01
Genomic Profiling:
Implications for Clinical Research
Robert Pirker, MD
Traditional Classification and Treatment of NSCLC
02
Classification
Treatment: “One-Size-Fits All” Approach
Platinum
Doublet
1. Li et al. J Clin Oncol. 2013;31(8):1039.
2. NSCLC: ESMO Clinical Recommendations. Ann Oncol. 2007;18:(Supp 2):ii30-ii31.
However, NSCLC Is a Group of Heterogeneous and
Genetically Complex Tumours
Associated with a high rate of somatic mutations
03
Adenocarcinoma
Squamous
Lawrence et al. Nature. 2013;499:214-18.
NSCLC Is Characterised by Various Driver Mutations
04
Li et al. J Clin Oncol. 2013;31(8):1039.
There is a Need for a More Precise Treatment Approach
Based on Molecular Features in NSCLC
05
Traditional “One-Size-Fits All” Approach
All patients with the same diagnosis receive
same treatment
Precision Medicine Approach
Treatment strategy based on patient’s
unique genetic profile
Genetic Profile A
Targeted Therapy
Genetic Profile B
Standard Therapy
• Biologic diversity provides opportunities for exploitation of interpatient tumour
heterogeneity by ungrouping a population into molecularly defined subsets in
which mutations and/or abnormal gene expressions drive cancer cell growth and
survival and can serve as drug targets1
• Treatment decisions made based on tumour phenotype and genomic profile hold the
promise to maximize efficacy and minimize toxicity1
Image adapted from http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/pmc_age_of_pmc_factsheet.pdf
1. Li et al. J Clin Oncol. 2013;31(8):1039.
Impact of Precision Medicine in the Treatment of Cancer:
Personalized vs Non-personalized Therapeutic Strategy
Meta-analysis of Phase II single-agent studies (570 trials; 32,149 patients)
Schwaederle et al. J Clin Oncol. 2015.61.5997 [Epub ahead of print].
06
Biomarker-based Precision Medicine Has Significantly
Improved Treatment of Patients With NSCLC
Targeting cancer drivers improves survival
EGFR common mutation+
ALK rearrangement+
1.Sequist LV et al. J Clin Oncol. 2013;31:3327-3334; 2. Shaw AT et al. N Engl J Med. 2013;368:2385-2394.
07
Consensus Recommendation of EGFR Mutation and ALK
Rearrangement Testing in All NSCLC by NCCN, ASCO, and ESMO
Lung Treatment Guideline
08
1. NCCN Treatment Guideline for NSCLC v7. 2015.
2. Leighl N et al. J Clin Oncol. 2014;32:3673-3679.
3. Kerr KM et al. Ann Oncol. 2014;25:1681-1690.
Types of Biomarkers:
Prognostic vs Predictive Biomarkers
09
Prognostic Marker
• Information about disease
outcome independent of
treatment
• Example: EGFR mutation in
NSCLC
• Mutation+ : better prognosis
• Mutation- : worse prognosis
Predictive Marker
• Information on disease outcome
related to a specific treatment
• Example: EGFR mutation in
NSCLC
• Mutation+ : ≈70% probability of
response to EGFR TKI therapy
• Mutation- : <5% probability of
response to EGFR TKI therapy
Some biomarkers are both prognostic & predictive.
Only predictive biomarkers can be used to indicate “which patients
should be treated with which drug” (a targeted therapy).
Predictive biomarkers can also identify patients who may be
harmed by “targeted therapy.”
Low and High EGFR Expression in FLEX
Pirker R et al. Lancet Oncology 2012, 13, 33
Low
HR 0.99 [95% CI 0.84 - 1.16]
High
HR 0.73 [95% CI 0.58 - 0.93]
Interaction p-value=0.044
IPASS: PFS by Mutation Status
Mok T et al. NEJM 2009, 361, 947
EGFR Mutation Positive
EGFR Mutation Negative
HR 0.48 (95% CI o.36-0.64)
HR 2.85 (95% CI 2.05-3.98)
The Importance of Validation in Biomarker Development
012
• Mutations are abundant in cancer cells
• “Driver” mutations are defined as mutations involved in development
or progression of a tumour
•
•
Constitute the minority of mutations
A subset of drivers (such as EGFR or ALK) and their component cellular
pathways may be “actionable” (i.e. have significant diagnostic, prognostic, or
therapeutic implications in subsets of cancer patients and for specific therapies
• Most mutations do not appear to play a role in cancer progression
•
“Passenger” mutations are indicative of a high mutation rate resulting from
carcinogens and DNA instability
Dancey et al. Cell. 2012;148:409.
Currently, There Remains a Need for the Identification and
Validation of Additional Biomarkers in the Treatment of NSCLC
013
1. Li et al. J Clin Oncol. 2013;31(8):1039.
2. NCCN Clinical Practice Guidelines. NSCLC Version 7.2015
014
Efforts to Identify Actionable Mutations for Treatment
of NSCLC
Strategies to Identify Biomarkers in NSCLC
015
Oxnard GR et al. J Clin Oncol. 2013;31:1097-1104.
016
Key Technologies Driving the Development of
Biomarkers
• Advances Beyond 1st-Generation/Sanger Sequencing
• Next-Generation Sequencing
Advances in Sequencing Technology and Human
Genomics
017
Li et al. J Clin Oncol. 2013;31(8):1039.
Revolution in Cancer Molecular Diagnosis Involves
High-Throughput Technology
018
Li et al. J Clin Oncol. 2013;31(8):1039.
Comparison of Traditional (Sanger) and NGS Methods
019
Ross JS et al. Am J Clin Pathol. 2011;136:527-539.
The Need for NGS Methods
020
Ross JS et al. Am J Clin Pathol. 2011;136:527-539.
021
Comprehensive Genomic Characterisation and Identification
of Targetable Genetic Lesions in NSCLC
High Rates of Somatic Mutation Were Seen in
Adenocarcinoma of the Lung
022
Somatic mutations (mean 8.9 mutations per megabase)
• 230 resected adenocarcinoma of the lung were profiled and analysed as
part of the Cancer Genome Atlas initiative
Cancer Genome Atlas Research Network. Nature. 2012;511:543-550.
New Candidate Driver Mutations Identified in
Non-Squamous NSCLC
023
• Aberrations in NF1, MET, ERBB2, and RIT1 occurred in ≈13% of the
cases and were enriched in samples lacking an activated oncogene,
suggesting a driver role for these events in certain tumours
Cancer Genome Atlas Research Network. Nature. 2012;511:543-550.
Significantly Mutated Genes in SCC of the Lung
024
•
178 squamous cell carcinomas of the lung were profiled and analysed as part of
the Cancer Genome Atlas initiative
Cancer Genome Atlas Research Network. Nature. 2012;489:519-525.
Potential Targetable Alterations in SCC of the Lung
025
Alterations in targetable oncogenic pathways in SCC of the lung
• PI4/RTK/RAS signalling altered in 69% of patients
• Alterations in the PI3K/AKT pathway genes were mutually exclusive
with EGFR alterations
Cancer Genome Atlas Research Network. Nature. 2012;489:519-525.
026
Genomic Profiling in Screening Patients
in Biomarker-driven Trials in NSCLC
Second-line Therapy in Squamous Lung Cancer
(LUNG-MAP): Study Design
027
Fresh tumour biopsy or archival FFPE tumour from eligible patients with stage IIIB or IV lung SCC whose
disease has progressed on first-line therapy is evaluated using NGS (FoundationOne) and, in some cases,
molecular assays (e.g., IHC-based), carried out in a CLIA-certified laboratory for the presence of drug-specific
biomarkers relevant to lung SCC that may serve as targets for drugs currently under study in Lung-MAP.
Results are returned within 10–14 days of tissue submission.
Herbst RS et al. Clin Cancer Res. 2015;21:1514-1524.
Second-line Therapy in Squamous Lung Cancer
(LUNG-MAP): Schema for Sub-studies
028
*Archival FFPE tumour, fresh core needle biopsy (CNB) if needed.
TT = targeted therapy; CT = chemotherapy (docetaxel or gemcitabine);
TKI = tyrosine kinase inhibitor (erlotinib).
Herbst RS et al. Clin Cancer Res. 2015;21:1514-1524.
ALK Master Protocol in Advanced Lung Adenocarcinoma:
Proposed Design
029
A joint NRG/NCI clinical trial to test 2nd-generation ALK inhibitors*
PIs: Alice Shaw, MD, Shakun Malik, MD
*Ariad: AP26113; Ignyta: RXDX-101; Novartis: ceritinib; Pfizer: PF-0643922;
Roche/Chugai: Alectinib; Tesaro: TSR-011; Xcovery: X-396
SWOG Web site. http://swog.org/Visitors/Spring15GpMtg/PlenaryI/02_Abrams.pdf. Accessed August 26, 2015.
ALCHEMIST Trial: Trial Design
030
*
*NGS to understand the mechanisms of drug resistance and genomic evolution.
1. www.clinicaltrials.gov. Accessed August 26, 2015; 2. Gerber DE et al. Clin Pharmacol Ther. 2015;97:447-650.
031
Genomic Profiling in NSCLC: Key Considerations and
Future Perspectives
Considerations for Genome Profiling in the Management of
Cancer, Including NSCLC
032
• Sampling1
– High intratumour heterogeneity presents challenges1
– Dynamic changes during tumour progression or response
to therapy
– The need to improve regulatory system to ensure the quality of
conducting genetic and genomic testing (quality and quantity of
tumour tissues)
• Analysis1
– Distinguish between driver mutation from passenger
genetic abnormalities
– Large computer capacity needed to properly and efficiently analyse
the huge amount of data generated
• Close collaboration among all stakeholders1
– Multidisciplinary health care providers (surgeons, pulmonologists,
radiologists, pathologists, translational scientists, medical oncologists,
insurers, regulatory agencies and patients are required for successful
clinical implementation of NGS in genotyping and genomic testing1
1. Li T et al. J Clin Oncol. 2013;31:1039-1049.
Conclusions
033
• Identification of predictive biomarkers is fundamental for precision
medicine to fulfill its promise to maximize efficacy and minimize toxicity
– Key driver mutations (i.e. EGFR and ALK) in subpopulations of patients with
NSCLC, and their inhibition have resulted in significant improvement in clinical
outcomes for such patients
• Continued advancement of biomarker-driven precision medicine is
challenged by the genetically complexity of tumours and paucity of
validated, actionable mutations
• Advances in genome technology, especially through NGS, promise rapid
and high-throughput ways for large-scale whole genome-wide profiling
and analysis with the capacity for better biomarker identification
• Its increased use in translational research and clinical development
holds the promise of improving our current understanding of
oncogenesis and advancing personalised cancer treatment