Levels of evidence required for reporting variants and guiding patient treatment - PowerPoint Presentation

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Levels of evidence required for reporting variants and guiding patient treatment

Dr Howard L. McLeod

Medical Director, DeBartolo Family

Personalized Medicine Institute

Chair, Department of Individualized Cancer Medicine

Senior Member, Division of Population Sciences

State of Florida Endowed ChairSlide2

The clinical problem

Multiple active regimens for the treatment of most diseasesVariation in response to therapy Unpredictable toxicity

With choice comes decision

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Practical choices

Selection from amongst ‘equals’

Clinical trial options, beyond non-specific or anatomical

‘acceptable’* levels of toxicity*to the patient, not prescriberSlide4

Wang L et al. N

Engl

J Med 2011;364:1144-1153.

Cancer Pharmacogenomics and Tumor and

Germline Genomes.Slide5

Pharmacogenomic examples-2017

bcr

/

abl or 9:22 translocation—imatinib mesylate*HER2-neu

—trastuzumab**C-kit mutations—imatinib mesylate**

Epidermal growth factor receptor mutations

—gefitinibBRAF-vemurafenibALK-Crizotinib

ROS-1_CrizotinibTPMT-mercaptopurine and azathioprine*UGT1A1-irinotecan**

CYP2C9/VKORC1-warfarin*HLA-B*5701-abacavir *HLA-B*1502-carbamazepine *IL28B-interferon

CFTR-

ivacaftor CYP2C19-clopidogrel, voriconazoleCYP2D6-5-HT3 receptor antagonists, antidepressants, ADHD drugs, and codeine derivatives*

Pain controlAntiemeticsAntidepressantsADHD drugsAnticoagulants

Not just tumor markers!!Slide6

Lot’s of patientsSlide7

2017 Personalized Cancer Medicine Cases (n=996)

Others with <5 cases: 4 (CMML, Bladder), 3 (Cholangiocarcinoma, Esophageal, Endometrial), 2 (Testicular, Multiple Myeloma,

Thymic, Gastric, GIST) 1 (Adenoid cystic carcinoma, Uterine, Urethral, CNS, Pheochromocytoma)573 (57.5%) solid423 (42.6%) heme Slide8

Clinical ActionabilityGenetic alteration predicts response to a particular therapy

Benefit or resistance to a particular therapy

FDA approved therapy for the patient’s type of cancerClinical trial for the particular alteration or reasonable based on molecular biologyUse of FDA approved therapy for ‘off label’ types of cancerGenetic alteration provides diagnostic or prognostic informationClinically relevant germline alteration that informs disease risk or pharmacokinetic or pharmacodynamicsSlide9

Levels of Evidence

Supporting Data

Comparative trial with biomarker selection/stratification (patient’s tumor type or different tumor type)Retrospective cohort or case-control trialsBiomarker association with response less robust (secondary endpoint)Case study or case seriesPreclinical data only (in vitro or in vivo models)Clinical ActionabilityFDA approved therapy in patient’s tumor typeFDA approved therapy in different tumor typeClinical trial based on specific mutationClinical trial based on application of pathway biologyPrognostic informationNot clinically actionable at this timeSlide10

Implementation in Clinical Practice

Referral to Clinical Genomic Action CommitteeSlide11

Patient Recommendations

Recommendation Summary

: As detailed below, this patient has an FGFR amplification which would qualify him for the Phase I trial of a pan-FGFR inhibitor enrolling at Moffitt (MCC 17565) (Level 3). Additionally, the multi-tyrosine kinase inhibitor pazopanib, inhibits FGFR and is FDA approved for soft tissue sarcoma (Level 1). When choosing the order of these treatments, please consider the inclusion criteria of MCC 17565. Additionally, other phase I trials not enrolling at Moffitt are available based on the TP53 mutation (Level 5). Use of a CDK 4/6 inhibitor is not recommended based on inactivation of Rb.

Additionally, based on the presence of the TP53 and RB mutations, referral to the genetic risk assessment service is recommended1FDA approved drug for patient's specific cancer2FDA approved drug for another cancer or indication

3Clinical trial available at Moffitt for this gene4Clinical trial available at Moffitt based on pathway biology5

Clinical trial available at a non-Moffitt site for this gene

6Clinical trial available at a non-Moffitt site based on pathway biology7Human data available, no currently active clinical trial8

In vitro or animal data available 9No information availableSlide12

Implementation in Clinical Practice

Referral to Clinical Genomic Action CommitteeSlide13

Bioinformatics

Leukemia

PCM Fellow

Genetic CounsMedical Gen.

ThoracicAnat Pathology

GU

Hem/onc fellowBreast

Mol PathologySarcoma

Heme PathologyMyeloma

Pharmacy

MCC Clinical Genomic Action Committee (CGAC)13Slide14

Impression Tracking

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Practical choices

Selection treatment from amongst ‘equals’

Clinical trial options, beyond non-specific or anatomical

Longitudinal monitoring for futility/next options

‘acceptable’* levels of toxicity We have to ask! *to the patient, not prescriberPreemptive assessment of benefit:risk, to AVOID risk and ASSURE the best change of benefit