Download Feasibility Study of Genomic Biomarker Profiling for

Feasibility Study of Genomic Biomarker Profiling for Patients
with Metastatic Colorectal Cancer
Bradley L. Smith1, Philip Breitfeld1, Jennifer Cubino1, Victor Weigman1, Donald P. Richards2, Ki Y. Chung3.1
1 Quintiles, Durham, NC;
2 Texas Oncology - Tyler, TX;
3 Cancer Center of the Carolinas, Spartanburg, SC
Abstract
Background: The adoption of Next-Generation Sequencing (NGS) platforms
AmpliSeq Cancer Hotspot Panel v2 assay, enriching for hotspots within 50 cancer-
therapies in other indications. 84.3% of patients had variant associated with open
and development of targeted oncology drugs have enabled matching of patients
related genes. Clinical annotation and reporting to the doctors was provided by
clinical trials. Of these 43 patients, 32 had multiple biomarkers with associated
and drugs. The authors undertook an observational, clinical study to explore the
N-of-One. Basic demographic and clinical information was collected but formal
trials. Overall, more than 100 mutations were identified including alterations in
feasibility and potential clinical benefits of an upfront approach to the genomic
disease monitoring and follow-up was not performed. Clinicians were asked to
KRAS, BRAF, EGFR, PIK3CA, GNAS, TP53, APC and other genes. The number
profiling of tumors from metastatic colorectal cancer (mCRC) patients. The study
report the impact of the genomic test report on patient recommendations.
of actionable mutations was not associated with progressor status. Doctors
sought to determine the number of drug targetable genomic changes, which
Results: The study enrolled and profiled 51 stage IV mCRC patients from July
recommended clinical trials following profiling and reporting of genomic alterations
occur within mCRC patients including a comparison of patients who progress early
2013 to October 2013 from 14 sites in the U.S.; one additional patient was enrolled
in 15 out of the 43 patients (35%) that had actionable mutations.
over the targeted number. Subjects were stratified by time to progression prior to
Conclusions: The outcome of this observational study demonstrates the
Methods: The study targeted enrollment of 50 mCRC patients within the U.S.
entering the study. The study population was evenly distributed across early
feasibility of rapid screening and reporting of NGS genomic results targeting
Oncology Network followed by collection of archival formalin-fixed paraffin
(<1 yr) and late progressors (>1 yr) with a median age of 62. Test turn-around time
actionable mutations in mCRC. The lack of an association between early and late
embedded (FFPE) samples and genomic testing. Sample collection and
averaged 15 days. 98% of the bases sequenced in the genomic analysis reached
progressors, suggests that a greater sample size will be required for future studies.
processing was performed at Quintiles Central Laboratories followed by testing and
the target coverage necessary to identify 5% variant frequency in the sample.
The reported impact on clinician recommendations indicates the value of the
bioinformatic analysis at the Quintiles EA Genomic Laboratory. Genomic profiling
Genomic variants associated with approved therapies in mCRC were observed
results to inform treatment and clinical trial decisions.
was performed on the Ion Torrent PGM following enrichment of tumor DNA via the
in 7.8% of patients while 64.7% of patients had variants associated with approved
versus late.
Background
Introduction
• Cancer genomics is moving into practice driven by the increased molecular
complexity of cancer and drugs that target those genomic alterations.
• Explosion of targeted agents in cancer; 22% of the pipeline agents currently in
pivotal trials are being developed in a biomarker-defined patient population.
Potential solution:
• Remove barriers to patient participation in clinical trials: multiplex testing allows
for efficient use of scarce tumor samples and rapid testing of the sample ensures
patients are not delayed in receiving treatment.
• Genomic profile patients to match study criteria prior to site startup.
• Recent technical development of genomic platforms enables rapid and broad
genomic profiling.
• Clinically annotate and report results to clinician.
Patient pre-profiling platform
Summary:
mCRC 50 patient trial with 50-gene NGS profiling and reporting to clinicians
performed in collaboration with U.S. Oncology Research (USOR) Network
The Challenge: efficient execution of programs targeting niche oncology
populations with specific genomic alterations.
Feasibility study to demonstrate pre-profiling operational platform
• How do I cost-effectively develop a drug with an anticipated high screen failure
rate in a timely fashion?
Primary objective:
•To determine the number of drug targetable genetic changes, which occur within
patients with mCRC. The number of clinically actionable mutations with FDAapproved drugs will be compared to the number without FDA- approved drugs
and to actionable mutations with associated clinical trials.
Secondary objectives:
•To determine the feasibility of collecting tumor samples and having those patients
undergo tumor genomic analysis.
•To investigate the number and cause of failed analyses after registration and
tissue submission.
•To determine if physicians took into consideration regimens that were suggested
by the results of the sequencing analysis when deciding their patients’ next line
of therapies.
Operational results
Pilot study description
Ion Torrent PGM NGS Platform
Introduction
•50 genes; Hot Spot coverage (not total open reading frames)
•2800 COSMIC mutations
•~26kbp of captured sequence
Study Characteristics
• Total months of enrollment: Approx. 3 months (planned for 6 months)
• Number of Sites: 14 (all within U.S. Oncology Research Network and the U.S.)
• Sample type: FFPE archival slides or blocks
• Total patients in Early (recurrence <1 year) Occurrence arm: 25 patients
• Total patients in Late (recurrence after 1 year) Occurrence arm: 26 patients
• Total patients diagnosis: 100% Stage IV Colorectal Cancer
• Both recurrence and gender were distributed evenly across patient age groups
• 80% of enrolled patients were Caucasian
Performance
•> 400X depth of coverage for ≥ 95% of the targeted regions
•98.4% of samples in study were powered to identify alleles
at ≥5% frequency (i.e. “callable bases”)
• 10% of patients in this study had callable bases with
between 90-95% coverage, potentially due to biological
factors
Genomic test turn-around-time (TAT) summary
PGM - GENE LIST
ABL1
EZH2
JAK3
PTEN
AKT1
FBXW7
IDH2
PTPN11
ALK
FGFR1
KDR
RB1
APC
FGFR2
KIT
RET
ATM
FGFR3
KRAS
SMAD4
BRAF
FLT3
MET
SMARCB1
CDH1
GNA11
MLH1
SMO
CDKN2A
GNAS
MPL
SRC
CSF1R
GNAQ
NOTCH1
STK11
CTNNB1
HNF1A
NPM1
TP53
EGFR
HRAS
NRAS
VHL
ERBB2
IDH1
PDGFRA
ERBB4
JAK2
PIK3CA
TAT summary:
Min: 9 Days
Max: 21 Days
Avg: 15 Days
Five samples were excluded due to prospective decision to re-sequence samples
Genomic & clinical results
Results of Genomic Analysis & Clinical Annotation
Distribution of mutations in patient population
Influence of genomic data on clinician decision making
(3 categories of actionable genomic alterations)
Approximately 3% of oncology patients participate in clinical trials in the U.S. The much higher percentage of patients informed
of relevant trials in the preprofiling study suggests preprofiling may improve clinical trial participation. This may be due to:
1. Providing genomic data improves awareness and interest in trial options
2. Patients enrolled in pre-profiling were more likely to be eligible or interested in clinical trials than patients not enrolled in preprofiling
Overall 100 mutations were observed, encompassing all 3 categories of action-ability including mutations in
PIK3CA corresponding to open clinical studies.
• Distribution of clinical recommendations and associated therapies or trials was similar across gender and age
• Data provided by N-of-One
• Number and distribution of mutations was similar between early and late progressors.
• However, a few genes/mutations were primarily found in one group and not the other (BRAF, CDKN2).
Summary
Test / profiling feasibility and performance
• High quality genomic data and a clinical report was delivered
to doctors in a reasonable time (average 15 days from sample
submission to report) utilizing archival FFPE samples
• Rapid patient enrollment indicates clinician and patient excitement
for this type of information
Profiling results
• Overall 100 mutations were observed, encompassing all 3 categories
of action-ability
• 60 distinctly different actionable alterations were observed in 43 out of
the 51 total patients (84%)
*Physicians response was limited to a single category
**8/51 patient samples had no actionable mutations or clinical recommendations
***Physicians may have reported “not influenced” due to existing use of standard of care FDA approved drug consistent with
preprofiling report
Discussion
• The most frequent actionable mutations had associated clinical
trials, followed by therapeutics approved in other indications and
therapeutics approved in CRC
• The number of actionable mutations did not statistically correlate with
patient demographics or progression status
• Progression status did not statistically correlate with specific
alterations although further investigation may be warranted
Study impact
• Genomic pre-profiling and the genomic report impacted clinician
recommendations for available clinical trials in a significant percentage
of cases that reported actionable mutations (15/43; 35%)
• Patient pre-profiling may rapidly identify qualified patients for
biomarker-driven oncology drug development
• Pre-profiling may improve trial timelines by increasing the pool of
patients participating and screened for clinical trials
• Implementation of pre-profiling will require collaboration across key
stakeholders including sponsors, CROs, clinicians and patients