1. Getting to the Right Patient, with the Right Drug(s) at the Right Time(s)
Kenna R. Mills Shaw, Ph.D.
Executive Director
Khalifa Institute for Personalized Cancer Therapy

2. Precision Medicine and the Paradigm Shift
Treatment landscape in prostate cancer. Courtesy of William K. Oh, MD.
DEATH
Population Based  Individual “Genotype-Phenotype” Based

3. Why Multiplex Testing Changes Our Approach
AKT1 29 patients
AKT1 1.4%
2% in breast cancer
Test 2500 patients to enroll 25 patients (50%) $800 per test:
2 million dollars

4. Evolution of Cancer Genomic Sequencing Panels
2012
2013
2014
Within each gene, hundreds of variants may be reported within different cancers.
Lack of community consensus re: number of targets to sequence; push towards exome

5. Rapid, Efficient Identification for Basket Trials
VEGF M/T
TRK M/T
FGFR M/T/A
RET M/T,A
BRAFV00E
EGFR M/A
cKIT M/T
FLT3 M/T?A
HER2 M
HER3 M
CSFR1 M/T
PDGFR M/T
Dovitinib
Neratinib
Dabrafenib/Trametinib Vemurafenib
Multiple histologies as single cohort
Multiple histologies to be analyzed as separate cohorts
for very rare aberrations M
Mutation T
Translocation A
Amplification L
Loss

6. Thousands of Patients Tested, How Many Get the RIGHT Drug?
Cornell, Vanderbilt, Michigan, MD Anderson, International cohorts
Testing between 50-20,000 genes
Average 5-11% of patients with mutation in an actionable gene go on subsequent genotype matched therapy.
Are we just really, really, really BAD at this?

7. “Right” Defined as “Matched”
Genes whose products are potentially targetable with established or investigational therapeutics
directly
indirectly (eg inhibiting downstream signaling)
33 of 50 genes on the panel were considered “potentially actionable”

8. Clinical Trials Categorized by Type of “Match”
Genotype-selected trials: Trials requiring a specific genomic status for enrollment
eg trials for patients with BRAF V600E-mutant tumors
Genotype-relevant trials: Trial with a drug that directly or indirectly targets product of an gene that is altered, but does not require biomarker for eligibility
Indirectly: eg inhibiting downstream signaling
Eg enrolling a patient with BRAF V600E-mutant tumors on a MEK inhibitor trial
Genotype-matched trials: Genotype selected or relevant

9. Percentage of Patients with Mutation in ‘Actionable’ Gene
39.45%
29.60%
10.25%
20.70%
Potentially actionable somatic mutations %
Non-actionable somatic mutations %
Likely germline variants %
No mutation/variant %
Total %

10. Enrollment on Genotype Matched Trials
Mutation in Potentially Actionable Gene
Underwent Genomic Testing
N = 2000
Genotype-matched trial after genomic testing?
No (1211)
Genotype-Selected
Trial N = 54
Genotype-Relevant
Trial N = 29
Yes (789)
No (706)
Yes (83)
11% of pts with mutations
in actionable genes went
on genotype-matched trials

11. Lack of Enrollment NOT Due to Lack of Available Matched Trials
Increasing number of histology-agnostic or multiple histology “basket” trials
Increase % patients with actionable alterations with larger platforms and copy number data

12. Mutations in Patients Enrolled in Genomically Matched Trials

13. Analysis Suggests Opportunities to Improve Patient Recruitment on Targeted Trials
Insurance Denial (1)
Did Patient Return to Clinic after Testing? (n=429)
No (75)
No (124)
Poor PS (4)
Treatment
Elsewhere (2)
Non-Investigational Treatment (17)
Not Eligible (11)
No Trials or Slots (4)
Non-Genotype Matched
Trial (5)
Genotype Relevant
drug Off-Protocol (1)
New regimen at MDACC?
Yes (354)
Yes (230)
Was the result mentioned in the patient’s chart?
Enrolled?
Yes (61)
No (45)
No (72)
Yes (158)
Yes (106)
No (52)
Were genotype-matched trials discussed?
Could a easy-to-access decision support infrastructure, coupled with a proactive alert system and accurate clinical trial tracking improve our ability to optimize patient recruitment onto genotype-selected and genotype-driven trials?
69% had test results mentioned
67% had genotype-matched
trials discussed
58% enrolled on
genotype-matched trials

14. ~13,000 Patients; ~6,000 Variants
Basic annotations communicated without assessment of ‘actionability’
Actionable = Variant is likely driving tumorigenesis and there is an available therapeutic option to inhibit it.
Requires knowledge of the function of the gene (ex: BRAF)
Requires searching and reading through published articles within PubMed and conference abstracts for any known effects of the variant of interest (ex: BRAF V600E).
Requires scouring drug databases and the published literature for drugs that may target the variant

15. Not All Mutations Are Equally ‘Actionable’
Phase II Imatinib in KIT-Mutant/Amplified melanoma
Common in mucosal and acral melanoma
Selection critical
Recurrent Mutations (K642E, L576P)
40% RR
Non Recurrent Mutations 0%
CSD indicates melanoma arising from chronically sun-damaged skin; NA, not applicable. The melanoma subtype, KIT mutational and amplification status, the ratio of mutant to wild-type alleles as determined by their respective electropherogram peak heights, and the RECIST (Response Evaluation Criteria in Solid Tumors) response achieved for each patient treated with imatinib mesylate is shown. Amplification was defined as a KIT -to-centromere ratio of 2.5 or more, with the pattern of amplification described as uniform (homogeneous) or mixed (heterogeneous) across the tumor specimen. The best response as determined by RECIST is identified by the color of the bar. The length of the bar represents the duration of time in weeks that each patient remained receiving therapy. aMutations previously identified in melanoma8,9 and gastrointestinal stroma tumors.35,36 bTumors with mutant to wild-type allelic ratios of more than 1:1, which are those hypothesized most likely to respond to therapy with KIT inhibition. cPatients receiving treatment at the time of this report.
Carvajal, R. D. et al. JAMA 2011;305:

16. From Lists to Decision Support
Alterations
Retrieve literature, aggregate data (including unpublished internal data)
Manually annotate the functional significance of the alterations
Drugs
Annotate drug targets, development status (FDA approved or clinical development) and therapeutic implications (if any)
Clinical Trials
Manually annotate the trials’ genotype/biomarker-specific selection criteria
Annotate for other inclusion criteria, including tumor type, bring in NLP

17. Personalizedcancertherapy.org Website: 26 genes
>1,408 functionally significant SNVs > SNVs reviewed
Single Patient Annotation Effort:       3200 Single patients annotated
Drug Curation Effort:                              drugs annotated
Clinical Trial Curation Effort:                cancer clinical trials annotated

18. Functional Genomics of VUS Identifies Actionable Alterations

19. Decision Support in Real Time
Mutation annotation inquiries and clinical trial searching can now be done in real time
Dear Dr. J. Doe,
Thank you for submitting your annotation request for
Gene_Mutation: CDKN2A H83Q
Tumor Type: Endometrial adenocarcinoma
Trial Consideration (if requested):
Gene
Alteration
Allelic frequency
Copy Number Variation (log2)
Functional Significance
Annotation
Actionable gene
Actionable variant
CDKN2A
H83Q
Not applicable
Unknown
This variant is of unknown functional significance. While this variant (c.249C>G p.H83Q) has not been reported in dbSNP, a synonymous alteration (c.249C>A p.H83Q) has been reported in dbSNP (rs ) and COSMIC. There is limited literature discussing the functional consequence of this alteration. One study predicted this alteration to be functionally significant via polyphen computational analysis (Rajasekaran et al., 2008; PMID: ). However, no other literature has been found that functionally supports this prediction. This alteration is within the third ankyrin repeat of CDKN2A. ANK repeat domains are necessary for protein-protein interaction. Another codon 83 mutation (H83Y) decreases CDK4 binding, decreases protein half-life, and is defective in cell cycle arrest (Castellano et. al., 1997; PMID: ; Shapiro et. al., 1995; PMID: ; Yarbrough et. al., 1999; PMID: ).
YES
Potentially
Frequency
Alteration
cBIO
COSMIC
CMS50
T200
Gene_Alteration
1 / 7437 (<1%)
1 / (<1%)
0 / 3212 (0%)
0 / 1774 (0%)

20. 34 inferred inactivating 291 variant of unknown significance
Decision Support in Real Time Improves ‘Matching’ to ‘Right’ Drug
All patients with identified somatic variants
188 patients with mutation(s) only in non-actionable gene
196 patients with variant in actionable gene
68 known activating
11 enrolled
4 inferred activating
7 inactivating
7 enrolled
34 inferred inactivating
1 benign
291 variant of unknown significance
22 enrolled
Approximately 25% of patients with mutations in actionable genes were enrolled on clinical trials using matched therapies (~12% can be potentially enrolled - still awaiting progression)

21. Communicating Annotations in Real Time in Effective Reporting Format

22. Responses vary significantly
Designing the Right Trials (to collect the Right Data) for Patients at the Right Time
Responses vary significantly
RECIST 30% Decrease
Sosman J et al. NEJM 2012
The cancer genome is a highly inter-connected and redundant network of aberrations… we need to treat it (and design trials and support testing strategies) as if we KNOW it.

23. Acknowledgements Khalifa Institute for Personalized Cancer Therapy-
MD Anderson Cancer Center