NCI-COG Pediatric MATCH Study

(Molecular Analysis for Therapy Choice)

Peter C. Adamson, MDD. Will Parsons, MD, PhDNita Seibel, MD

Pediatric MATCH

• Is there a clearly defined target or biomarker?

• Can the target/biomarker be detected with the

proposed testing platform?

• What is the frequency of target alterations in

pediatric solid tumors and lymphomas?

• What is the evidence linking the target to activity

of the agent? (clinical vs. pre-clinical)

• What are the specific agents in the drug class?

• Are trials of the agents already planned in

biomarker-defined patient populations?

Target/Agent Prioritization

• Level 1: FDA approved; evidence of target

inhibition, or proof of mechanism; demonstration

that patient selection with CDx are more likely to

respond

• Level 2: Agent met a clinical endpoint (objective

response, PFS, or OS); with evidence of target

inhibition; plausible evidence of a predictive or

selection assay/analyte

• Level 3: Agent demonstrated evidence of clinical

activity with evidence of target inhibition; some

evidence of a predictive or selection assay

Target/Agent Prioritization

Agent classes initially reviewed

ALK inhibitor MEK inhibitor

BET bromodomain inhibitor PARP inhibitor

BRAF inhibitor PDGFRA/B inhibitor

CDK 4/6 inhibitor PI3K/AKT/mTOR inhibitor

EGFR inhibitor ROS1 inhibitors

ERK inhibitor SMO inhibitor

FGFR inhibitor TRK inhibitor

IDH inhibitor

Target/Agent Prioritization

Agent classes not initially reviewedMDM2 inhibitors Target (MDM2 amplification) uncommon

ERBB inhibitors Target uncommon

Met inhibitor Target (met amplification) uncommon

Src/Syk inhibitor Target uncommon

c-Kit inhibitor Target uncommon

Anti-angiogenic (VEGF and Ang/Tie) Not sufficiently targeted to define biomarker

Pan-tyrosine kinase inhibitors Not sufficiently targeted to define biomarker

Aurora kinase inhibitors Target/Biomarker not known

Base excision repair inhibitor (TRC102) Target/Biomarker not known

ATR kinase inhibitor (VX-970) Target/Biomarker not known

FAK inhibitor Target/Biomarker not known

CK2 inhibitors Target/Biomarker not defined by genomic alteration

IGF1R inhibitors Target/Biomarker not defined by genomic alteration

Target/Agent Prioritization

Pediatric Match Subprotocols

(Subprotocols in development – subject to change)

• FFPE tumor samples

• Oncomine DNA/RNA mutation panel (Life

Technologies/ Thermo Fisher Scientific)

• >140 genes

• >4000 mutations of interest

• defined set of SNVs, indels, CNVs, gene fusions

• Analytic pipeline adapted for pediatric study

• Sequencing to be initially be performed at two

existing MATCH laboratories

• Plan to perform germline sequencing in parallel

Clinical Sequencing

• Level 1: Gene variant approved for selection of an approved

drug (BRAF V600E and vermurafenib). The variant will be

Level 1 in all tissues open to treatment with the approved drug.

• Level 2a: Gene variant is an eligibility criteria for an ongoing

clinical trial for that treatment

• Level 2b: Gene variant has been identified in an N of 1

responses (TSC1 and everolimus) for that treatment

• Level 3: Preclinical inferential data (in vivo and in vitro models)

that provide biological evidence sufficient to support the use of

a variant for treatment selection

Levels of Evidence: Variants

• Genomic evaluation of tumors can reveal both

tumor and germline cancer mutations

• Need plan for interpretation and return of germline

results detectable by the study mutation panel

Tumor and Germline Mutations

NCI-COG Pediatric MATCH Study

Study committees• Study design and logistics: Stacey Berg, Beth Fox

• Target/agent prioritization: Katie Janeway, Jae Cho

• Sequencing platform/analysis: Will Parsons, Jim Tricoli

• Germline result reporting: Sharon Plon, Steven Joffe

• Biospecimens: Julie Gastier-Foster

• Informatics: Hema Chaudhary, David Patton

COG leadership and staff• Peter Adamson, Catalina Martinez, Rita Tawdros, Todd Alonzo, Thalia Beeles,

Heather Day…

NCI/CTEP leadership and staff• Nita Seibel (NCI study PI), Malcolm Smith, adult NCI-MATCH leadership (Conley,

Chen, Williams, Patton…)

FDA leadership• Martha Donoghue, Greg Reaman

NCI-Molecular Analysis for Therapy Choice

(NCI-MATCH EAY131)

A phase II precision medicine cancer trial

Co-developed by the ECOG-ACRIN Cancer Research Group and

the National Cancer Institute

Mutational Burden

Lawrence MS, et al. Nature 2013:499(7457):214-218

NCI-MATCH Testing and Enrollment as of 1/29/17

4094 patients with tumor samples (N=6000)

3516 patients had received their test results

642 had a gene abnormality matching an available treatment

And proceeded to be further evaluated for the specific eligibility for the arm to which they matched

429 patients had enrolled for treatment

NOTE: These are strictly numbers reflecting a point in time and cannot be used to calculate overall rates; some are assigned and still in evaluation for eligibility for an arm; estimated 72% of those assigned will enroll

NCI-MATCH Expanded to 24 Arms May 31, 2016

Arm / Target Drugs(s)

A EGFR mut Afatinib

B HER2 mut Afatinib

C1 MET amp Crizotinib

C2 MET ex 14 sk Crizotinib

E EGFR T790M AZD9291

F ALK transloc Crizotinib

G ROS1 transloc Crizotinib

H BRAF V600 Dabrafenib+trametinib

I PIK3CA mut Taselisib

N PTEN mut GSK2636771

P PTEN loss GSK2636771

Q HER 2 amp Ado-trastuzumab emtansine

Arm / Target Drug(s)

R BRAF nonV600 Trametinib

S1 NF1 mut Trametinib

S2 GNAQ/GNA11 Trametinib

T SMO/PTCH1 Vismodegib

U NF2 loss Defactinib

V cKIT mut Sunitinib

W FGFR1/2/3 AZD 4547

X DDR2 mut Dasatinib

Y AKT1 mut AZD 5363

Z1A NRAS mut Binimetinib

Z1B CCND1,2,3 amp Palbociclib

Z1D dMMR Nivolumab

(8-10 additional arms in review/in development)

Red = accrued 35 patients; Green = nearing 35 patient

Arms to be added: Feb 2017

• EAY131-J: Herceptin + Perjeta/HER2 Amp (to follow Arm Q).

• EAY131-L: MLN0128/mTOR Mutations (New target)

• EAY131-M: MLN0128/TSC1/TSC2 Mutations (New target)

• EAY131-Z1C: Palbociclib/CDK4/CDK6 Amplification (New target)

• EAY131-Z1E: Loxo 101/NTRK Fusions (New target)

• EAY131-Z1I: AZD1775/BRCA1, BRCA2 mutations (New target)