should all gi cancer patients should undergo ngs testing ... · all patients with advanced gi...
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Michael Pishvaian, MD, PhD
Associate Professor, GI Medical Oncology
Co-director for Clinical Research at the Sheikh Ahmed Bin Zayed Al Nahyan
Center for Pancreatic Cancer Research
The University of Texas, MD Anderson Cancer Center
Should all GI Cancer Patients Should Undergo NGS Testing? – Definitely, yes!
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MD Anderson
▪ Speaker/Consultant:• AstraZeneca/MedImmune, Caris Life Sciences, Celgene, Merrimack,
Perthera, RenovoRx and Sirtex Medical, Merck▪ Travel, Accommodations and Expenses Support:
• AstraZeneca/MedImmune, Caris Life Sciences, Perthera and SirtexMedical, Merck
▪ Stock:• Perthera
▪ Research Funding to my Institution:• ARMO BioSciences, Bavarian Nordic, Bayer, Bristol-Myers Squibb,
Calithera Biosciences, Celgene, Celldex, Curegenix, Fibrogen, Genentech,Gilead Sciences, GlaxoSmithKline, Halozyme, Karyopharm Therapeutics,MedImmune, Merck, Novartis, Regeneron, Pfizer, Pharmacyclics andTesaro
▪ I will be discussing “off-label” use of approved therapies• Almost by definition
Disclosures
2All Patients with Advanced GI Cancers Should Undergo NGS Testing
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▪ Advanced GI cancers are deadly
• While outcomes have improved, chemo benefits are limited
• Standard treatment (chemotherapy) is EXPENSIVE
▪ Testing DOES reveal legitimately actionable mutations
• Panel vs. single gene
▪ Actionable mutations lead to a disproportionate benefit
• There is survival benefit
Why NGS for Advanced GI Cancers
Should be the Standard of Care
3All Patients with Advanced GI Cancers Should Undergo NGS Testing
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▪ GI Cancers cause >3 million deaths each year worldwide
Advanced GI Cancers are Deadly
4All Patients with Advanced GI Cancers Should Undergo NGS Testing
Fitzmaurice C, et al. JAMA Oncol 2015;1(4):505-27; Mayer, RJ, et al. NEJM 2015; 372 (20):1909-1919;
Von Hoff, DD, et al. NEJM 2013; 369 (18):1691-1703; Fuchs CS, et al. 2014; 383(9911):31-39
▪ Benefits from “standard” therapies have only been incremental
• OS improvements of <2 months have → FDA approval
TAS-102 vs. Placebo, CRC
7.1 vs. 5.3 months
Gem-Nab-Pac vs. Gem, Panc
8.5 vs. 6.7 months
Ram vs. Placebo, Gastric
5.2 vs. 3.8 months
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Standard treatment is EXPENSIVE
5All Patients with Advanced GI Cancers Should Undergo NGS Testing
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)
▪ 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
TAS-102 vs. Placebo, CRC
7.1 vs. 5.3 months
Gem-Nab-Pac vs. Gem, Panc
8.5 vs. 6.7 months
Ram vs. Placebo, Gastric
5.2 vs. 3.8 months
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▪ Definition of actionability
• Literature supports high degree of benefit in patients with that
molecular abnormality (any cancer type)
OR
• Possible implication of response to therapy, based on mechanism or pathway
▪ Actionable mutations identified in every GI malignancy• Pancreatic cancer - ~25%
• Biliary Cancer - ~20%
• Upper GI Cancers - ~30% (includes HER2/ERBB2)
• CRC - ~10% (70% if you count RAS/RAF)
GI Cancers DO Harbor Actionable Mutations
6All Patients with Advanced GI Cancers Should Undergo NGS Testing
Pishvaian, et al. CCR 2018; 24(20):5018-5027; Aguirre, et al, Cancer Discovery, 2018; Nakamura H, et al. Nat Genet 2015; 47(9):1003-10;
Jain A and Javle M. J Gastro Onc 2016; 7(5):797-803; Cristescu R, et al, Nat Med 2015; 21(5):449-456
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Actionable Mutations in Pancreatic Cancer
▪ 17 – 48% of pancreatic
cancers harbor
actionable findings
All Patients with Advanced GI Cancers Should Undergo NGS Testing
Singhi, et al, Gastroenterology, 2019; Pishvaian, et al, Clinical Cancer Research, 2018; Heeke,
et al, JCO Precision Oncology, 2018; Aguirre, et al, Cancer Discovery, 2018; Witkiewicz, et al,
Nat Commun, 2015; Lowery, et al, Clinical Cancer Research, 2017; Waddell, et al, Nature,
2015; Bailey, et al, Nature, 2016; Biankin, et al, Nature, 2012; Collisson, et al, Nat Med, 2011;
Pishvaian and Brody, Oncology (Williston Park). 2017
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Actionable Mutations in Biliary Cancer
▪ Up to 40% of biliary cancers harbor actionable findings
• HER2
• FGFR
• IDH1/2
▪ Mutation profile depends upon subtype
All Patients with Advanced GI Cancers Should Undergo NGS Testing
Nakamura H, et al. Nat Genet 2015; 47(9):1003-10; Jain A and Javle M. J Gastro Onc 2016
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
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▪ If an actionable mutation is identified the “appropriate” therapy is typically not FDA approved in that disease
▪ But, there have been biomarker-based approvals
• E.g. pembrolizumab in MSI-high disease
o 3-5% of CRCs
o 22% of gastric cancers
o 1% of pancreatic cancers
Patients with Actionable Mutations
Benefit Disproportionately: MSI-High
9All Patients with Advanced GI Cancers Should Undergo NGS Testing
Le DT, et al. Science 2017; 357: 409-413
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Disproportionate Benefit: TRK inhibitors
10All Patients with Advanced GI Cancers Should Undergo NGS Testing
Drilon A, et al. NEJM 2018; 378(8):731-739
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Disproportionate Benefit: TRK inhibitors
11All Patients with Advanced GI Cancers Should Undergo NGS Testing
Pishvaian, et al, JCO-PO, 2018
▪ Entrectanib case report• 2 NTRK fusion and 1 ROS1 fusion cases
• Prolonged, and occasionally dramatic benefit
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Disproportionate Benefit: BRAF
12All Patients with Advanced GI Cancers Should Undergo NGS Testing
Van Cutsem. JCO. 2019;[Epub]. 2. Kopetz. ASCO 2017. Abstr 3505.
Slide thanks to Axel Grothey and Clinical Care Options
▪ SLI: Encorafenib, cetuximab, binimetinib in CRC• ORR 48%; mPFS 8.0 months
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BRAF Mutated Pancreatic Cancer
▪ From the KYT database - of 766 patients
▪ 18 BRAF mutations
• 5 V600E
• 13 others
• Almost always exclusive of KRAS mutations
▪ Sustained PR in a BRAFV600E mutated patient
treated with dabrafenib + trametinib
All Patients with Advanced GI Cancers Should Undergo NGS Testing
Guan, et al. ASCO-GI, 2017
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Disproportionate Benefit: Others
14All Patients with Advanced GI Cancers Should Undergo NGS Testing
Sartore-Bianchi A, et al. 2016;17(6):738-756; Javle M, et al. JCO 2018; 36(3):276-282
▪ HER2 Amplified CRC• 5% of screened patients
• ORR 30%
▪ FGFR Mut Cholangio• 13 – 17% of IHCC
• ORR 15%
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HR-DDR Mutations in Pancreatic Cancer▪ 17 – 25% of pancreatic adenocarcinomas harbor mutations in the DDR genes
• Homologous recombination DNA damage response (HR-DDR) mutations
• BRCA1, BRCA2, ATM, PALB2, ATRX, RAD51, and others
All Patients with Advanced GI Cancers Should Undergo NGS Testing
Gene N (616 Total)
ATM 28 (4.5%)
BRCA2 18 (2.9%)
SMARCA4 10 (1.6%)
BAP1 8 (1.3%)
BRCA1 8 (1.3%)
BRIP1 6 (1.0%)
PALB2 5 (0.8%)
CHEK2 4 (0.6%)
FANCA 4 (0.6%)
FANCC 3 (0.5%)
RAD50 3 (0.5%)
STAG2 2 (0.3%)
BARD1 1 (0.2%)
CHEK1 1 (0.2%)
FANCG 1 (0.2%)
▪ Know Your Tumor®
(KYT) Dataset
• 16.5% HR-DDR
▪ Caris Database
Review
• 16.9% HR-DDR
Pishvaian, et al, Clinical Cancer Research, 2018; Heeke, et al, JCO Precision Oncology, 2018;
Aguirre, et al, Cancer Discovery, 2018; Witkiewicz, et al, Nat Commun, 2015; Lowery, et al;
clinical Cancer Research, 2017; Waddell, et al, Nature, 2015; Bailey, et al, Nature, 2016;
Biankin, et al, Nature, 2012; Collisson, et al, Nat Med, 2011
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PARP Inhibitors in Pancreatic Cancer
All Patients with Advanced GI Cancers Should Undergo NGS Testing
Lowery MA, et al. Oncologist. 2011;16:1397-1402; Kaufman B, et al. J Clin
Oncol. 2015;33:244-250; Shroff RT, et al, JCO Precis Oncol. 2018;2018
▪ Anecdotal evidence in pancreatic cancer- Consistent evidence of efficacy in BRCA1/2 mutant tumors• Lowery, et al - 15 patients with known BRCA1/2 mutations
o 4 patients with PARPi-based therapy
o 3PRs and one SD for 6 months
• Kaufman, et al - Olaparib in 23 patients with germline BRCA1/2 mutationso 23 pancreatic cancer patients
o 22% ORR, 1 CR & 4 PRs
• Shroff, et al, - Rucaparib in 19 BRCA1/2mutated patientso 16% ORR, 1 CR and 2 PRs
o Benefit in somatic mutated patients
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PARP + Platinum in Pancreatic Cancer
All Patients with Advanced GI Cancers Should Undergo NGS Testing
Lowery MA, et al. Eur J Cancer. 2018 Jan;89:19-26;
• Phase 1B: Cisplatin, Gemcitabine, Veliparib• O’Reilly, et al, 2018 – 1 CR and 6 PRs
o Phase Ib dose-finding ORR = 78%, mOS (gBRCA+) = 23 months
o Randomized Phase II trial in pancreatic cancer ongoing
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▪ Pennell, et al – recent analysis in NSCLC▪ Compared NGS vs. sequential single gene testing
vs. “exclusionary” testing + single gene sequential testing vs. hotspot panel testing
▪ Evaluated time-to-test results and costs
▪ Time to test results were fastest with the NGS and hotspot panels
▪ NGS panel testing was the most cost efficient
▪ 200+ genes for the cost of 2-3 single gene tests
A Panel is More Cost and Time Effective
18All Patients with Advanced GI Cancers Should Undergo NGS Testing
Pennell NA, et al. JCO Precision Oncology 2019
Single
Genes
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• One time NGS panel
“Standard” Panel for CRC
19All Patients with Advanced GI Cancers Should Undergo NGS Testing
“Standard of Care” Testing for CRC• KRAS
• NRAS
• BRAF
• MLH1
• MSH2
• MSH6
• PMS2
• HER2
• NTRK1/3
• FGFR
• ALK/ROS
and/or MSI testing
$400
$400
$400
$400
$400
$400
$400
$400
$3200
$2860
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Gold Standard: Overall Survival Benefit
All Patients with Advanced GI Cancers Should Undergo NGS Testing
Pishvaian, et al, ASCO, 2019; Manuscript submitted
▪ 1028 pancreatic cancer patients
▪ All underwent molecular profiling (w/NGS)
▪ 677 patients with outcome information
• 189 with Actionable Findings○ 46 received molecularly matched
therapy○ 143 received “unmatched” therapy
• 488 with no actionable findings
▪ Overall survival
• Matched 1y > unmatched
• Matched 1.3y > no actionable marker
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▪ Actionable mutations are not “rare”
• EU definition of rare: <1/2000 people = .05%
▪ Testing is MUCH less expensive than standard (and targeted) therapies
▪ Testing DOES reveal legitimately actionable mutations
▪ Actionable mutations lead to a disproportionate benefit
• With survival benefit
Summary: We Should be Testing
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2019 NCCN: Pancreatic Cancer
All Patients with Advanced GI Cancers Should Undergo NGS Testing
NCCN Guidelines. Pancreatic Adenocarcinoma. Version 2.2019;
https://www.nccn.org/professionals/physician_gls/pdf/pancreatic_blocks.pdf. Accessed April 25, 2019
“Germline testing is recommended for any patient with
confirmed pancreatic cancer, using comprehensive
gene panels for hereditary cancer syndromes”1
“Tumor/somatic gene profiling is recommended for
patients with locally advanced/metastatic disease [80%
of patients] who are candidates for anti-cancer therapy
to identify uncommon but actionable mutations”1
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Thank you and Questions?
23All Patients with Advanced GI Cancers Should Undergo NGS Testing