Molecular diagnostics for clinical trials

Question 1

What qualities wanted in a new drug?

Answer 1

Safety
Efficacy
Convenience
Affordability

Question 2

What are the limitations of the current drug development pipeline?

Answer 2

• Slow
• Expensive
• High failure rate @ phase 2 to 3 transition
• Significant patient resource

Question 3

What is an example of poor trial design in high-risk early breast cancer patients?

Answer 3

Group of patients that despite having treatment for early breast cancer are at risk of developing metastatic disease, thus adjuvant studies used to distinguish whether or not we can reduce the risk of patients that relapse.

Such studies are lengthy as essentially identifying an event where patients presenting with disease recurrence or metastasis disease and large sample size required

Majority of studies conclude negative results. Those that do conclude positive results, the upfront treatment has changed thus difficult to evaluate value of treatment

Question 4

What are biological complexities that lead to the high likelihood of clinical trial failures?

What should researchers be conscious of?

Answer 4

Multiple Targetable alterations and pathways

Pathway re-programming in response to therapy drives resistance

Combinations of pathways and sequencing of treatments during trial

Question 5

What is the path forward to clinical trial success?

Answer 5

Need short term efficacy surrogates to triage our ideas in smaller quicker trials

Companion Diagnostics

Question 6

What are two examples of short term efficacy surrogates to triage our ideas in smaller quicker trials?

Answer 6

Pre-surgical window of opportunity trials

Post Neoadjuvant Pre-surgical Window of Opportunity Trials

Question 7

What do pre-surgical window of opportunity trials involve?

What do they evaluate?

How can this expedite the drug development process?

Answer 7

Patient who presents with new diagnosis of cancer before surgery will have short exposure to drug

Target modulation and pharmacokinetic assessment

• Improving the understanding of an agent’s biologic effect early
• Validating predictive biomarkers

• Targeting select patients in subsequent clinical trials that are powered to detect changes in clinical outcome.

Question 8

POETIC is an example of a pre-surgical window of opportunity trial.

What did this involve?

What were the achievements of this?

Answer 8

Postmenopausal women with ER/Pgr positive invasive breast cancer, divided with one cohort given preoperative therapy AI treatment for 2 weeks and then post operatively for 2 weeks, other cohort do not receive any therapy

• Integration of protocol into busy breast surgical clinics across UK
• Cancer waits time agreement -> entry into perioperative trial counts as start of treatment
• Change in routine service delivery e.g. allowing fast track of ER status report
• Securing national high-level agreements (HTA: storage of tissue-in-transit)

Question 9

Post Neoadjuvant Pre-surgical Window of Opportunity Trials is another example of a pre-surgical window of opportunity trial.

1. What does this involve?
2. What are advantages of this?

Answer 9

1. Platform for rapid drug development for patients at very high risk of metastatic disease

Part 1: Proof-of-concept response signal biomarker endpoint study in biologically assessable NACT resistant residual primary tumour.

Part 2: An exploratory response signal biomarker endpoint study in micrometastatic disease.

Important value in linking within any patient the signals from the PART 1 and PART 2

2. Rapid assessment of signal of drug efficacy, Examine drug resistance/reprogramming mechanisms, Allow smaller sample size, Biomarker development & Validation

Triage of good and bad ideas

Allows single drugs to fail early and rationale combinations to be developed more rapidly

Question 10

What are pharmaceutical companies increasingly looking to develop?

Answer 10

A drug and diagnostic test simultaneously, in a process referred to as drug-diagnostic-co-development so-called companion diagnostic (CDx), to better define the appropriate patient population for treatment.

Question 11

Why are CDx increasingly important tools?

Answer 11

1. Reduced costs through pre-selected (smaller) patient population;
2. Improved chances of approval;
3. Significantly increased market uptake;
4. Added value for core business (late phase);
5. Regulatory trend to have CDx mandatory.

Question 12

How can biomarkers be categorised?

Answer 12

Prognostic biomarkers

Predictive biomarkers

Pharmacodynamic biomarkers

Question 13

What biomarkers are used for drug development?

Answer 13

Predictive biomarkers

Pharmacodynamic biomarkers

Question 14

What do Prognostic biomarkers provide information about?

Answer 14

Disease course independent of treatment

Question 15

What do Predictive biomarkers indicate?

Answer 15

The likelihood of response to a given therapy.

Question 16

What do pharmacodynamic biomarkers provide?

Answer 16

Information about the pharmacologic effects of a drug on its target

Question 17

What type of biomarker is her2?

Answer 17

Prognostic - HER-2 amplified breast cancer

Predictive -Response to transtuzumab in HER2 amplified breast cancers

Question 18

Response to EGFR tyrosine kinase inhibitors in EGFR mutated Non-small-cell lung carcinoma (NSCLC) is an example of what?

Answer 18

Predictive biomarker

Question 19

Predominant PD effect of vemurafenib in BRAF mutated melanomas is through on-target inhibition of MAPK signaling

What is this an example of?

Answer 19

A pharmacodynamic biomarker

Question 20

What is a molecular Biomarker from Scientists viewpoint concerned with?

Answer 20

Large-scale sequencing projects like the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA).

• Mutational signatures
• Focal genomic abnormalities
• Subtype classification
• Estimates of distribution and number of driver genes

Question 21

There is no shortage of new biomarkers available for clinical translation

True or false

Answer 21

True

Question 22

What is a molecular Biomarker from a clinicians viewpoint concerned with?

Answer 22

Opportunities for diagnostic assay development:

Stratification-
Select patients to increase likelihood of therapeutic success

For disease management of this is to select best treatment/ drug for each patient

Efficacy-
As “early killers” or as approved surrogate markers

For disease management improve patient compliance in the absence of clinical improvement

Differentiation-
Differentiate efficacy or safety of a drug within the same class

For disease management select the best treatment/drug for each patient

Toxicity-
Exclude certain patient groups from clinical trials/therapeutics

For disease management monitor and avoid potential toxic effects

Screening-
Patient recruitment for clinical trial/therapeutics

For disease management early disease detection, early treatment

Prognostic:
Patient recruitment for clinical trials

For disease management predict likely course of disease

Question 23

What are the challenges to clinical translation?

Answer 23

• Source: Convenience sampling
• Reproducibility – Biology
– Assay
– Analysis
• Pharmaco-economics of genomic tests
• End-user of the test: Physicians and patients

Question 24

Why is convenience sampling a challenge to clinical translation?

Answer 24

• Discovery-based genomic studies rely on “convenience samples”
• All of the serous ovarian cancer samples analyzed in TCGA were harvested from women with advanced (Stages III and IV) tumour – making it difficult to identify critical early changes
• To be meaningful in a screened population, diagnostic biomarkers must be discovered in early-stage, non-metastatic cancers since biomarker expression can change over the course of a disease.

Question 25

Why is reproducibility a challenge to clinical translation?

Answer 25

Assay: Little research on quality control of genomic studies

• A recent study extracted DNA once from each part of a tumor/normal pair and shipped aliquots of this sample to five large international sequencing centers (Buchhalte et al. 2014)
• Each center sequenced and analyzed the same sample using their own protocols = ∼ 20% of mutations common to 5 sites & 1/3rd predicted by only a single center.

Biology:

Intra-tumoural heterogeneity-
Individual tumors are comprised of myriad cell types present at different frequencies in different spatial sites.

Small populations of cancer stem cells that might be the source of metastatic cells and therefore represent most important information

Multiple core biopsies ? How many is enough? Feasibility in a patient population

Stromal interactions
Interactions of the malignant cells with the surrounding stroma, or stochastic factors that are not captured by any biomarker, are important in the progression of early lesions

Analysis

• Significant diversity in the analysis of cancer genomic data.

• Even small differences in the way a data set is preprocessed and analyzed can yield massive differences in the predictions of a final biomarker
– appears that the more complex the biomarker, the more sensitive it is to processing differences, both in terms of computational methodologies and sample fixation processes.

• However, analysis methods cannot yet be standardized because there is very little consensus in the field about the best methods for different problems.

Question 26

Why is pharmaco-economics of genomic testing a challenge to clinical translation?

Answer 26

• Costly

* Limited number of pharmaco-economic studies for genomic biomarkers to date.

Question 27

Why is attitude/ end-user of the test: Physicians and patients a challenge to clinical translation?

Answer 27

• For routine use – it requires adoption and interpretation by clinicians and patients
• The sheer number of biomarkers - can directly hinder clinical application – creates confusion/fosters “its too dynamic for practical application”

• Clinicians & patients like a binary test:
- But merging data suggest that existing cancer biomarkers should be used to assess risk as continuous variables

• Complex discussions: Requires considerable time,
  Not create confusion

• How to deliver this information to patients compassionately is a significant challenge.

Question 28

What are success stories of biomarkers in cancer?

Answer 28

• 2004: Activating EGFR mutations found in a subset of NSCLC patients
• Subsequently 50% of lung adenocarcinomas shown to possess genetic alterations in oncogenic drivers
• Several of these genetic alterations, such as EGFR mutations and ALK rearrangements, are predictive markers for sensitivity to treatment with genotype- specific tyrosine kinase inhibitors (EGFR TKI and ALK TKI - crizotinib)
• Other genetic alterations may serve as negative predictive biomarkers, such as KRAS mutations or the EGFR T790M gatekeeper mutation, which are associated with lack of responsiveness to EGFR inhibitors

EGRF TIKI and ALK TKI is recommended for all patients with advanced lung adenocarcinomas with EGFT mutants and ALK rearrangments