New Targets in GI CancerThiago Jorge, MD

Medical Oncologist and Innovation in Oncology Coordinator at

BP– A Beneficência Portuguesa de São Paulo

Disclosures

• Travel Grant: Bayer

• Speaker: Roche, Merck, Lilly, Zodiac, Nestlé

Mutation IHCC EHCCA GBC Therapy

HER2 amp or mut 11 - 20% 10 -15% Trastuzumab, lapatinib

FGFR 10 - 20% e.g. BGJ398, TAS-120

IDH1/2 22 - 28% AG-120, AG-881

PIK3CA 6 - 13% PI3Ki

BAP1 15 - 25% HDACi

EGFR 4 - 13% Erlotinib, cetuximab

Nakamura H, et al. Nat Genet 2015; 47(9):1003-10; Jain A and Javle M. J Gastro Onc 2016

Até 40% dos pacientes com mutações passíveis de ação

The Cancer Genome Atlas Network Nature 487, 330-337 (2012) doi:10.1038/nature11252

5MD Anderson All Patients with Advanced GI Cancers Should Undergo NGS Testing

Standard treatment is EXPENSIVE

The Medical Letter on Drugs and Therapeutics, June 6, 2016 (https://secure.medicalletter.org/w1496f); Goldstein DA, et al. Med Oncolo 2016; 33 (5):48; Kuznar W.

OncLive Jan 19, 2018 (https://www.onclive.com/conference-coverage/gi-2018/adding-ramucirumab-to-frontline-chemo-does-not-improve-survival-in-gastric-cancer)

Presented by Dr. Pishvaian at WGICC 2019

NGS Testing + Fusion testing RETAIL costs• At most, $7800

• Recent panel - $1800 including RNA sequencing

28 days of TAS-102

$10,948

28 days of Gem-Nab-Pac

$12,221

28 days of Ramucirumab

$14,889

7.1 vs. 5.3 months 8.5 vs. 6.7 months

TAS-102 vs. Placebo, CRC Gem-Nab-Pac vs. Gem, Panc Ram vs. Placebo, Gastric

5.2 vs. 3.8 months

Drilon A, et al. NEJM 2018; 378(8):731-739 Le DT, et al. Science 2017; 357: 409-413

TRK Receptor

Gene (Chromosomal

Location)

Functions

Natural LigandsDevelopmental Adult

TRKA NTRK1 (1q23.1) Cellular differentiation/sensory neuron subtype

specification and development of pain and

thermoregulation modalities1,3

Pain signaling, thermoregulation

Nerve growth factor (NGF), neurotrophin-3 (NT-3)

TRKB NTRK2 (9q21.33) Development of sensory neurons in the brain1,3

Regulation of movement, memory, mood, appetite, body weight

Brain-derived neurotrophic factor (BDNF), neurotrophin-3/4/5 (NT-3/4/5)

TRKC NTRK3 (15q25.3) Neuronal differentiation, axon outgrowth/guidance, and

synaptic plasticity1,3Proprioception NT-3

NTRK Fusions

Nakagawara A. Cancer Letters. 2001;169:107-114. Vaishnavi A, et al. Cancer Discov. 2015;5:25-34. Blake J, et al. EORTC-NCI-AACR Conf. 2016;69:ENA-0491/Poster No. 442.

Aria Vaishnavi et al. Cancer Discovery 2015;5:25-34

CNS

Astrocytoma1

Low-grade glioma2

Glioblastoma3

GI

Colorectal cancer2,4

Cholangiocarcinoma5

Pancreatic cancer6

Head and Neck Squamous cell

carcinoma2

Lung

Adenocarcinoma2,7

Large cell neuroendocrine carcinoma8

Other

Acute myeloid leukemia9

Breast-invasive carcinoma2

Melanoma2

Adult sarcoma2

Congenital mesoblastic nephroma10,11

Recurrent papillary thyroid cancer12

Pontine glioma13

Spitzoid melanoma14

Pediatric and young adult soft tissue sarcomas15

Pan-negative gastrointestinal stromal tumors (GIST)16

Mammary analogue secretory carcinoma (MASC) of the salivary gland17

Secretory breast carcinoma18

Infantile fibrosarcoma19

References: 1. Jones DT, et al. Nat Genet. 2013;45:927-934. 2. Stransky N, et al. Nat Commun. 2014;5:4846. 3. Kim J, et al. PLoS One. 2014;9:3. 4. DeBraud F, et al. ASCO. 2014 (abstr 2502). 5. Ross JS, et al. Oncologist. 2014;19: 235-242. 6. Bailey P, etal. Nature 2016;531:47-52. 7. Vaishnavi A, et al. Nat Med. 2013;19:1469-1472. 8. Fernandez-Cuesta L, et al. AACR. 2014 (abstr 1531). 9. Kralik JM, et al. Diag Path. 2011;6:19. 10. Argani P, et al. Mod Path. 2000;13:29. 11. Rubin BP, et al. Amer J Path.1998;153:1451-1458. 12. Leeman-Neill RJ, et al. Cancer. 2014;120:799-807. 13. Wu G, et al. Nat Genet. 2014;46:444-450. 14. Wiesner T, et al. Nat Commun. 2014;5:3116. 15. Morosini D, et al. ASCO. 2015 (abstr 11020). 16. Brenca M, et al. J Path.2016;238:543-549. 17. Bishop JA, et al. Hum Pathol. 2013;44:1982-1988. 18. Tognon C, et al. Cancer Cell. 2002;2:367-376. 19. Bourgeois JM, et al. Am J Surg Pathol. 2000;24:937-946.

≤5% 5%-25% ≥75%

4Presented by Nathenson at WGIC 2019

-100

40

20

0

-20

-40

-60

-80

60 Biliary tract

Pancreas

Appendix

GIST

Colon

Gall bladder

Be

st c

han

ge f

rom

bas

elin

e in

tar

get

lesi

on

s(%

)

9

Objective response rate (95% CI) 67%

Partial response 7

Complete response 1

Stable disease 3

Progressive disease 1

*

*One patient initially diagnosed as GIST was determined to have peri-rectal undifferentiated soft tissue sarcoma

Note: Investigator assessmentPresented by Nathenson at WGIC 2019

6 21 24 279 12 15 18

Overall treatment duration (months)

0 3Median time to response = 1.8

months

10

Treatment after progression

Treatment ongoing

First objective response

Complete response

Note: Investigator assessmentPresented by Nathenson at WGIC 2019

Data cut-off: 31 May 2018

CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; MASC, mammary analogue secretory carcinoma

Baseline characteristics

NTRK+All

patients

(n=54)

NTRK+ CRC

patients

(n=4)

NTRK+pancreatic

patients

(n=3)

NTRK+cholangio

patients

(n=1)

Age, years Range 21–83 56–75 31–50 34

Sex Female Male

59%41%

40

03

10

Race White Asian

80%13%

31

30

10

ECOG PS 0 43% 0 2 11 46% 3 1 0

2 11% 1 0 0

Prior lines of systemic

therapy

01

≥2

37%20%

43%

20

2

11

1

00

1

CNS mets at baseline 22% 0 0 0

Presented by Siena at WGIC 2019

Efficacy

outcomes by

BICR

NTRK+ CRC

patients

(n=4)

NTRK+pancreatic

patients

(n=3)

NTRK+cholangio

patients

(n=1)

ORR,† % 25.0 66.7 100

PR, n 1 2 1

DoR, mos 4.8 7.1,12.9 9.3

PFS range, mos 0.6–5.7 6.2–17.5 12.0

OS range, mos 0.6–23.4 9.1–20.3 17.1

Results per Blinded Independent Central Review (BICR)

Best

% c

ha

ng

e f

rom

ba

se

lin

e*

Note: one CRC patient without matched pre/post therapy scans was excluded from the plot

Presented by Siena at WGIC 2019

Other fusions in GI cancer

J Clin Oncol. 2018 Jan 20;36(3):276-282

Infigratinib

Laurent-Puig ate WGIC 2019

BRAF mutant

Presented by Kopetz at WGIC 2019

Presented by Kopetz at WGIC 2019

Triplet therapy

ENCO + BINI + CETUX

n = 205

Doublet therapy

ENCO + CETUX

n = 205

Control arm

FOLFIRI + CETUX, or

irinotecan + CETUX

n = 205

R

1:1:1

Phase 3

A separate Safety Lead-in cohort of n=7

in Japan was enrolled subsequently.

Results will be reported at a later time.

Primary

Endpoints:

OSOverall

Survival

Randomization was stratified by ECOG PS (0 vs. 1), prior use of irinotecan (yes vs. no),

and cetuximab source (US-licensed vs. EU-approved).

Patients with BRAFV600E mCRC with disease progression after 1 or 2 prior regimens; ECOG PS of 0 or 1;

and no prior treatment with any RAF inhibitor, MEK inhibitor, or EGFR inhibitor

Triplet vs Control

Secondary Endpoints: Doublet vs Control OS & ORR, PFS, Safety

ORR

(Blinded

Central Review)

Safety Lead-in

ENCO + BINI + CETUXN = 30

Encorafenib 300 mg PO daily

Binimetinib 45 mg PO bid

Cetuximab standard weekly

dosing

Presented by Kopetz at WGIC 2019

Median OS in months (95% CI)

Triplet Control

9.0 (8.0–11.4) 5.4 (4.8–6.6)

HR (95% CI), 0.52 (0.39–0.70)2-sided P<0.0001

Su

rviv

al P

rob

ab

ilit

y(%

)100

90

80

70

60

50

40

30

20

10

0

Triplet 224 186 141 103 69 37 24 14 6 4 2 0

Control 221 158 102 60 34 18 15 7 4 2 1 0

0 2 4 6 8 10 12

Time (months)

14 16 18 20 22

Presented by Kopetz at WGIC 2019

Doublet

N=73

N=87 N=98

Triplet

Control

HER 2

Cell. 2018 Apr 5;173(2):321-337

HER 2 in CRC

A consensus driven diagnostic algorithm for ‘HER2 positivity’in mCRC was previously built on 348 tumor colon samples

Diagnostic algorithm

Main features in CRC:• IHC U-shaped as in gastric• Good correlation IHC-ISH• Cellularity of amplification

quite homogeneous• Low intra-sample

heterogeneity

Bianchi at WGCI 2019

Lancet Oncol. 2016 Jun;17(6):738-746

30%

Trastuzumab + Lapatinib

Patient selection:• FISH or CISH +

(HER2/Ch17 > 2 or HER2 GCN > 6)

• NGS: HER2 amplification based on copy number gain

• IHC 3+

32%

Lancet Oncol. 2019 Apr;20(4):518-530

Trastuzumab + Pertuzumab

Her-2 in PADC and BTC

The “Undruggable” mutation - KRAS

DNA Repair

J Natl Compr Canc Netw 2017;15(8):1063–1069

Conclusions

• NGS is common practice and recommended for PADC and BTC

• Most of the drugs are still off label

• Always look for “agnostic”indications – MSI, NTRK

• Germline BRCA is recommended for PADC