9th Oct 2019Room 2004, TRI, Princess Alexandra Hospital,

Woolloongabba, QLD

Queensland Molecular Tumour Board

Clinical Trial finding PA Cohort studies

Methodology:

Match Molecular Mutations to ascertain relevant clinical trials

Matching can be done at gene and/or mutation level

As some somatic mutations maybe be just passengersExamples PIK3CA mutatedPIK3CA:p.H1047R (well know activating mutation, appears 2300 times in TCGA cancers)PIK3CA:p.A345T (mutation never seen in TCGA cancers, unknown significance)

Match with Gene and protein level is preferred!

Examples for PA sequencingExperience in Lung cancers –Data Presented at WCLC 2019 :

O'Byrne et.al The Clinical Utility and Performance of Whole-Exome Sequencing for NSCLC Patient Care: A Comparison to Standard-of-Care WCLC Poster 2019

N=36 patients. From eBUS and FFPE samples a relevant mutation was found in most samplesThere were a variant of different types:

Matching at the gene /mutation level, recruiting Australian clinical trials: (they excluded TMB as an immunotherapy biomarker- 11 out of 36 had a high TMB )

24 % of lung cancer patients matched clinical trails in routinely tested gene EGFR, KRAS, NRAS, or BRAF were used

41% is samples could be match if the other large panel gene were included trails below

ExamplesPreliminary results for Renal cancers :

In n=30 patients there are no Australian clinical trails specific to RCCand specific molecular biomarker

There were clinical trials for patients with“advanced or Metastatic cancers targeting pathways involved in mutation in:MSH6, SK11, SMARCB1, BRCA2, TSC1, FBXW7, EGFR, CDK12 , NRAS, BRAF

OF which ~ 30% of patients has a mutation

Handoo et al, under preparation

Breast cancers – A similar analysis is underway:

Roberts et.al . Establishing whole-exome sequencing for Breast patient care SABCS 2019 Poster accepted

N=81. On average 1.5 somatic variants (Level A-C described in large clinical trails):ABCC3, AKT1, CCND1, CCNE1, CDKN2A, ERBB2, ESR1, FGF3, FGFR1, FGFR2, MTOR, NCOA3, NF2, PIK3CA, PIK3R1, PTEN, RB1, RSF1, SF3B1, TP53

In Breast Cancer Copy number loss and amplifications are more important

Matching at the gene mutation level

• What trials might capture the largest % of the cohort?• What are the unmet needs?• What genes are the most informative?• Does the profile assist in directing to the most relevant clinical trial?

A clinical trial matching tool: molecular match was used to assign clinical trials based on molecular profiling reports:https://app.molecularmatch.com

0

5

10

15

20

25

30

35

40

45

PIK3C

A

FGFR1

CCND1

ERBB2

MSH2PTEN

MSH6

STK11

EGFR

FBXW7

NTRK1

SMARCA4

BRCA2

CCND3

SMARCB1APC

TOP1

CDKN2BEZH2

FGFR2TSC1 AR

ATMBRAF

CDK12CDK4

ESR1

NTRK3RAF1

TP53

KMT2D

KMT2CFGF3

RSF1RB1

NF2CDH1

SOX10

LRP1B

AURKA

MRE11

BIRC7

CEBPA

NCOA3SMO

ABCC3

FANCC KIT

MAPK1

PTCH1

SMAD4

STAG2

DNMT3A

GSTP1POLE

PRDM1

RICTOR

TERT

ASXL1

CCNE1

CDKN2ACRBN

MTOR

NOTCH1

PDGFRAVHL

AKT1

BCOR

FOXP1REL

RUNX1

SF3B1TET2

U2AF1

% P

atie

nts

with

Mut

atio

n (n

= 7

9)

Gene

Australian Trial Available

No Australian Trial Available

By taking into account all mutations that might be informative for clinical trails we identify other genes /mutations in these patients:

85% patient had mutations which could potentially be linked to a clinical trial- Some had >1 relevant mutation

0

2

4

6

8

10

12

PA2036

295

PA2092

708

7959

51

PA8885

50

2051

182

3009

79

PA0515

86

PA9169

40

2051

995

7205

60

PA2053

030

PA8112

98

2042

327

2064

981

6179

49

PA1091

020

PA2070

255

PA3733

17

PA6215

75

1066

395

2043

180

2056

700

3813

91

5285

70

ORN3614

10

PA1034

448

PA1458

03

PA2064

980

PA2066

451

PA4288

19

PA4978

11

PA6417

68

PA7525

33

PA8946

42

1276

62

4805

29

8592

72

PA1000

44

PA2060

160

PA7344

28

No.

of m

utat

ed g

enes

with

an

avai

labl

e tri

al

Patient ID

The improvement from 77% to 85% came from genes not typically reported for Breast Cancer . But are relevant to trials in metastatic cancer that are accessible to Breast Cancer Patients

Examples

FGFR1 : 22 patientsSMARCB1/EZH2 : 5 patients

Molecular Tumor BoardSuggested strategy: Discuss relevant trials using quick approach utilizing all variants in metastatic patients

Include those of well established clinical utility and those that match to clinical trails in metastatic cancers

UR:355656

DOB: 23/04/1971

ER.PR.HER.2: 60%/60%/neg

T3N1M1 Grade 3 De novo Met

Gene Mutation Trial? No Trails Trials Drugs

CCND1 6x yes 2

NCT02107703,

NCT03701334

Abemaciclib +

Fulvestrant

CCNE1 23x no 0

FGF3 6x no 0

FGFR1 23x yes 1 NCT02052778 TAS-120

PIK3CA p.Glu545Lys yes 1 NCT03337724 Ipatasertib, Paclitaxel

RSF1 7x no 0

TP53 p.Arg213Ter no 0

Clinical Trial Discussion:PIK3CA.p.G545L:

NCT03337724 ; A Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Participants With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor-Positive, HER2-Negative Breast Cancer(Phase 3 local)

CCND1 6xNCT02107703 - A Study of Abemaciclib (LY2835219) Combined With Fulvestrant in Women With Hormone

Receptor Positive HER2 Negative Breast Cancer (Phase 3 local)

NCT03701334 - A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer

NCT02052778 - A Study of TAS-120 in Patients With Advanced Solid Tumors

FGFR1 23x

NCT02052778 - A Study of TAS-120 in Patients With Advanced Solid Tumors (NSW only)