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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