The Genetics of Cancer: Is Personalization of Cancer Treatment - - PowerPoint PPT Presentation

The Genetics of Cancer: Is Personalization of Cancer Treatment Possible?

Keith T. Flaherty, M.D. Massachusetts General Hospital Cancer Center

Disclosures

• Board of Directors: Clovis Oncology, Loxo Oncology
• Scientific Advisory Board: Sanofi, Ziopharm, Oncoceutics, Raze, X4

Therapeutics

• Consultant: GSK, Novartis, Roche, Merck, Amgen, Array, Cerulean,

Momenta

Somatic mutation burden by cancer type

Alexandrov et al. Nature 2013

Mutation patterns sort into distinct subgroups

Alexandrov et al. Nature 2013

BRAF, NRAS and NF1 define mutually exclusive subsets of melanoma

Cancer Genome Atlas Research Network et al. TCGA symposium 2012

200

50% 25% 10%

Melanoma: the model of MAP kinase dependence

Sullivan RJ & Flaherty KT. CCR 2014

Recurrent concomitant mutations in BRAF mutant melanoma

Cancer Genome Atlas Research Network et al. TCGA symposium 2012

AKT3 MDM2 BRAF MITF

Tumor regression V600EBRAF mutant melanoma patients (vemurafenib)

RECIST 30% Decrease

Sosman J et al. NEJM 2012

• 100
• 80
• 60
• 40
• 20

20 40 60 80 100

BRAF vs. BRAF/MEK combination in V600EBRAF mutant melanoma patients

Maximum percent reduction from baseline measurement

Best confirmed response Complete response Partial response Progressive disease Stable disease

• 100
• 80
• 60
• 40
• 20

20 40 60 80 100

Dabrafenib monotherapy Dabrafenib 150 mg BID/Trametinib 2 mg QD

Long G et al. ESMO 2012

Tumor regression to erlotinib in EGFR mutant NSCLC

Rizvi N et al. CCR 2011

Tumor regression to crizotinib in ALK translocated NSCLC

Camidge R et al. Lancet Oncol 2012

BRAF inhibition in V600EBRAF melanoma & colon cancer

Kopetz, ASCO 2010

melanoma colorectal

Sosman J et al. NEJM 2012

Feedback mechanisms in the MAP kinase pathway

Mendoza et al. Trends Biochem Sci. 2011

Vemurafenib (BRAFi) or dabrafenib/trametinib (BRAF/MEKi) in BRAF mutant colorectal cancer

Kopetz, ASCO 2010 Corcoran ASCO 2012

NCI MATCH

• Identify mutations/amplifications/translocations in

patient tumor sample - eligibility determination

• Assign patient to relevant agent/regimen
• Need to sequence large numbers of tumors and

need to have large numbers of targeted treatments

• Tumor biopsies & sequencing at progression to

illuminate resistance mechanisms

– De-identified samples submitted to central labs – Whole-exome sequencing (research purposes)

Study agent Stable Disease, Complete or partial response (CR+PR)1 Actionable mutation detected No additional actionable mutations, or withdraw consent Genetic sequencing Progressive disease (PD)1 Off study PD Continue on study agent until progression Check for additional actionable mutations2 Yes No

SCHEMA

1CR, PR, SD, and PD as defined by RECIST 2Rebiopsy; if additional mutations, offer new targeted therapy

Eligibility

• Patients with solid tumors or lymphomas whose

disease has progressed following at least one line

• f standard systemic therapy (or with tumors that

do not have standard therapy)

– Exclude histologies that had been approved by the FDA or had shown lack of efficacy with an agent

• Tumor accessible to biopsy and patient willing to

undergo biopsy

• Adults
• Performance status ECOG 0-1
• Adequate organ function

Patient population considerations

• Target: at least 25% of total enrollment to be

patients who have “rare” tumors

• “Common” defined as breast, NSCLC, colon,

prostate

Statistical Design

Statistical Considerations (within each drug-by-mutation category)

Primary Endpoint:

• Overall Response Rate 5% vs. 25%
• One stage design 31 evaluable patients per arm

CLIA lab network

• Genetic platform: Ion Torrent PGM Ampliseq

custom panel

– About 200 genes – SNV, indel, CNV, targeted translocations

• Validation within and across sites: same SOP
• Selected IHC, FISH
• Competitively chosen lab sites:

– MDAnderson (Hamilton) – MGH (Iafrate) – Yale (Sklar)

Tumor Biopsy

• Prior to study entry a biopsy (4 cores) FFPE, shipped to MDACC
• Adjacent section H&E stained, examined by pathologist for

tumor content, % necrosis, inflammation, and scanned into high resolution image database

• RNA and DNA extracted from the same tissue section
• Planned research assays:

– If sufficient DNA is available, whole-exome sequencing can be performed for research

– RNA will be used for research grade gene expression profiling by either whole-transcriptome or miRNA microarray analysis

• Biopsy on progression

MATCH Assay

Workflow and Turnover Time 22

Tiss issue Fix ixation Path Review Nuc ucleic Ac Acid Ex Extraction Lib Library/Template Prep Seq Sequencing aM aMOI OI Rep eport Review

Sang Sanger Ver erifi ification

Biop iopsy Received 3 DAYS 1 DAY 1 DAY 1 DAY 1 DAY 3 DAYS

10 10-14 days

Fin Final l Report Tumor content >50% DNA yield > 20 ng

Library yield > 20 pM

Test fragments Total read Reads per BC Coverage NTC, Positive, Negative Controls

Rules of evidence for “actionable” variants

• Level 1: Credentialed for selection of an FDA

approved drug

• Level 2a: Eligibility trial for an ongoing trial
• Level 2b: N-of-1 response (with mechanistic basis)
• Level 3: Preclinical data with known PK/PD

– Selective activity in biomarker-defined model – Functional evidence that alterations in target lead to upregulation & dependence – Functional evidence of pathway activation as consequence

• f loss of function in tumor suppressor

First round of committed agents

Drug Molecular Targets Afatinib EGFR activating (non NSCLC) Afatinib HER2 kinase activating AMG 337 MET amplification AMG 595 EGFR vIII AZD 9291 EGFR T790M (non NSCLC) Crizotinib ALK fusions Crizotinib ROS translocations Dabrafenib + Trametinib BRAF V600E (nonmelanoma) GDC 0032 PIK3CA ampl/mut; WT RAS, No PTEN loss GSK2636771 PTEN Mut, PTEN IHC+ GSK2636771 PTEN Mut, PTEN IHC – GSK2636771 PTEN wt, PTEN IHC - JNJ 493 Ampl FGFR 1,2, or 4; FGFR mut MLN 0128 mTOR mut MLN 0128 TSC1 or TSC2 mut Sunitinib KIT mutations TDM-1 HER 2 ampl (non breast or gastric) Trametinib BRAF nonV600E or fusions Trametinib NF1 mut (arm1) GNAQ,GNA11 mut (arm 2) Trastuzumab/pertuzumab HER2 ampl (non breast or gastric) Vismodegib SMO or PTCH mut VS 6063 NF2 loss

Logistics

• Master Protocol with Multi-arm phase II trials
• IND for protocol template

– Arms could be added or deleted without affecting

• ther arms
• Single agents or combinationsf where recommended

phase 2 dose is known

• FDA Approved (for a different indication) or

investigational agents

• Central IRB
• 2400 NCTN sites
• CLIA lab network: validated assay

NCI: Developing a National Strategy for Precision Medicine

• NCI-MATCH Clinical trial (Genotype to

Phenotype)

– Screen for molecular features that may predict response to a drug with a given mechanism of action

• Genomics of Exceptional Responders

(Phenotype to Genotype)

– Tumor from patients who had an exceptional response to a drug for which predictive biomarkers are not known

Acknowledgements

MATCH trial leadership: NCI - Alice Chen, Barb Conley, Mickey Williams ECOG-ACRIN - Peter O’Dwyer, Stan Hamilton