negative results

Comprehensive molecular characterization of gastric adenocarcinoma. 2014. Nature

�The Cancer Genome Atlas - GC

� Reliable molecular subgrouping of mGC

� Multiple targets with multiple potential drugs/Tx

Clinically useful classification of GC• 438 AGC with palliative chemotherapy (Jan 2014 –Oct 2015)

• Histologic classification

+

• IHC-based molecular classification

� EBV associated: EBER ISH

� MSI-H marker: hMLH1, hMSH2, hMSH6, PMS2

� CIN with RTKs: HER2, EGFR, c-MET, PTEN, p53

� GS - all negative

-> adding reliable markers including PD-L1

EBV EBV MSIMSI

PTENPTEN p53p53 HER2HER2 EGFREGFR c-METc-MET

* Oncotarget 2016

� Stage dependent biology, Ethnic differences * Kim/Rha et al. Oncotarget 2016

Different subtype proportion from TCGA

TCGAEBV + 8.9

MSI-H 21.7

GS 19.7

CIN 49.8

YCC- metastatic GC (n=438)EBV + 3.3

MSI-H 4.8

GS 39CIN 52.2

YCC- operable Korean pts (TMA 1,302)

MSI-H 11.2

EBV + 6.6

GS 40.2

CIN 42

• 92.5% : stage I-III • 19% Asian (Vietnam, Korea)

• Most common (~40%)• With druggable targets • HER2 negative group (~90%)

-> in need of drug development

Triple Negative Gastric Cancer (EBV negative, MSI negative, HER2 negative)

-> Proper screening and new drug development!

• Most common in Korea/ Asia(30~40%)• No druggable targets• Necessity of new targets/drugs

• Potential for Immune Tx• Less incidence( ~12%)

PD-L1 / CD2747

6

5

4

3

2

1

0

mR

NA

Exp

ress

ion

(RN

A S

eq R

PK

M)(

log2

)

CIN EBV GS MSIMolecular Subtype

GroupN(%)

hMLH1 (-) or hMSH2 (-)

hMLH1 (+) and hMSH2 (+)

MSI-H (n=203)

185 (91.1) 18 (8.9)

MSS (n=261)

4 (1.5) 257 (98.5)

hMLH1 loss Intact hMSH2

YS Bae/HK Kim et al. Gut and Liver 2015; 9;629, ST Kim et al. Nat Medicine 2018;24; 1449

Proper and practical MSI screening; PCR vs IHC vs TMB

• PCR confirmed 464 GC TMA(YCC)

MSI-H case

• Mutational load in 55 GC tissues(SMC)• PCR confirmed MSI-H: 7

• MSI-H correlates with TMB(6/7)• 1 heterogeneity case of mixed population

• IHC correlates with PCR

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

F/X + C

F/X + C + Trastuzumab

Months

294290

277 266

246223

209185

173143

147117

11390

9064

7147

5632

4324

3016

2114

137

126

65

40

10

00

No. at risk

Probability of survival

Events

167182

HR

0.74

95% CI

0.60, 0.91

p value

0.0046

MedianOS

13.811.1

11.1 13.8

F, 5-FU; X, Xeloda®; C, cisplatin Bang et al. Lancet 2010

� HER2-positive : IHC 3+ or HER2 FISH (+)

Targeting HER -2 in GC: TOGA trial

Soularue et al, Bull Cancer. 2015 Apr;102(4):324-31..

Ryu et al, Eur J Cancer. 2015 Mar;51(4):482-8.Gong et al, BMC Cancer. 2016 Feb 8;16:68.

N Chemotherapy

partner

ORR mPFS mOS

Soularue et al* 34 FOLFOX/XELOX 41% 9m 17.3m

Ryu et al 55 XELOX 67% 9.8m 21.0m

Gong et al 55 XELOX 68% 9.2m 19.5m

*retrospective

Outcomes appear similar to cisplatin and 5FU in TOGA

Caveat: Phase II, uncontrolled data

NCCN Gastric Cancer Guidelines 2018

Trastuzumab + cisplatin/5FU – Category 1

Trastuzumab + other chemotherapy – Category 2B

Alternative chemotherapy regimens: Oxaliplatin -based + trastuzumab

Treatment naïve advanced HER2 positive* gastric

cancer

S-1 80-120 mg

D1-14

Cisplatin 60

mg2 D1 q21D

+

Trastuzumab

n=55

HERBIS-1

Median OS and PFS were 16.0 months and 7.8 months

Kurokawa et al, Br J Cancer. 2014 Mar 4;110(5):1163-8.

*IHC 3+ or FISH positive

ORR 68%

Alternative chemotherapy regimens: Cisplatin + S1 (SP) + trastuzumab

Treatmentnaïve advanced HER2 positive* gastric cancer

Age ≥65y

S-1 80-120 mg

D1-14

q21D

+

Trastuzumab

n=51

JACCRO GC-06

Median OS and PFS were 15.8 months and 5.1 months

Kimura et al, Gastric Cancer. 2017 Sep 21.

*IHC 3+ or FISH positive

ORR

40.8%

Alternative chemotherapy regimens: S1 + trastuzumab

HER2 positive treatment naïve

GEJ/ GC

CF/X + Trastuzum

ab

(n=388)

CF/X + Trastuzumab +

Pertuzumab

(n=392)

International multicentre trial

Primary endpoint = OS

Tabernero et al, ESMO 2017

Objective response rate (ORR) in evaluable

patients

CF/X + T CF/X + T + P

ORR (%) 56.7 48.3

Duration of

ORR (m)

10.2 8.4

Progression free survival

CF/X + T CF/X + T + P

PFS (months) 7.0 8.5

HR 0.73 (95%CI 0.62 -0.86)

CF/X, cisplatin, 5-fluorouracil or capecitabine

Despite 3.3 month absolute benefit in OS, no statistically

significant benefit in OS for addition of pertuzumab

Pertuzumab & Trastuzumab in HER + GC: JACOB trial

Objective response rate (ORR) in evaluable

patients

Taxane TDM1

ORR (%) 19.6 20.6

Duration of

response

3.7m 4.3m

Progression free survival

Taxane TDM1

PFS

(months)

2.9 2.7

HR 1·13 (0·89–1·43), p=0·31 (two-sided)

Thuss-Patience et al, Lancet Oncol. 2017 May;18(5):640-653.

mOS taxane vs TDM1 8.6m vs 7.9m

HR 1·15 (0·87–1·51), p=0·86*

2nd line anti-Her-2 Tx : GATSBY trial

Iwata H et al. ASCO 2018 (Abst 1031)

• ORR 43.2% (19/44)

• DCR 79.5% (35/44)

• PFS 5.6 months

DS-8201a: A novel HER2 ADC

TOGA HER2 positivity

by site and histology

Site of tumour

Gastric 451/2112 21%

GEJ 65/202 32%

Lauren subtype

Diffuse 68/1108 6%

Intestinal 606/1904 32%

Van Cutsem et al, Gastric Cancer (2015) 18:476–484, Lordick & Janjigian Nat Rev Clin Oncol. 2016 Jun; 13(6): 348–360. Ock et al, Clin Cancer Res.

2015 Jun 1;21(11):2520-9, Gomez-Martin et al, J Clin Oncol. 2013 Dec 10;31(35):4445-52

Her-2 IHC as a proper biomarker: Heterogeniety, Proper cut-off?!

HER2/CEP17 ratio of ~4.5 as optimal for predicting benefit from trastuzumab therapy

INACTIVE monomers ACTIVE dimer

VEGF-A

Ligand sequestration

Bevacizumab, Aflibercept

Block ligand

binding at D2/3

Ramucirumab

Block dimerization

binding D4-7

33C3a 2E11b

TKI

Sunitinib Sorafenib

(>20 others)

Angiogenesis

a Kendrick et al 2011 Mol Cancer Thera, 10, 770-783,

b Tvorogov et al, 2010, 18, 630-640

Revisiting angiogenesis in GC

Study/ Line Target Regimen N PFS OS Result (p)

AVAGAST(Asian 49%)

1st VEGF XP ± B 387387

6.75.3

12.110.1

-(0.10)

Ram/folfox(PII, Western)

1st VEGFR mFolfox6 ±Ram

8484

6.76.4

11.711.5

-

REGARD(Western 70%)

2nd VEGFR BSC ± Ram(2:1)

238117

2.11.3

5.23.8

+(0.047)

Apatinib(China)

3rd VEGFR BSC ± apatinib(2:1)

17691

2.61.8

7.65.0

+(0.0145)

RAINBOW(Asian 29%)

2nd VEGFR Pac ±Ramucirumab

330335

4.42.8

9.67.4

+(0.017)

RAINBOW subanalysis(Japan, 140)

2nd VEGFR BSC ± apatinib(2:1)

6872

5.62.8

11.511.4

-(0.5)

INTEGRATE 2nd

(PhII) VEGFR Regorafenib

Placebo152 3.9w

11.1w5

6.2PFS

(p<0.0001)

Ohtsu A, et al. J Clin Oncol. 2011;30:3968, Harry H. Yoon, et al. ASCO 2014, Charles S Fuchs, et al. Lancet 2014, Wilke H, et al. Lancet Oncol 2014, ASCO-GI 2015, Shukui Qin, ASCO 2014, #4003, Shuichi Hironaka, ASCO 2014, # 4005, Nick Pavlakis et al. ASCO GI 2015, All studies are not enriched!

Phase III trials targeting VEGF/VEGFR axis

RAM+PTX RAM mono100

90

80

70

60

50

40

30

20

10

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Ramucirumab＋paclitaxel

Placebo＋paclitaxel

Censored

No. at riskRamuciruamb+ paclitaxel

Placebo+ paclitaxel

330 308 267 228 185 148 116 78 60 41 24 13 6 1 0

335 294 241 180 143 109 81 64 47 30 22 13 5 2 0

Time from randomization (months)

(％)

Overall survival

Censored

(％)

No. at riskRamucirumab

Placebo

238 154 92 49 17 7 3 0 0

117 66 34 20 7 4 2 1 0

Time (months)

Overall survival

PlaceboRamucirumab

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28

Wilke H, et al: Lancet Oncol 15: 1224-1235, 2014 Fuchs CS, et al: Lancet 383: 31-39, 2014

(RAINBOW study) (REGARD study)

Ramucirumab 9.6 monPlacebo 7.4 mon

HR=0.807 [0.678-0.962]P=0.017

Ramucirumab 5.2 monPlacebo 3.8 mon

HR=0.776 [0.603-0.998]P=0.047

Prolonged survival in two Phase III studies

• No obvious increase of AEs in patients with ascites when treated with ramucirumab.

Safety

With ascites Without ascites

RAM/PTX(N=130)

PTX alone(N=103)

RAM/PTX(N=197)

PTX alone(N=226)

GI perforation 1 (0.8%) 0 3 (1.5%) 1 (0.4%)

Ileus 2 (1.5%) 4 (3.9%) 7 (3.6%) 5 (2.2%)

Venous thrombosis 6 (4.6%) 8 (7.8%) 7 (3.6%) 10 (4.4%)

Renal failure 4 (3.1%) 2 (1.9%) 0 5 (2.2%)

Proteinuria-related events

21 (16.2%) 8 (7.8%) 34 (17.3%) 12 (5.3%)

Jaundice 1 (0.8%) 1 (1.0%) 2 (1.0%) 2 (0.9%)

Safety in patients with ascites in RAINBOW trial

Study/ Line Target Regimen N PFS OS Result (p)

Apatinib(China)

3rd VEGFR BSC ± apatinib(2:1)

17691

2.61.8

7.65.0

+(0.0145)

INTEGRATE 2nd

(PhII) VEGFR Regorafenib

Placebo152 3.9w

11.1w5

6.2PFS

(p<0.0001)

Charles S Fuchs, et al. Lancet 2014, Wilke H, et al. Lancet Oncol 2014, ASCO-GI 2015, Shukui Qin, ASCO 2014 #4003 , JCO 2016, Nick Pavlakis et al. J Clin Oncol. 2016;34:2728-2735. All studies are not enriched!

3rd line Phase III trial targeting VEGF/VEGFR axis

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8

Months from randomisation

PlaceboRegorafenib

(HR 0.40; 95% CI: 0.28-0.59; P < .001)

Median PFS 2.6 vs 0.9 ms

LBA43: Randomized phase 3 ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastat ic gastric cancer who failed ≥2 prior chemotherapy regimens – Kang Y-K, et al

Study objective• To investigate the efficacy and safety of rivoceranib (apatinib) + BSC in patients with previously treated advanced or

metastatic gastric cancer

Kang Y-K, et al. Ann Oncol 2019;30(suppl):abstr LBA43

PRIMARY ENDPOINT• OS

R2:1

PD*/toxicity

Stratification• Geographic region (Asia vs. North America/Europe)• Disease measurability• Prior ramucirumab use• Line of therapy (3L vs. ≥4L)

Rivoceranib 700 mg/day po+ BSC (n=308)Key patient inclusion criteria

• Advanced/metastatic gastric or GEJ cancer

• Failed ≥2 prior lines of chemotherapy

• ECOG PS ≤1

(n=460) PD/toxicity

Placebo + BSC (n=152)

SECONDARY ENDPOINT

• PFS, ORR, DCR, QoL, safety

*Patients permitted to continue treatment beyond PD at the investigators’ discretion

LBA43: Randomized phase 3 ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastat ic gastric cancer who failed ≥2 prior chemotherapy regimens – Kang Y-K, et al

Key results

Kang Y-K, et al. Ann Oncol 2019;30(suppl):abstr LBA43

OS

Time from randomisation, months

Sur

viva

l pro

babi

lity

100

80

60

40

20

00 3 6 9 12 15 2418 21

Rivo 308 239 8 5143 74 32 16 1

Placebo 152 108 5 262 30 16 6 0

No. at risk

Median follow-

up, mo

Pts with event,

n (%) mOS, mo

HR

(95%CI) p-value

Rivoceranib 13.7 250 (81.2) 5.8 0.93

(0.74, 1.15)0.4850

Placebo 12.1 119 (78.3) 5.1

5.8 months

5.1 months

RAMN=16

RAMN=80

PLN=5

PLN=46

Ove

rall

Surv

ival

(mon

ths)

HER2-NegativeHER2-Positive

• Patients with Her-2 positive or who received prior trastuzumab were not excluded

from REGARD and RAINBOW.

• REGARD: among 147 pts tested for Her-2 status, 21 were HER2+ve

-> 16 patients received Ram; no different efficacy of ram in HER2+ve patients

• RAINBOW: 39 out of 665 patients received 1st line trastuzumab

-> 20 in the ramucirumab plus paclitaxel arm; 19 in the paclitaxel arm

-> similar efficacy to Her-2 negative patients

OS by HER2 Status

RAMN=16

RAMN=80

PLN=5

PLN=46

Pro

gres

sion

-free

Sur

viva

l (m

onth

s)

HER2-NegativeHER2-Positive

RAM

N=16

PL

N=5

RAM

N=80

PL

N=46

RAM

N=16

PL

N=5

RAM

N=80

PL

N=46

(Fuchs CS et al. ASCO 2015. Abastrct 4029)

PFS by HER2 Status

Ramucirumab as a 2nd line Tx in Her-2 + GC?

HER2+ve: OS 8.6 months, PFS 3.7 months

could be considered as future reference for 2nd line studies in HER2+ve GC

Jung et at. Gastric Cancer 2018

P=0.605P=0.321

Korean EAP evidence with Ram+ Paclitaxel (N=228, 14% (n=32) Her-2 +)

Dynamic changes in HER2 expression

HER status changes post trastuzumab therapy

22 pairs pre and post treatment biopsies.

7/22 (32%) HER2 negative following treatment.

More common in IHC2+ vs IHC3+ !

Pietrantonio et al, Int J Cancer. 2016 Dec 15;139(12):2859-2864.

Janjigian et al, ESMO 2016

Continue anti-her-2 treatment in Her-2 + GC?

MDACC retrospective study

2010 Jan- 2014Dec, n= 43

Humaid Al-Shamsi et al, J Gastrointestinal Oncol 2016; 7(4); 499-505.,

Juliette Palle et al, Oncotarget;2017; 8(60); 101383-101393.

Feasible, Safe, and improve survival!

Trastuzumab beyond disease progression in Her-2 + GC(I)

Multicenter AGEO retrospective study

2010 May – 2015 Dec

With trastuzumab (n= 39) vs without trastuzumab (n= 65)

Chinese 3 sites retrospective study

2012 Sep – 2015 Oct

With trastuzumab (n= 32) vs without trastuzumab (n= 27)

Qian Li et al., Oncotarget 2016;7(31); 50656-50665.

Feasible, Safe, and improve survival!

Trastuzumab beyond disease progression in Her-2 + GC(II)

Chaganty et al. Cancer Letters; 43:47, 2018, Ott PA, et al. Front Oncol 2015;5:202, Motz GT et al. Nat Rev Immunol. 2011:11:702, Huang Y et al. Blood. 2007;110:624.

Crosstalk between cancer cells – endothelial cells – immune suppression

Trastuzumab

IO: Nivolumab/Pembrolizumab etc.

� Promotes inhibitory immune cells

• Tregs

• MDSCs

• TAMs

� Compromises APC and T effector cell function

� Impairs lymphocyte development and trafficking

Currently, 2nd line phase Ib/II trial with Paclitaxel + Ramucirumab + Trastuzumab

combination at YCC

Dual blocking tumor with

oncogenic driver and

angiogenesis

Dual blocking Immune

suppressive aniogenesis and

immune checkpoints

(Ramucirumab + Pembrolizumab)

Dual blocking tumor with oncogenic driver and immune checkpoints?

-> YCC 1st line PANTHERA trial (HXP + pembrolizumab), MSKCC, KN 811 tria

Ramucirumab

� New agents in development

• New agents targeting known targets: Her-2, MET, FGFR, angiogenesis

• Ab-drug conjugates

• DDR targeting in combination with IOs

• GS-5745 (MMP-9 inhibitor)

• Napabucasin(BBI608) – stemness inhibitor

• IMAB362: Anti-CLDN18.2 antibody

• Anetumab- targeting mesothelin

• CDK4/6 inhibitors

• Epigenetics modulators: BET inhibitor

• TGF-b inhibitor

• Etc …

• Immunotherapy

� Proper patients selection: Precision Medicine