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Leading the Way to Precision Care: Molecular Diagnostics and
Therapeutics in Lung Cancers
Mark G Kris, MDMemorial Sloan Kettering
New AmsterdamUSA
Molecular Therapeutics in Lung Cancers
Financial Disclosures
AstraZeneca - Consultant
Additional DisclosuresI was born a medical oncologist but was raised by thoracic surgeons
I am a chemotherapy guy who has gone molecular
• Revolution: targeting oncogenic drivers in lung cancers• Growing opportunities from multiplex NGS testing• New agents disrupt current standards: EGFR and ALK• New Targets: NTRK, NRG, MET• Expanding the use of targeted therapies
• Adjuvant• Neoadjuvant• Oligometastases and oligoprogression
• Intersection of targeted therapies with immunotherapeutics• New research directions
Molecular Therapeutics in Lung Cancers
Introduction
Stage IV Lung Adenocarcinomas: Drug Therapy 1975-2018
No Chemotherapy 0% 10% 0%
Single Agent 15% 20% 10%
Two Drugs (Pemetrexed + Cisplatin) 25% 50% 18%
Three Drugs 35% 35% 20%
Two Drugs plus Bevacizumab 35% 51% 23%
Pembrolizumab with >50% PD-L1 45% 70%
Osimertinib with EGFR
Exon 19/21 Mutation80% 90% 72%
Alectinib with ALK
Rearrangement83% 84% 75%
Crizotinib with ROS1
Rearrangement72% 85% 74%
Response Rate 1 Year Survival 2 Year Survival
Initial Gefitinib Investigators Meeting 14 July 1996
Jose Baselga Eric Rowinsky
6 FEB 2002 11 FEB 2002
Results with Gefitinib 250 mg Daily
Lung Cancer Mutation Consortium LCMC2 Oncogenic Drivers
Aisner Clin Cancer Research 2018
N=423
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
YEARS
SUR
VIVA
L
group=ALKgroup=Doubgroup=EGFR(o)
group=EGFR(s)group=KRAS
LCMC1: Survival with the five most frequent oncogenic drivers
Altered Gene N Median Survival (95% CI)
EGFR (sensitizing) 140 4.0 years (2.7 to 5.4)
EGFR (other) 50 3.3 years (2.2 to 6.2)
ALK 73 4.3 years (3.0 to NA)
KRAS 231 2.4 years (1.9 to 3.6)
Drivers in Two Genes 32 2.0 years (1.6 to 4.6)Kris and Johnson JAMA 2014
“Looking for a Target on Every Tumor” Science 2009; 326: 218-220 www.science mag.org
Marc Ladanyi
Evolution of Multiplexed Testing Platforms
Now-Gen
MSK LC-MAP
8 genes
Point mutations only
Next-Gen
MSK IMPACT™
468 genes
Point mutations plus deletions, insertions,
amplifications
Comparable cost
MSK-IMPACT™Integrated Mutation Profiling of Actionable Cancer Targets
Capture DNA for410 cancer genes*
Next-gen Sequencing (500 - 1000 x)
DNA from FFPE Tumorand Normal cells
Align to genomeand analyze
Won H, et al., Journal of Visualized Experiments, Oct 2013Cheng D, et al., J Mol Diagnostics, March 2015
Somatic Mutations (Tumor-Normal Pairs):Base Substitutions
Small IndelsCopy Number Alterations
Select Rearrangements*As of February 2017 468 genes
Landscape of Lung Cancers by NGS
Jordan Cancer Discov 2017
XXXXXX
XXX
XXX
XXXXXX
XXX
Ryma Benayed
MSK-IMPACT™: determinants of success
• DNA fragments of 120-200bp with half life of ~2 hours
• Real-time, non-invasive, multi-lesions
• Cheaper because it does not require a biopsy
• Often very low amount of ctDNA in the sea of wild type DNA -”Needle in a farm”
• Specific to tumor
Diaz J Clin Oncol 2016
NGS Testing Using Cell free DNA from Plasma
Concordance:
Concordance
Tissue vs Plasma 40/42 (95%)
Plasma vs Tissue 26/42 (62%)
• Forty two patients had concurrent tissue NGS (42/86, 49% of MSK patients)– Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)
– DNA isolated from tumor tissue and matched normal peripheral blood subjected to hybridization capture and deep-coverage NGS to detect somatic mutations in 468 cancer related-genes
– Mean overall coverage of sequencing depth ranged from 500 – 1000X.
NGS results in patients with lung adenocarcinomas with no drivers with non-NGS testing
Sales
6%(n=2/31)
29%(n=9/31)
39%(n=12/31)
26%(n=8/31)
Genomic
alteration with targeted
therapy in
NCCN guidelines
Tumor from
same procedure as tumor
subjected to
non-NGS testing
Patient’s clinical course
EGFR G719A
BRAF V600ESOCS5-ALK
CLIP4-ALK
CD74-ROS1KIF5B-RET
KIF5B-RETCCDC6-RET
yes
yesyes
yes
yesyes
noyes
recently started erlotinib, response evaluation pending
subsequently passed awaydisease shrinkage (<30%) with crizotinib
partial response to crizotinib
recently started crizotinib, response evaluation pendingpartial response to cabozantinib
disease shrinkage (<30%) with cabozantinibcandidate for cabozantinib after progression on chemotherapy
Genomic alteration
with targeted agent available on or off a
clinical trial
Targeted therapeutic (clinicaltrials.gov
number) with potential activity available at institution
CDKN2A LossEGFR L747P
EGFR exon 18 del (n=2)
EGFR exon 20 ins
ERBB2 L755F
FGFR1 T141RKRAS G12C
KRAS Q61H
MDM2 Amp (n=3)
CDK4/6 inhibitor (NCT01237236)erlotinib, afatinib
pan-ERBB inhibitor (NCT01858389)
pan-ERBB inhibitor (NCT01858389)
pan-ERBB/mTOR inhibitor (NCT01953926)
FGFR inhibitor (NCT01948297)ERK inhibitor (NCT01781429)
ERK inhibitor (NCT01781429)
MDM2 inhibitor (NCT01877382)
Genomic
alteration/s identified with
no targeted therapy option
No genomic
alteration identified
Drilon Clin Cancer Res 2015
IFCT: Frequency of molecular alterations in six genes from 18,679 analyzed samples: overall population
Barlesi Lancet 2016
Gallant Cancer Discov 2015
EGFR-KDD kinase domains (GLY 696-PRO 1370)
Gallant Cancer Discov 2015
5 DECEMBER 2017
Strategies to Improve Outcomes in Patients with EGFR-mutant Lung Cancers
Arbour and Riely Cancer 2018 (in press)
AngiogenesisImmunotherapy
Chemotherapy
Targeted Therapies: Target Dependent and Independent
RadiationSurgery
Clinical Trials
Components of care for patients with lung cancers with oncogenic drivers
Unknown18%
Small Cell Transformation +MET Amplification (1%)
Small cell (1%)
METAmplification (3%)
HER2Amplification (8%)
T790M +HER2 Amplification (4%)
T790M + MET Amplification (3%)
T790M + Small Cell (2%)
T790M Alone60%
Yu Clin Cancer Res 2013
The Stale Pie: Mechanisms of acquired resistance with 1st and 2nd generation
EGFR TKIs
Published online 1 May 2015Published online 4 May 2015
Published online 7 May 2015 Acquired resistance to osimertinib and other 3rd generation agents
in patients with acquired resistanceto 1st or 2nd generation EGFR TKIs
Genetic alterations associated with acquired resistance to osimertinib
Target-dependent Target-independent
• C797S• G724S• L718Q• G796S/R/D• L792F/H/Y
• MET amplification• HER2 amplification• HER2 exon 20 insertion• EGFR amplification• KRAS amplification• KRASG12S
• BRAFV600E
• MEK1G128V
• JAK2V617F
• FGFR3-TACC3 fusions• small cell transformation
The Pie in the Oven
31 AUGUST 2017
TRK fusions found in diverse types of cancersBrain cancers (glioma, GBM, astrocytoma)
Salivary (MASC)
Lung cancer
Secretory breast cancer
MelanomaColon
Sarcoma (multiple)
32
Infantile fibrosarcoma
Gliomas
Thyroid cancer
Congenital nephroma
Sarcoma (multiple)
Common cancer with low TRK fusion frequency
Rare cancer with high TRK fusion frequency
CholangiocarcinomaPancreatic
GIST
Thyroid cancer
Spitz nevi
Hyman, LBA2501
Estimated 1,500–5,000 patients harbor TRK fusion-positive cancers in the United States annually
Larotrectinib efficacy regardless of tumor type
33Hyman, LBA2501
*
93.2
-100
-90
-80
-70
-60
-50
Max
imum
cha
nge
in tu
mor
siz
e (%
)
-40
-30
-20
-10
0
10
20
30
40
50
#
IFS
Breast
Salivary gland
Cholangiocarcinoma
Pancreas
Thyroid
Colon
Melanoma
Soft tissue sarcoma
Lung
GIST
Appendix
Science 2017
Garber Science 2017
CD74- NRG1 Fusion Activation of HER3-HER2
Fernandez-Cuesta Clin Can Res 2014
Autocrine
Juxtacrine
HER3 Inhibitors
Fernandez-Cuesta Clin Can Res 2014
NRG1 Fusion Response to anti –HER3 MAb86 man with lung adenocarcinoma with CD74-NRG1 fusion detected by MSK-IMPACT™.
baseline week 11
Alexander Drilon MD, Thoracic Oncology Service
Ado-trastuzumab emtansine for patients with HER2 mutant lung cancers
ORR was 44% (8/18, 95% CI 22-69%), study met primary endpoint.
Adjuvant OsimertinibEGFR-mutant Lung Cancers
Proposed Phase III Study Design
• Trials are designed with Power = 90%, 2-sided alpha = 0.05• Based on enrolment rate of 23 patients/month, to be confirmed by detailed feasibility
• Assumes 35% death rate at time of DFS (50% maturity)
Placebo
Osimertinib
80mg QD
Adjuvant
chemotherapy
No adjuvant
chemotherapy
3 year
treatment1:1
Stage IB–IIIA
EGFRm NSCLC
(exon 19 del
or L858R)
Complete surgical
resection
1 yr: DFS
2 yr: OS
N=660
Randomisation
stratification:
prior adjuvant
chemotherapy,
mutation type,
stage
Major pathologic response rateCorrelates in persister cellsAdjuvant therapy -investigator’s choice followed by personalized strategies per future research studies
Crizotinib(Doebele)
Osimertinib(Bivona)
ChemotherapyT-cell checkpoint inhibitor
Resectable IB-IIIB (8th ed)Enroll with local genotyping or ctDNA
EGFR
Scans, Repeat ctDNA
LCMC 4.0 Neoadjuvant Precision Multimodality Therapy
DNA Sequence Not The Whole Story
• DNA Sequencing
• Copy Number Changes
• Fusion Proteins
• Epigenome
• Gene expression profiling
• Proteome
Thomas Lynch, MD
T-Cell Checkpoint Inhibitors in Patients with EGFR-mutant Lung Cancers
• Patients with EGFR-mutant lung caners excluded from pivotal clinical trials … scant data
• Tumors with EGFR mutations generally have a low mutational burden. PR in 4%, PD-L1 >50% in 11%, high level TILs in 2% (Gainor Clin Cancer Res 2016)
• No consensus on what to do if a patient tumor has both EGFR mutation and PD-L1 > 50%. Some data Recommend frank discussion with the patient….favor PD-L1 drug 1st.
WES is a challenge to apply as a diagnostic tool… but targeted NGS is routinely used now and good estimate
Zahir, Benayed, Nature Medicine 2017Rizvi H, Sanchez-Vega, JCO [in press]
Variety of tumor typesSame DNA libraries for both
NSCLC only (Same tumor tissue in 80% cases)
Direct use of TMB from targeted sequencing as a biomarker
Rizvi H, Sanchez-Vega, JCO [in press]
Lessons learned from molecular revolution: Toward precision immunotherapy
Beatty, ASCO 2017
Don’t discard low response rates in unselected patients … just need to find the right population of people to give it to.
YES1 amplification: a new mechanism of acquired resistance to all EGFR kinase inhibitors in EGFR-mutant lung cancers
• YES1 is a Src family kinase (SFK) that phosphorylates YES1-associated protein 1 (YAP1), a Hippo pathway effector implicated in resistance to multiple targeted therapies
• Overexpression of YES1 a resistance mechanism in the EGFR-mutant PC9 lung adenocarcinoma cells by two different approaches: 1) generation of osimertinib-resistant cells through gradual dose escalation and 2) a forward transposon mutagenesis screen to recover afatinib-resistant PC9 derivatives
• Cells overexpressing YES1 exhibited resistance to all 3 generations of EGFR TKIs but sensitivity to SFK inhibitors
• Analysis of MSK-IMPACT data for 136 cases of acquired resistance to EGFR TKIs revealed 4 cases with YES1 amplification, 3 of which lacked other mechanisms of resistance
Ichihara, Cancer Research 2017, Fan (MSK) submitted for publication
Day 0
TKI Therapy
baseline scan &
pre-treatment biopsy
Scan*
sample for
pathology
sample for
whole-exome
sequencing,
RNAseq
4 6 8 10 12 14 16Week 2 18 20 22 24
scan showing initial
clinical response (ICR)
biopsy of ICR*
sample for
pathology
sample for whole-
exome
sequencing,
RNAseq, and PDX
first on-treatment scan
at 4 2 weeks
subsequent scans
every 8 2 weeks
≤ 4 weeks
26 28
Scan* Scan* Scan*
Characterization of drug-tolerant persister cells and adaptive resistance mechanisms in patients with EGFR-mutant lung adenocarcinomas treated with erlotinib or osimertinib
MSK IRB #17-290
Helena Yu, PI
Bending the survival curve in lung cancers
Hellmann JAMA Oncology 2015
Stage IVLung cancers - Today
All Lung cancers - Tomorrow
There are no “Good Prognosis” Lung Cancers
8th
Edition
5 Year
Survival
5 Year Survival
T Stage
(all N0M0)
Primary Size
(cm)
N (%) Clinical
Stage
Pathological
Stage
T1a 0.1-1 785 (8) 92% 92%
T1b 1.1-2 3157 (31) 83% 86%
T1c 2.1-3 2469 (24) 76% 81%
T2a 3.1-4 1944 (19) 67% 74%
T2b 4.1-5 612 (6) 60% 65%
T3 5.1-7 814 (8) 52% 57%
T4 >7 403 (4) 38% 47%
Rami-Porta J Thorac Oncol 2015
Components of Carefor the Therapy for Lung Cancers
Angiogenesis
Immunotherapy
Chemotherapy
Targeted Rx
RadiationSurgery
Clinical Trials
• The discovery of oncogenic drivers and the identification of drugs to target them has transformed the care of persons with lung cancers• Multiplex NGS testing at diagnosis permits the selection of the best initial targeted and immunotherapies• New trial designs can accelerate progress across diseases• Disease agnostic therapies have arrived…more are on the way• New therapies and paradigms have radically changed research priorities. Time to reboot.• As we search for cures, we must meet the challenge to bring the best drug at the best time to each patient with lung cancer today
Molecular Therapeutics in Lung Cancers
Conclusions
“ Here's my sequence...”
2005 2012
Kris
Kris
XXXXXXXXXXXXXXXXX
Response to Vemurafenib
BRAF V600E Mutant Lung Cancer
baseline 6 weeks on vemurafenib
When there are thousands of starfish and only one of you. What difference can you make throwing just one back in the water?
You can sure made a difference to this one