Oncology biomarkers for safety and efficacy

Oncology biomarkers for safety and efficacy
by
David Ross, M.D., Ph.D.
Office of Oncology Drug Products
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

* Why biomarkers?
* Biomarkers for safety
* Biomarkers for efficacy
* Scientific and regulatory challenges
* FDA views pharmacogenomics and biomarkers as part of a new paradigm for oncology therapeutics development
* Developing new cancer treatments via biomarkers will require a coordinated public-private approach between academia, industry, government, and other stakeholders

Development issues in oncology – I

* Represents >100 diseases/indications
o Different natural histories
o Different etiologies/molecular biology
* Efficacy assessment is difficult
o Most investigational therapies fail to show efficacy
o Even promising agents may have small treatment effects
* Safety assessment is difficult
o most candidates (even targeted) are toxic
o underlying disease may confound safety assessment
* Investigational nature of discipline
o cancer centers, cooperative groups, NCI
* Multi-disciplinary approaches
o chemotherapy, biologics, surgery, radiation therapy, devices, supportive care, diagnostics

Development issues in oncology – II

* Life-threatening nature of diseases
* Potential for distant recurrences
* Drugs have multiple MOAs; used in combination
* Risk/benefit ratio--different perspective on serious adverse events; highly trained specialists using drugs rather than GP
* Off-label uses may be standard of care
* New technologies/concepts piloted in oncology

Research vs. results
The paradox of drug development

1. Clinical trials provide evidence of efficacy and safety at usual doses in populations
2. Physicians treat individual patients who can vary widely in their response to drug therapy

All patients with same diagnosis


Therapy C
Therapy B
Therapy A
Some respond to treatment
Some don’t
Some develop adverse reactions
Why the differences in response?

Standard therapy

Responders and Patients

Not Predisposed to Toxicity

All patients with same diagnosis

Alternate therapy
non-responders
and toxic responders
Responding to variability

Pharmacogenomics applied to oncology therapeutics development

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Evolution of pharmacogenomics

* Phenotypic variation known for >50 y
o Isoniazid rapid acetylators, G6PD-associated hemolysis
o Application required development of new assay for each phenotype
* Sequencing of entire human genome
* Genotype – drug response correlations
* Analytic biochemistry advances
o Development of bioinformatics
o Multiplex gene analysis platforms
o Application of fluidics and IC manufacturing techniques to gene chip fabrication
* Oncology therapeutic strategies
o Clinically relevant genotypes identified
o Development of validated assay for genotype
o Safety – correlation of clinical risk with genotype
o Efficacy – clinical benefit via genotype targeting

Irinotecan (Camptosar®)

* Irinotecan ~ proven 1st (5-FU and leucovorin) and 2nd line prodrug therapy for metastatic colon/rectal cancer
* Providers/patients face a clinical predicament ~ what is the optimal dose?
o Incidence of grade 3-4 neutropenia is 35%
o Nearly 70% of patients need dose reduction
o Toxicity associated with active drug exposure

Irinotecan metabolism
UGT1A1 gene structure

UGT1A1: promoter polymorphism and toxicity

* Prodrug (irinotecan) metabolized to SN-38 (active drug)
* Rate-limiting metabolic enzyme encoded by UGT1A1
* Five exons
* Promoter contains run of TA repeats; most common allele has 6 repeats; unusual allele has 7

Problem: accumulation of SN-38

* Exposure dependent on metabolism of camptosar by UGT1A1
o Wide interpatient variability in UGT1A1 activity
o Patients with *28 variant (7 TA repeats) have reduced enzyme activity
o Homozygous deficient (7/7 genotype) patients have the greatest risk of neutropenia
o Neutropenia matters to patients
* Original label was silent on UGT information; approved dose not optimized

UGT1A1 TA repeat→irinotecan neutropenia

Camptosar Label Revised and FDA Approved UGT Test

“Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele (see DOSAGE AND ADMINISTRATION). Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses.”

EGFR as a therapeutic target

o Epidermal growth factor receptor (EGFR) gene (erbB1) first sequenced in a four-member family of structurally related type or subclass 1 receptors known as tyrosine kinases.
o Critical for mediating the proliferation and differentiation of normal cell growth
o Widely expressed in epithelial, mesenchymal, and neuronal tissues
o Aberrant activation of the kinase activity of these receptors appears to play a primary role in solid tumor development and/or progression
o Breast, brain, lung, cervical, bladder, gastrointestinal, renal, and head and neck squamous cell carcinomas, have demonstrated an over expression of EGFR relative to normal tissue, which is associated with a poor clinical prognosis

Erlotinib (Tarceva®)

* Potent EGFR tyrosine kinase inhibitor
o MW 428 Da
o IC50 20 nM
* Pre-clinical anti-tumor activity
o Inhibits tumor cell line growth
o Activity in mouse xenograft models
* Increased RR, PFS, and OS in Phase 3

Current pharmacogenomic examples

* bcr/abl or 9:22 translocation—imatinib mesylate (Gleevec)*
* HER2-neu—trastuzumab (Herceptin)**
* C-kit mutations—imatinib mesylate (Gleevec)**
* Thiopurine S-methyltransferase—mercaptopurine and azathioprine*
* UGT1A1-irinotecan (Camptosar)**
* Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists and codeine derivatives*
* *-FDA package insert information
* *-FDA-approved device

Scientific challenges

* Biomarker/transcript profile selection
* Definition of response predictors
* Assay development
o Platform and reagent standardization
o Defining sensitivity
o Minimizing variability
* Pharmacodynamic modeling
* Biomarker validation
* Biomarker ≠ surrogate

Regulatory challenges

* Ensuring assay reliability/validity
* Addressing drug/diagnostic co-development
* Understanding physiologic, toxicologic, and clinical significance of biomarkers
* Defining criteria for biomarker validation
* Extrapolation across populations
* Endpoint definitions
* Addressing exclusion of patients without target
* Defining standards for transmission, processing, and storage of pharmacogenomic data
* Communication with diverse stakeholders

Platform standardization
Summary

* Biomarkers hold enormous promise
o Conventional oncology development - small benefit in a large patient population
o Targeted drug development – may define large benefit in smaller population
* The devil will be in the details
* New development structures must be built
o Flexible regulatory mechanisms
o Need for drug-device co-development paradigm
o Need for new partnerships between industry, government, academics

FDA Pharmacogenomic Guidances

March 2004, CDER:
Pharmacogenomic Data Submissions
http://www.fda.gov/cber/gdlns/pharmdtasub.htm

April 2005, CDER/CDRH/CBER/OCP:
Drug-Diagnostic Co-development Concept Paper http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf

February 2006, CDRH:
Multiplex Tests for Heritable DNA Markers, Mutations and Expression Patterns: Draft Guidance for Industry and FDA Reviewers http://www.fda.gov/cdrh/oivd/guidance/1549.pdf

Oncology biomarkers for safety and efficacy