CON: C Can ctDNA as as a a Mar arker o of f Minimal Residua - - PowerPoint PPT Presentation

AL B BENSON III, MD, FACP, FASCO PROFESSOR OF MEDICINE ASSOCIATE DIRECTOR FOR COOPERATIVE GROUP ROBERT H LURIE COMPREHENSIVE CANCER CENTER OF NORTHWESTERN MEDICINE

CON: C Can ctDNA as as a a Mar arker o

• f

f Minimal Residua dual D Disea ease e Be Used t d to Direc ect A Adjuv uvant Therapy i in Co Colon Can Cancer?

MD Anderson

Relative potential of ctDNA applications for cancer patients

2

Minimal residual disease Treatment monitoring

Serial molecular profiling Initial molecular profiling Other

Incidence of ctDNA based on tumor histology

• Stage II (5% prevalence of ctDNA+)

NGS Assay

Assay with 197 genes; at least one mutation detected 99.3% of tumor tissue 57% sensitivity for recurrence; 100% specificity

• Stage III (16% prevalence of ctDNA+)

HR 54.4 95% CI: 9.5-311.7 p<0.0001 HR 20.0 95% CI: 5.9-67.8 p<0.0001

Diehn et al ASCO ‘17

Ho How d do w we i e improve o

• utcomes f

for thes ese p patients ts?

• Stage II (5% prevalence of ctDNA+)

NGS Assay

Assay with 197 genes; at least one mutation detected 99.3% of tumor tissue 57% sensitivity for recurrence; 100% specificity

• Stage III (16% prevalence of ctDNA+)

HR 54.4 95% CI: 9.5-311.7 p<0.0001 HR 20.0 95% CI: 5.9-67.8 p<0.0001

Diehn et al ASCO ‘17

Do w we n e need eed a as m much t therapy f for thes ese p patients ts?

• Met at ASCO ’18, with goal of evaluating ctDNA utility, making recommendations to industry, and

identifying NCI opportunities in 4 key areas:

• Use of ctDNA for management of minimal residual disease, Monitoring of metastatic disease,

Acquired resistance against targeted therapies, and Specific issues relevant to rectal cancer.

NCI / Colon Cancer Task Force ctDNA Workshop

6

MD Anderson

Recommendation: Assay characteristics necessary for routine testing for minimal residual disease

• For escalation applications
• High specificity/PPV, even at the expense of lower sensitivity
• PPV should be >90-95%; No more than 1 in 10 false positives
• Turnaround time will be critical to make real-time decisions. May require non-

personalized approaches.

• Having matched tumor available – which would require enrollment at the time
• f surgery
• Multi-gene would be preferred to allow broad capturing of potential patients.

NCI / Colon Cancer Task Force Workshop ‘18

Use of ctDNA to guide escalation of adjuvant therapy

• Need additional data: clearance
• f ctDNA with chemotherapy
• Is the presence of ctDNA after

surgery purely prognostic?

• Is there an opportunity to

change outcomes with therapy?

• Can standard chemotherapy

clear these patients?

• FOLFOX in stage III disease
• Novel therapies may be

needed

Tie, et al. ASCO 201

NCI / Colon Cancer Task Force Workshop ‘18

Phase 2 Adjuvant Studies:

cfDNA to facilitate drug development in early stage tumors

Cu Current L Landsc scape

• No mechanism to obtain proof-
• f-concept for adjuvant efficacy
• Requires commitment for

n>1000 patient studies

• Result: Very few adjuvant studies

conducted, and only with approved therapies in mCRC

Potential A App pproach ch

• Validate cfDNA as a surrogate

marker of relapse

• Perform proof-of-concept

through small phase 2 studies looking at cfDNA clearance

• Result: Reduced risk and

increased innovation for adjuvant studies

ARGUMENTS AGAINST CTDNA

Concordance between tumor and liquid biopsies for mutational analysis

Commercially available testing kits

Courtesy of Dr. Julie Lang, USC

Driver mutations seen in non-cancer patients

Sensitivity of testing remains low and unreliable

Not all tumors shed ctDNA at same rate

Concordance with tissue NGS remains poor

• Concordance of genomic alterations between two commercially

available ctDNA (guardant) and tissue biopsies (tempus) was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies.

• Across all genes, concordance between the two platforms was 91.0% to

94.2%.

• genomic alterations in either assay (e.g., excluding wild type/wild type

genes), concordance was 10.8% to 15.1% with full plus partial concordance of 13.8% to 19.3%.

• Concordant mutations were associated with significantly higher variant

allele frequency.

• Over half of mutations detected in either technique were not detected

using the other biopsy technique Chae et al, 2017. Mol Can Thera

MD Anderson

• Disease monitoring applications now require prospective studies
• Early detection of resistance does not necessarily result in better outcomes
• Approval of this indication will require well-designed studies in discrete

indications

• Minimal residual disease applications have tremendous opportunity
• Requires larger, prospective cohorts
• Great opportunities for novel drug development
• Private/public partnerships will likely be required

Conclusions

19

NRG Stage II Adjuvant Study: CR1643 Evaluating early intervention for Minimal Residual Dz

Morris, Kopetz Primary objective: Clearance of cfDNA (to undetectable levels) for patients cfDNA+ at randomization

Van Morris

Slide 27

Presented By Ryan Corcoran at 2019 ASCO Annual Meeting

Thanks to Scott Kopetz and Aparna Kalyan for use of their slides

EXTRA SLIDES

• Adjuvant t

t therap apy c can c clear ctDNA

• ctDNA cleared in 50% (9 of 18) patients who completed the entirety of adjuvant

chemotherapy with a 5-fluorouracil/oxaliplatin combination.

• Persistence of ctDNA after chemotherapy was associated with a worsened

recurrence risk (HR 7.1, p < .001).

• Se

Seria rial m l monitorin ing w will i increase s sensitiv ivit ity

• Nearly 10% of the initially ctDNA-negative population converted to a positive status

after chemotherapy

24

Tie et al , ASCO 2018;36(15_suppl):351

“Phase II” Adjuvant Studies

25

Phase I e II Phase III III

ctDNA+ population (~100% rate of radiographic recurrence)

Novel Interventio n

1° endpoint: DFS

• or-

Clearance of ctDNA “De-risk” a traditional phase III

Novel intervention

1° endpoint: DFS or OS

SOC R

Integral biomarker: ctDNA+ population

Novel intervention

1° endpoint: DFS or OS

SOC R

• Endpoint of clearance of ctDNA, where

this is ne necessary but no y but not s t suf ufficient for cure

• High event rate, so feasible for DFS

endpoint as well

• Holy Grail: Can we use ctDNA as an FDA-

approved surrogate endpoint for registration of novel therapies?

Use of ctDNA to guide de-escalation of adjuvant therapy

• The group felt that sensitivity of

90-95% was required to guide de-escalation (vs. escalation)

• Need to define how disease

characteristics may influence sensitivity of the test

• eg. peritoneal disease may not

shed ctDNA at same rate

• These studies are typically

larger due to a non-inferiority design

• International consortia are needed

NCI / Colon Cancer Task Force Workshop ‘18

Concordance of genomic alterations in tissue and ctDNA categorized by potential functionality. Shown here is tissue (T) and ctDNA. T + ctDNA+, concordant in both platforms. T − ctDNA+: variant found in ctDNA, but not

• tissue. T + ctDNA−: variant found in tissue, but not ctDNA..

Chae et al 2017, Mol Can Therap

Concordance with tissue NGS remains poor