Post on 25-May-2020
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 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