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Incorporating DecisionDx-Melanoma into Clinical Practice:

Molecular Information for Personalized Management Decisions

Eric D. Whitman, MD, FACS Medical Director, Atlantic Health System Cancer Care Director, Atlantic Melanoma Center Morristown and Summit, New Jersey

Castle Biosciences provides molecular diagnostic solutions for patients with underserved and dermatologic cancers

15-GEP test accurately identifies aggressive tumor biology Adds further prognostic accuracy for UM patients NGS panel offers comprehensive genomic profiling

Uveal Melanoma

Standard of care 31-GEP test accurately identifies risk of recurrence independent of traditional staging factors and informs SLNB decisions NGS test identifies actionable BRAF, NRAS and KIT mutations in melanoma tumors

Cutaneous Melanoma

Proven impact on management decisions for 1 of 2 patients tested Active research and development programs in skin cancers (e.g. cSCC) and other underserved cancers Development of biomarkers for treatment response prediction Sequencing capabilities to enhance precision medicine

Development Programs

Informing clinical decisions Gene Expression Profiling (GEP) Next Generation Sequencing (NGS)

12,000+

melanoma test orders in 2018

Tests performed in CAP-accredited, CLIA-approved laboratory

Individual risk drives management decisions for melanoma patients – including informing SLNB

Management of Stage I‐III melanoma patients involves making decisions on:

• Frequency of follow‐up
• Frequency and modality of surveillance imaging
• Referral to Surgical Oncology
• Sentinel Lymph Node Biopsy
• Referral to Medical Oncology
• Adjuvant therapy

What’s the risk?

NCCN guidelines recognize that a patient’s individual risk of recurrence should drive management decisions

Sentinel Lymph Node Biopsy

NCCN guidelines also recognize that a patient’s individual risk of SLN positivity drives SLN biopsy recommendations

1 2 3

Staging-only approach misses patients with aggressive tumor biology

• While AJCC clinicopathologic factors are helpful clinically, the majority of deaths occur in early

stage disease1-5

1AJCC v7 J Clin Oncol 2009 ; 2SEER data release 2017; 3Morton et al. N Engl J Med 2014; 4Whiteman et al. J Invest Dermatol

2015; 5Shaikh et al. J Natl Cancer Inst 2016; 6Poklepovic and Carvajal. ONCOLOGY 2018

• Prognostic accuracy needs to be

improved as it has direct implications on patient follow up

• Newer therapies and regional

interventions have shown effectiveness in the adjuvant setting

• Early intervention is consistently

shown to be a significant (or the most significant) predictor of response6

80% 12% 8%

Stage at Diagnosis

Stage II Stage III Stage I

Excludes Stage IV

26% 34% 40%

Melanoma Deaths by Stage at Diagnosis

Stage II Stage III Stage I

Excludes Stage IV

Patients with Stage I-III melanoma Class 1: Low risk of melanoma recurrence within 5 years Class 2: High risk of melanoma recurrence within 5 years  Quantifies expression

• f 31 genes from

primary tumor using RT- PCR  Applies a validated algorithm  Accurately classifies patients as low or high risk

DecisionDx-Melanoma was developed to assess risk of recurrence independent from traditional clinico-pathologic factors using tumor biology

Gerami et al. Clin Cancer Res 2015; Gerami et al. JAAD 2015; Zager et al. BMC Cancer 2018; Gastman et al. JAAD 2019

1A

Lowest risk

2B

Highest risk

2A

Increased risk

1B

Low risk

DecisionDx-Melanoma test in clinical use: T1a / Stage IA melanoma patient case

• 34‐year‐old female with melanoma on arm
• Breslow depth: 0.6mm, no ulceration (T1a) , mitotic rate <1/mm2
• AJCC Stage IA
• DecisionDx‐Melanoma ordered by Dermatology:
• Class 2B result

Case contributed by Medical Oncologist, Topeka, KS

Clinical management of patient with Class 2B tumor

• Referred to Medical Oncologist for high‐intensity surveillance
• CT scan ‐ clear
• CT scan six months later ‐ biopsy proven oligomet to the lung, BRAF negative
• Radiotherapy to lung metastasis
• Started on combination ipilimumab/nivolumab, and doing well (clear scans) after 36 months

4 5 6

DecisionDx-Melanoma validation, performance and clinical impact studies include >2,900 patients across 19 peer-reviewed publications

Prospective Studies

• Keller et al. Cancer Med 2019 -

NEW

• Podlipnik et al. JEADV 2019 -

NEW

• Greenhaw et al. Dermatol Surg

2018

• Hsueh et al. J Hematol Oncol

2017

• Renzetti et al. SSO 2017

Prospective studies confirm validity

Clinical Impact Studies

• Mirsky et al. J Drugs Dermatol

2018 - NEW

• Dillon et al. SKIN 2018
• Schuitevoerder et al. J Drugs

Dermatol 2018

• Hyams et al. WCD 2018
• Svoboda et al. J Drugs Dermatol

2018

• Farberg et al. J Drugs Dermatol 2017
• Berger et al. CMRO 2016

Management decisions impacted for 1 in 2 patients tested

Validation & Performance Studies Validation & Performance Studies

• Vetto et al. Future Oncol 2019 -

NEW

• Gastman et al. JAAD 2019 - NEW
• Gastman et al. Head & Neck

2019 - NEW

• Zager et al. BMC Cancer

2018

• Gerami et al. CCR 2015
• Gerami et al. JAAD 2015
• Cook et al. Diagn Pathol 2018

Newly validated clinical utility to inform SLNB discussions

Combined validation cohort demonstrates accurate, independent prognostic value of DecisionDx-Melanoma test to identify patients’ risk for metastasis

• DecisionDx‐Melanoma test was clinically validated

to predict risk of recurrence in three published studies:

• Gerami et al. CCR 2015
• Gerami et al. JAAD 2015
• Zager et al. BMC Cancer 2018
• Gastman et al. JAAD 2019 publication combines

unique patients from these previous validation studies to enable analysis of clinically relevant subgroups:

• SLNB negative
• Stage I‐IIA
• Thin tumors (≤1 mm)

Gastman et al. JAAD 2019

Cumulative validation cohort for DecisionDx-Melanoma includes 690 evaluable patients that met inclusion criteria

Gastman et al. JAAD 2019

• IRB approved protocol to collect Stage I‐III

melanoma with recurrence/metastasis or more than 5 years of f/u without recurrence

• Eighteen U.S. dermatologic and surgical

centers

• Diagnosed between 1998 and 2014
• Enrollment began in 2011 with data

updates in Oct 2017

• 782 patients were enrolled in the studies
• 690 met the inclusion criteria and were

evaluated

• 483 of those were Stage I/II
• 57% of patients were low risk (Class 1);

43% were high risk (Class 2) Attribute Summary Age (years) Median (range) 59 (18 – 94) Breslow depth (mm) Median (range) 1.3 (0.1-29) Ulceration present 190 (32%) Mitotic rate ≥1/mm2 352 (74%) Node status positive 200 (29%) Stage I 333 (48%) II 150 (22%) III 207* (30%) GEP Class 2 298 (43%)

* Seven cases had Stage III, SLN negative disease All non-metastatic cases with ≥5 years follow up

7 8 9

Clinical validity and prognostic value of DecisionDx-Melanoma have been demonstrated in 690 Stage I-III patients

Time (Years)

% Recurrence Free

RFS

p<0.0001 Time (Years)

% Distant Metastasis Free

DMFS

p<0.0001 Time (Years)

% Survival

MSS

p<0.0001

Class 1A Class 1B Class 2A Class 2B n=312 n=80 n=84 n=214

Gastman et al. JAAD 2019

Median time to distant recurrence for patients with Class 2 result:

• Stage I‐II patients: 1.6 years (70 Class 2 patients recurred)
• Stage III patients:

1.0 year (92 Class 2 patients recurred)

DecisionDx-Melanoma test further informs risk obtained by AJCC 8th edition staging

Stage I II III

Melanoma-Specific Survival (%) Low Risk Stage I‐IIA High Risk Stage IIB‐III

99.6% ≈IA 89.5% ≈IIIA >99% ≈IA 84.7% ≈IIIB 94.8% ≈IIA 61.2% ≈IIIC+ 98%

NCCN Risk Category 100 90 80 70 60 Class 1A Class 2B AJCC MSS

90% 77%

Prado et al. SKIN J Cutan Med 2018:suppl 2 N=690

Meta-analysis objective and methodology

• Objective: To evaluate the cumulative prognostic effect of the DecisionDx‐Melanoma test across

multiple cohorts, with a focus on risk difference between Class 1A and 2B

Cohort 1: Greenhaw et al. 2018 Cohort 2: Hsueh et al. 2017 Cohort 3: Gastman et al. 2019 Multivariate analysis DDx‐Melanoma result (Class 1A, 1B, 2A, 2B) Breslow thickness Ulceration Node status Age Meta‐analysis Comparisons across and within studies and tests for heterogeneity DecisionDx‐ Melanoma effect (Class 1A vs. Class 2B) RFS DMFS 1,479 Stage I‐III patients

Greenhaw et al. Presented at AAD, Late‐Breaking Abstract 2019

Cohort 4: Novel cohort

10 11 12

Meta-analysis across four independent studies: DecisionDx-Melanoma class and correlated survival outcomes (n=1,479)

Class 1A Class 1B Class 2A Class 2B GEP Result 5-year RFS Event Rate GEP Result 5-year DMFS Event Rate 1A (n=790) 91.4% 6.7% 1A (n=597) 94.1% 5.5% 1B (n=169) 85.1% 14.2% 1B (n=148) 88.1% 12.2% 2A (n=159) 64.0% 35.8% 2A (n=133) 75.9% 24.1% 2B (n=361) 43.6% 50.1% 2B (n=345) 55.5% 38.8%

Greenhaw et al. Presented at AAD, Late‐Breaking Abstract 2019 *T1a with High-Risk Features

How do we select patients for the SLNB surgical procedure?

• Guidelines† recommend that the SLNB procedure can be considered for patients with

T1b tumors and above, as well as T1a tumors with high‐risk features, based on an expected risk of being SLN positive above 5%

Stage SLN+ Risk SLNB Eligibility T1a <5% No T1a‐HR* 5‐10%

Eligible

(consider or offer) T1b T2a >10% T2b T3 T4

• Threshold based on SLNB false negative rate of 5%
• bserved in MSLT‐I1
• Use of this threshold results in an overall rate of SLN

positivity of ~16%1

~84% of patients who undergo the SLNB surgical procedure will have a negative result

†NCCN Guidelines for Melanoma v2.2019, ASCO/SSO Guidelines for Sennel Lymph Node Biopsy 2017, AAD Guidelines for Melanoma 2018; 1 Morton NEJM 2014

Validation of DecisionDx-Melanoma for identifying patients at low risk for a positive SLN in a prospective 1421 patient cohort published in Jan 2019

Vetto et al. Future Oncol 2019

13 14 15

For SLNB eligible patients with T1-T2 tumors, DecisionDx-Melanoma Class 1A predicts low risk of SLNB positivity and favorable outcomes1

1Vetto et al. Future Oncol 2019

*SLNB eligible patients are T1b‐T2 and T1a with high‐risk histologic features. Data includes all T1‐T2 patients.

Class 1A 5-Year Outcomes

(All ages; n=281)

MSS OS DMFS RFS 99.6% 98.2% 95.3% 93.5% DecisionDx- Melanoma result Probability of a Positive Sentinel Lymph Node

(consideration for SLNB eligible T1-T2 Patients*)

All Ages (n=1065) ≥65 years (n=448) 55-64 years (n=247) <55 years (n=370) Class 1A 4.6% 1.6% 4.9% 7.6% Class 1B/2A 10.8% 6.9% 7.7% 19.6% Class 2B 18.8% 11.9% 30.8% 24.0%

The DecisionDx‐Melanoma test can help identify a population with a low risk for SLN positivity similar to T1a patients (for whom SLNB is not recommended) Class 1A patients show excellent 5‐year survival

• utcomes in retrospective studies

Risk for SLN+ Discussion with patientb Below threshold (<5%) Could avoid SLNB 5% to 10% Can consider SLNB >10% Offer SLNB

How do I use results from DecisionDx-Melanoma to inform SLNB discussions?

Patients with T1‐T2 SLNB eligiblea melanoma

(>5% risk for SLN+)b

DecisionDx‐ Melanoma test

Class 1A Class 2B

Class 1B/2A

a≥55 years old, bbased on guideline recommendations

• Avoid unnecessary surgical procedures in low‐risk patients
• Focus resources on patients at high risk for recurrence
• Increase yield from SLNB procedure
• Reduce healthcare costs

Benefits:

• 56‐year‐old male with superficial spreading melanoma on right back
• Breslow 0.9 mm, extending to Clark's level IV, mitotic rate >1/mm2,

no ulceration

• Invasive melanoma present at the deep and peripheral margins
• AJCC Stage T1b
• Patient very distressed by diagnosis and fearful of surgical complications

(mother had history of breast cancer). Patient requested to have DecisionDx‐Melanoma test performed and delay the decision about SLNB.

• DecisionDx‐Melanoma test was ordered after tumor board discussion:
• Class 1A result

DecisionDx-Melanoma test in clinical use: T1b/Stage IB melanoma

Case contributed by Dermatologist, Indiana University

Clinical management of patient with Class 1A tumor

• Based on the results of the DecisionDx‐Melanoma test the patient decided to forego the SLNB and

avoid any potential complications, however unlikely

• Patient’s anxiety and stress was also reduced based on the DecisionDx test results portending a low

metastatic risk

• Patient being managed with frequent clinical follow‐up by dermatology

16 17 18

• 49% of tested patients had a change in

clinical management.

• 91% of decreases in care provided to low-

risk Class 1 patients and 72% of increases in care provided to high-risk Class 2 patients.

• DecisionDx-Melanoma informs appropriate

clinical management and patient care, with similar changes to previously published studies.1-3

• 1. Berger AC, et al. Curr Med Res Opin 2016
• 2. Farberg AS, et al. J Drugs Dermatol 2017
• 3. Schuitevoerder D, et al. J Drugs Dermatol 2018

49% changed 36% changed 85% changed Class 2 n=66 Class 1 n=181

Prospective multicenter clinical utility study shows impact in management decisions similar to previous studies

Dillon et al. SKIN J Cutan Med 2018

Overall

Addition of DecisionDx-Melanoma test to staging consistently impacts clinical management decisions for one of every two patients tested

• Four consecutive clinical

impact studies have shown 47‐53% change in management

• Management changes

include:

• Clinical visit frequency
• Imaging and labs
• Referrals
• Sentinel lymph node

biopsy guidance

Study Design # of Patients % Change in Management Berger et al. CMRO 2016 Multicenter, prospectively tested patients. Medical record-based pre and post test plans. 156 53% Dillon et al. SKIN J Cutan Med 2018 Multicenter, prospectively tested and consented

• patients. Pre and post test

plans. 247 49% Farberg et al. J Drugs Derm 2017 Intended decision study of 169 physicians. Pre and post test treatment plans. n/a 47-50% Schuitevoerder et al. J Drugs Derm 2018 Academic center, prospectively tested

• patients. Post test plans,

decision-tree model. 91 52%

Clinical Management: AJCC staging with incorporation of DecisionDx-Melanoma Courtesy of John Vetto M.D., FACS, Oregon Health & Science University

Melanoma Staging WLE +/‐ SLNBx (per NCCN) DecisionDx Low risk: Class 1 DecisionDx High risk: Class 2 Increase Intensity (Trials) Decrease Intensity Continue High Intensity mgmt (Encourage trials) DecisionDx Low risk: Class 1 DecisionDx High risk: Class 2 Low Intensity mgmt (Derm) AJCC Low risk: Stage I, IIA AJCC High risk Stage IIB, IIC, III Early detection

• f recurrence

Appropriate treatment or clinical trial High Intensity Enhanced Surveillance ‐ H&P every 3 months x 2 years, then every 6 months to 4 years, then annually ‐ PET/CT or CT scans every 6 months x 4 years, then symptom‐guided imaging

19 20 21

Clinical Management: AJCC staging with incorporation of DecisionDx-Melanoma Courtesy of Nima Gharavi, MD, PhD, Department of Dermatology, Cedars-Sinai Medical Center AJCC Stage I‐III

Screening: Office visit q3m x 3 yrs, then q6m x 2 yrs, then annual Imaging: Stage IA‐IIB: Not performed Stage >IIB: q6m‐1 year x 5 yrs DecisionDx‐Melanoma Low Risk / Class 1 DecisionDx‐Melanoma High Risk / Class 2

Screening:

Office visits: Q4‐6m x 3 yrs, then Q6m x 2 yrs, then annual

Imaging:

Stage I/II: None, except for symptom‐guided imaging Stage >III: Per surgical/medical oncology

Screening:

Office visits: Q3m x 3 yrs, then Q4‐6m x 2 yrs, then annual Medical Oncology Referral

Imaging:

CT (C/A/P) Q6m x 3 yrs, then Q12 months x 2 yrs

DecisionDx-Melanoma test in clinical use: T2a / Stage IIA melanoma patient case

• 52 year old male with melanoma on right lower leg presented to

general surgeon for discussion of SLNB

• Breslow depth: 1.2mm, no ulceration (T2a), mitotic rate <1/mm2
• SLN of right groin – negative
• AJCC Stage IIA
• DecisionDx‐Melanoma test ordered after SLNB
• Class 2B result

Clinical management of patient with Class 2B tumor

• Patient sent to medical oncology for high intensity surveillance and clinical trial consideration
• Initial PET/CT scan ‐ intense, abnormal uptake on the left lateral deep cervical node
• Biopsy & removal of left lateral deep cervical nodes
• Now Stage IV due to metastatic disease in contralateral nodes
• Offered immunotherapy for low‐burden metastatic disease.

Case contributed by General Surgeon, Fayetteville AR

Melanoma clinicians are including the DecisionDx-Melanoma test to inform management decisions in these common patient types

• Tumors 2 mm or less (T1‐T2)
• Add prognostic information to inform SLNB discussions/guidance
• Identify high‐risk patients missed by traditional prognostic tools and

inform decisions on follow up, surveillance and referrals

• Add confidence to management decisions for patients staged as

low‐risk by traditional prognostic tools

• Tumors greater than 2 mm thick (T3‐T4)
• Inform decisions on follow up, surveillance and referrals
• Refine risk for patients who decide not to undergo SLNB
• SLNB‐negative patients
• Identify high‐risk patients missed by staging
• Identify high‐risk patients for potential adjuvant therapy clinical trial participation
• Identify truly low‐risk patients who can be referred back to Dermatology
• SLNB‐positive patients, concerns about risk/benefit of adjuvant therapy
• Add information on distant metastasis risk to inform adjuvant therapy discussions

22 23 24

Eligible per Validation Studies  Stage I ‐ III cutaneous melanoma  Newly diagnosed or diagnosed within the last three years

 Can accept up to 5 years following diagnosis with clinical rationale

 All anatomic sites, including acral  Any Breslow’s depth  Availability of primary biopsy tumor Not Eligible per Validation Studies

• Melanoma in situ (Stage 0)
• Patients with metastatic melanoma
• Mucosal melanoma
• Age <18 years

A wide spectrum of melanoma patients are appropriate for testing with DecisionDx-Melanoma

• Our goal is to ensure all patients have access to the DecisionDx‐Melanoma test
• Castle Biosciences will submit and track insurance claims on your patients’ behalf

throughout the billing process, including appeals if necessary

• Patient will receive an Explanation of Benefits from their insurance company (not a bill)
• Depending on plan requirements, may need patient assistance with the reimbursement

process to sign appeal consent form

• Will need Letter of Medical Necessity to continue with insurance billing process
• Template Letter of Medical Necessity option available
• Signed Letter of Medical Necessity can be submitted with the requisition
• Castle offers an industry‐leading financial assistance program for both insured

and uninsured patients. Castle Biosciences offers patient-focused financial assistance and insurance billing services DecisionDx-Melanoma accurately predicts risk of metastasis to inform SLNB discussions and clinical management decisions

• Adds additional, actionable information to inform

SLNB discussions and other patient management decisions independent of traditional staging factors

• Consistent findings across multiple validation

and independent studies provide robust body of evidence in Stage I‐III patients

• Impacts clinical management decisions for 1 of

every 2 patients tested

• Newly diagnosed or within 3 years of diagnosis
• Can accept up to 5 years with clinical rationale
• Patient‐focused financial assistance and insurance

billing services

• www.SkinMelanoma.com to order

Predict risk to inform decisions

RFS: recurrence‐free survival n=690 1B 1A 2A 2B

Inform SLNB discussions in SLNB eligible T1‐T2 patients

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