“At The Leading Edge of Precision Medicine-Sorting Through ... · 39% of patients: Approved...

“At The Leading Edge of Precision Medicine-Sorting

Through a Complicated Landscape”

Phil Stephens; Foundation Medicine Inc

©2014 Foundation Medicine, Inc. | Confidential 2

Molecularly Targeted Therapy Is Rapidly Evolving


Genomics is Identifying Novel Cancer Genes at an Unprecedented Rate

2003 2016

Increasing Options for NSCLC Molecular Management

Modified and updated from Pao, W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med 2012 Mar 6;18(3):349-51.


From Test (2/2012)… … To Treatment (3/2013)

Oncogenic NSCLC RET Fusions: Discovery to Clinic In ~1 Year

Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies

Lipson D, Capelletti M, et al

RET, ROS1 and ALK fusions in lung cancer

Takeuchi K, Soda M,, et al

KIF5B-RET fusions in lung adenocarcinoma

Kohno T, Ichikawa H, et al


FoundationOne® For Solid Tumors

• One comprehensive genomic profile for all solid tumors

• Interrogates entire coding sequence of 315 cancer-related genes

• Requires small amounts of tissue routine FFPE samples

including needle biopsies and FNAs

• Validated high accuracy

• 11 day median turn around time from receipt of block

• Medicare approved for NSCLC; Colorectal ca, Melanoma and

AML imminent

• FDA approval Q4 this year with broad Medicare approval


Analytic Validation Demonstration of high accuracy and reproducibility required

for clinical use

Base Substitutions (MAF 5-100%)

Sensitivity: >99.9% PPV: >99%

Insertions/Deletions (1-40bp, MAF 10-100%)

Sensitivity: 98% PPV: >99%

Copy Number Alterations (zero or ≥8 copies)

Sensitivity: >95% PPV: >99%

Gene Fusions

Sensitivity: >95% (>99% for ALK fusion1) PPV: >99%

Frampton et al, Nature Biotechnology 2013

1. Yelensky et al, Presented at AACR 2014.


¼ EGFR mutations, 35% of ALK & ROS1 fusions missed by single gene testing

CGP detects clinically relevant alterations in 65% of

patients with pan-negative NSCLC tested at MSKCC

MSKCC testing: EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, AKT1, ALK,

ROS1 & RET

● 65% of patients harbored a clinically relevant alteration by FoundationOne

26% of patients: targeted therapy in NCCN guidelines

39% of patients: Approved therapy or active MSKCC clinical trial

Clinical Cancer Research Dec 2014: Broad, hybrid capture-based next-generation sequencing

identifies actionable genomic alterations in "driver-negative" lung adenocarcinomas. 158/1078-

0432.CCR-14-2683


• KIF5B-RET expression in Ba/F3 cells

led to oncogenic transformation

• KIF5B-RET transformed cells are

sensitive to RET inhibitors

Data suggest RET kinase inhibitors should be tested in prospective

trials in NSCLC patients with RET fusions

KIF5B (exons 1-15) RET (exons 12-20)

Kinesin Coiled coil Tyrosine kinase

KIF5B-RET

Collaboration with Pasi Janne, Dana

Farber

• Sequencing cohort of ~600 NSCLC

patients revealed frequency of ~1% in

Caucasians and 6.3% in Asian without

known driver mutations

Translation

Novel KIF5B-RET Fusion Identified In First Clinical Case


Case Presentation 1: NSCLC Patient

• Middle aged female never smoker

• Stage IV-B lung adenocarcinoma

• Sequenom negative

• ROS1 (FISH) & KIF5B-RET (PCR) testing negative

• Pemetrexed (Alimta), cisplatin and bevacizumab (Avastin) started x 6

cycles then pemetrexed and bevacizumab maintenance every 3 weeks

• 18 months after diagnosis progression of disease with new bony

metastasis


Repeat CT scan after 28 days of anti-RET therapy:

disappearance of paramediastinal and near

complete resolution of pleural disease.

Baseline CT scan showing paramediastinal and

pleural-based nodularities in left upper lobe.

Case Presentation 1: NSCLC Patient

Multiple patients with RET fusions are known to have responded to a RET inhibitor


0

5

10

15

20

25

30

35

% t

um

ors

wit

hin

su

bty

pe

HER2/ERBB2 Amplifications are standard of care


0

5

10

15

20

25

30

35

% t

um

ors

wit

hin

su

bty

pe

HER2/ERBB2 Alterations Across 27 Tumor Types


0

5

10

15

20

25

30

35

% t

um

ors

wit

hin

su

bty

pe

rearrangements insertions/deletions

base substitutions amplifications

Four times the number of patients harbor druggable

HER2 alterations than typically tested for

Multiple case reports of durable patient responses

HER2/ERBB2 Alterations Across 27 Tumor Types


EGFR alterations were identified across 13 different tumor

types

6.8% total cases


53 year old female diagnosed with metastatic Inflammatory Breast Cancer

involving liver and bone in June, 2010

EGFR Exon 21 L858R Point Mutation identified

Present in 10% of lung adenocarcinomas

Associated with unprecedented sensitivity to EGFR-TKIs such as gefitinib

(Iressa) and erlotinib (Tarceva)

Diagnosis confirmed as Breast Cancer (not a lung metastasis)

Case Presentation 2: Identification of EGFR

mutation in an inflammatory breast cancer patient


• EGFR mutation identified would never have been tested for in a patient with

breast cancer

• Genomic profile led to therapy with FDA-approved agent (off label)

• Erlotinib commenced resulting in symptomatic and radiographic

improvement: response ongoing greater than 18 months

September, 2012 November, 2012

Case Presentation 2: Identification of EGFR

mutation in an inflammatory breast cancer patient


Cancer Immunotherapies (CIT) are Transformative For Some Patients

Therapy Target Approved

indications

Ipilimumab

(BMS)

CTLA-4 Melanoma

Nivolumab

(BMS)

PD-1 Melanoma,

NSCLC,

RCC, HL

Pembrolizumab

(Merck)

PD-1 Melanoma,

NSCLC,

Head and

Neck

Atezolizumab

(Roche/GNE)

PD-L1 Bladder ca,

NSCLC

Avelumab

(Pfizer)

PD-L1 Merkel cell

Additional checkpoint inhibitors at various points across the cycle are in development

Picture adapted from Mellman et al. Nature, 2011

Anti-CTLA4

Anti-PD1/PD-L1 Pembrolizumab

(Merck)

PD-1 MSI

UNSTABLE


Despite Growing Success, Many Patients Will Not Respond to CIT

Response rates for the 5 currently approved checkpoint inhibitors typically range

from ~10-30% for solid tumors

Biomarkers that potentially modulate response to cancer immunotherapy

PD1/PD-L1 expression

Tumor infiltrating lymphocytes

Tumor Mutation Burden (TMB) / neoantigen load

Tetrapeptide neoepitopes

Loss of function JAK1/2 alterations (interferon unresponsiveness)

Loss of function B2M alterations (MCH/I presentation)


TMB Correlates with CIT Response in Several Tumor Types

Snyder et al., NEJM, 2014

High TMB Melanoma

MSI-High Colorectal Cancer

Le et al., NEJM, 2015

Van Allen et al., Science, 2015

Rizvi et al., Science, 2015

High TMB NSCLC

High TMB Melanoma

20

TMB Correlates with Whole Exome Sequencing (WES) vs. 1.1 Mb assay

High correlation between mutations per Mb in WES vs. FOne (1.1 Mb assay)

~1

Mb

as

say:

Mu

tati

on

s/M

b

WES Mutations/Mb

R2=0.976

R² = 0.881

1.0

10.0

100.0

1000.0

0.1 1.0 10.0 100.0 1000.0

F1 T

MB

(m

ut/

Mb

) WES TMB (mut/Mb)

High

Intermediate

Low

Status concordance: >90%

Correlation at low TMB breaks down but can distinguish low TMB from intermediate and high


Melanoma (n = 65) NSCLC (n = 464) Urothelial carcinoma (n = 94)

M Kowanetz et al, Annals of Oncology, 2017 Balar AV et al. Lancet, 2017

CGP derived TMB Predicts CIT Response in three Indications

DB Johnson et al., Cancer Immunol Research, 2017

PFS

OS

Time (days)


High TMB may Predict CIT Response Across Most Tumor Types

Razelle Kurzrock’s group: 63 patients from 19 tumor types (excluding NSCLC and melanoma) demonstrated

that HIGH TMB was independently associated with better outcome to CIT (multivariable analysis).

RR for patients with high TMB 58% vs. low to intermediate TMB 20%; (P = 0.0001)

Goodman A et al. Manuscript submitted

• Distribution box plots ranks indications according to mutations/Mb

• Red stars indicate approved indications, blue stars indicate likely approvals

Mu

tati

on

s/M

b

Distribution of Mutational Burden Across All Indications at FMI (n = >100,000)


Why is TMB not as Predictive of CIT Response in NSCLC?

M Kowanetz et al, Annals of Oncology, 2017

Progression Free Survival Overall Survival

1619 NSCLCs with genomic profiling and PD-L1 IHC

Correlation between TMB and PD-L1 IHC expression low

Are there NSCLC specific genomic modulators of response to CIT?


STK11 Alterations may be Immunosuppressive in NSCLC

STK11 alterations enriched in

TMB HIGH, PD-L1 LOW tumors

STK11 mutant NSCLCs may do

worse on immunotherapies

HR = 2.59; P = 0.0314 Bonferroni P = 3.23*10-12

While provocative, this observation requires validation in additional cohorts


BRAF and c-MET Alterations may be Immunogenic in NSCLC

BRAF alterations enriched in TMB LOW,

PD-L1 HIGH tumors c-MET alterations enriched in TMB LOW,

PD-L1 HIGH tumors

These observations require validation in additional cohorts

P = 1.43 x 10-4

P = 4.47 x 10-4


MDM2 Amplification is Associated with CIT Hyper-Progression

6/13/2016

8/18/2016

Atezolizumab 8/18/2016

Kato et al. Hyper-progressors after Immunotherapy. Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Research. 2017. Mar 29.


The majority of BRCAwt patient tumors exhibit LOH

signature (“BRCA-like”)

Tumor BRCA/LOH Status as Determined by HRD Test (N=121, ARIEL2 Pt1)

Source: Swisher, et al. SGO 2015 presentation of clinical efficacy and safety data

BRCAmut

25%

BRCA-like 42%

Biomarker negative

33%

• 17 germline BRCAmut

• 12 somatic BRCAmut

• 1 indeterminate

• High genomic LOH


ARIEL2 part 1 designed to assess rucaparib efficacy in

three prospectively defined HRD subgroups


Duration of response in BRCAmut, BRCA-like, and

Biomarker Negative patients

Negative patients


• Challenges of ctDNA based genomic profiling


Blood Based Tumor Detection is Extremely Challenging

• Clinical requirement for a highly sensitive and

specific assay

Tumor content in blood may be less than 1% of

total cell free DNA in plasma

TUMOR

TISSUE

Circulating tumor DNA

released from tumor tissue

HEALTHY

TISSUE

Cell free circulating

DNA released from

healthy tissue


ctDNA Assays Are Not Appropriate for Many Cancer Patients

Up to 40% of patients will be denied standard of care treatment using

ctDNA assays alone as they shed no detectable ctDNA into bloodstream

% Patients with at least one cancer-related

alteration

0%

20%

40%

60%

80%

100%

Kurzrock, et al (n=171) Schwaederle, et al(n=439)

FoundationCOREDatabase (n=21,155)

ctDNA

58%

FOne

98%

FOne

96%


Recent study: Comparison ctDNA and tissue for ER+ breast

cancer

Temporally matched ctDNA-tissue samples

• 94% of short variant mutations found in tissue were also found in

ctDNA

• 2 mutations in ESR1, were observed in ctDNA only

• High blood vs tissue in NSCLC, colon and melanoma


Recent study: blood vs. tissue in pancreatic cancer

• Concordance between tissue vs. cfDNA very low

• ctDNA-based assay missed KRAS variants in 14/20 tissue +ve patients (70%)

• ctDNA-based assay missed TP53 variants in 15/18 tissue +ve patients (83%)

• Similar results in brain cancers and sarcomas

Pishvaian MJ et al, Oncotarget, 2016


Foundation Medicine’s ctDNA Assay Optimized to Address

the Extreme Challenges of ctDNA Diagnostics

Genes interrogated

ABL1 CDKN2A FOXL2 MDM2 PIK3CA

AKT1 CRKL GNA11 MET PTEN

ALK** CTNNB1 GNAQ MPL PTPN11

ARAF DDR2 GNAS MTOR RAF1

BRAF EGFR** HRAS MYC RET**

BRCA1 ERBB2 IDH1 MYD88 ROS1**

BRCA2 ERRFI1 IDH2 NF1 SMO

BTK ESR1 JAK2 NMYC TERT

CCND1 EZH2 JAK3 NPM1 TP53

CD274 FGFR1 KIT NRAS VEGFA

CDH1 FGFR2 KRAS PDCD1LG2

CDK4 FGFR3** MAP2K1 PDGFRA**

CDK6 FLT3 MAP2K2 PDGFRB

• ctDNA assay

optimized for both

sensitivity and

specificity for all

alteration classes

• Base substitutions, short

INDELs, copy number

changes and fusions

• >5,000x coverage

• ~150,000 bps targeted

** Assayed for gene fusions


ctDNA summary

• Pros of ctDNA

• Can provide options for patients with no tissue biopsy

• Blood draw easy; no TAT to find block/pathology issues

• If exists, finds heterogeneity and resistance mutations (EGFR; T790M)

• Appropriately priced/accurate monitoring will transform care

• Cons of ctDNA

• ~40% patients have insufficient ctDNA to broadly profile

• Less genes interrogated as higher coverage required

• No mutation burden; amplifications missed in most patients

• Most physicians do not understand the nuances of ctDNA and the

potential for patient is high with poorly validated assay


Thank you!

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“At The Leading Edge of Precision Medicine-Sorting Through ... · 39% of patients: Approved...

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