Clinical Benefit of Integrative Genomic Profiling - PowerPoint Presentation

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Clinical Benefit of Integrative Genomic Profiling

in Advanced Solid TumorsEDRN Biomarker Development LabArul M. Chinnaiyan, M.D., Ph.D.American Cancer Society Research ProfessorHoward Hughes Medical Institute

Sequencing

Buccal swab

or

Blood

Disclosure of Results

Genetic Counselor

Analysis

Actionable Results?

Incidental Results?

Informed Consent

Tumor Biopsy

Genetic Counseling

MiOncoSeq

:

The Michigan Oncology Sequencing Program

Precision Medicine

Tumor Board

Roychowdhury

et al

Sci.Tran.Med

.

November 2011

MI-Oncoseq Clinical Sequencing

N>5000 patients

Multi-Disciplinary Precision Medicine Tumor Board (PMTB)

Since 2011:>100 PMTBs convened8 patients presented on average

>1000 patients at PMTB

MiOncoSeq: Clinical Sequencing Vignettes

NAB2-STAT6 is the pathognomonic driver fusion for Solitary Fibrous Tumors (SFTs)/hemangiopericytoma (Nature Genetics 2013a)Rare, targetable FGFR kinase family fusions are found across a diverse array of tumor types (Cancer Discovery 2013)ESR1 mutations are a common resistance mechanism in ER+ metastatic breast cancers treated with aromatase inhibitors (Nature Genetics, 2013b)Pediatric Oncology Clinical Sequencing Program(JAMA 2015)Integrative Clinical Genomics of Metastatic Prostate Cancer reveals upwards of 20-25% harbor defects in DNA repair (Cell, 2015)Integrative Genomics of Metastatic Cancer reveled pathogenic germline alteration in over 12% with advanced cancers (Nature

2017)

MET 500 Cancer Types

n=500 solid tumor metastases sequenced (subset of CSER1 cohort)Robinson et al, Nature August 2017

MET 500 Clinical Sites of Biopsy

n=500 solid tumor metastases sequenced (subset of CSER1 cohort)>90% biopsy success rateRobinson et al,

Nature

August 2017

Tiering of Molecular Events in MET1000 Cohort

Clinically Actionable

JAMA Oncology

, March 2021

Proportion of Cases Where DNA or RNA Sequencing Contributed to Identifying Clinically Relevant Genomic Alterations

Classes of Clinically Relevant Genomic Alterations in MET1000 CohortContributions of DNA and RNA Sequencing in Identifying Clinically Relevant Alterations

Potentially Actionable Genomic Alteration Identified

N = 696Received SDT

N = 122

No

Actionable Genomic Alteration Identified N = 197Exceptional ResponseN = 23Clinical BenefitN = 24No Clinical BenefitN = 75SDT = Sequencing Directed TherapyClinical Benefit = Stable Disease, Partial Response or Complete Response on SDT Lasting ≥ 6 monthsExceptional Response = Stable Disease, Partial Response or Complete Response on SDT Lasting ≥ 12 monthsPatients Receiving Sequencing-Directed Therapy (SDT)

N=1017

13%38.5%

Cobain et al,

JAMA Oncology

March 2021

Dedifferentiated Liposarcoma

CDK4 amp/CDKN2A delCDK4/6 InhibitorExtraskeletal Myxoid ChondrosarcomaPGR-NR4A3 fusSERM (Tamoxifen)

Unknown Primary Cancer

MSH2 p.Q409fs (germline)

PD-1 InhibitorOlfactory NeuroblastomaCDKN2A delCDK4/6 InhibitorProstate adenocarcinoma BRCA2 delPARP InhibitorLung adenocarcinomaEGFR p.E746_S752delinsV/p.T790MEGFR TKIBreast, ER positive, HER2-negativehigh TMBPD-1 InhibitorLung adenocarcinomaALK p.L1196MALK InhibitorUnknown Primary Cancerhigh TMBPD-1 Inhibitor

Lung Carcinoid Tumor

MEN1 p.P79fs

MTOR Inhibitor

Prostate Adenocarcinoma

BRCA2 p.R3052W

PARP Inhibitor

Lung adenocarcinoma

KIF5B-RET fus

RET Inhibitor

Well Differentiated LiposarcomaCDK4 amp

CKD4/6 Inhibitor

Breast, ER positive, HER2-negative

BRCA1 p.E730fs

PARP Inhibitor

Gastrointestinal Stromal Tumor

KIT p.A502_Y503dup

c-KIT TKI

Unknown Primary Cancer

ERBB2 ampHER2 Monoclonal Ab

Intrahepatic Cholangiocarcinoma

MATN4-FGFR2 fusINCB054828

Unknown Primary Cancer

FGFR2-CCDC6 fus

FGFR InhibitorUnknown Primary CancerBRCA1 p.Q1756fs (germline)

PARP Inhibitor

Prostate adenocarcinoma

BRCA2 del

PARP Inhibitor

Extraskeletal Myxoid ChondrosarcomaEWSR1-NR4A3 fus

PPAR-gamma Inhibitor

Salivary Gland Adenocarcinoma (Parotid)

CDKN2A delCDK4/6 InhibitorExtrahepatic Cholangiocarcinoma

high TMB

PD-1 InhibitorUnknown Primary Cancer

high TMB

PD-1 Inhibitor

Unknown Primary Cancer

ERBB2 ampHER2 Monoclonal Ab

Esophageal AdenocarcinomaERBB2 amp

HER2 Monoclonal Ab

Intrahepatic Cholangiocarcinoma

IDH1 p.R132C

IDH1 Inhibitor

Dedifferentiated Liposarcoma

CDK4 amp

CDK4/6 Inhibitor

Basal Cell Carcinoma of Skin

high TMB

PD-1

Inh

+ CTLA-4

Inh

Prostate Adenocarcinoma

CDK12 p.W1043*

PD-1 Inhibitor

Urothelial Carcinoma

FGFR3-TACC3 fus

FGFR Inhibitor

Esthesioneoroblastoma

CDKN2A del

CDK4/6 Inhibitor

Undifferentiated Pleomorphic Sarcoma

high TMB

PD-1 Inhibitor

Well Differentiated Liposarcoma

CDK4 amp

CDK4/6 Inhibitor

Prostate Adenocarcinoma

BRCA2 p.K2980fs

PARP Inhibitor

Gastic adenocarcinoma

BRCA1 p.E908* (germline)

PARP Inhibitor

Prostate Sarcoma

TPM3-NTRK1 fus

NTRK TKI

Breast invasive ductal carcinoma

high TMB

PD-1 Inhibitor

Endometrioid Stromal Sarcoma

PTEN p.G36L

MTOR Inhibitor

Chondrosarcoma

CDKN2A del

CDK4/6 Inhibitor

Spindle Cell Sarcoma

CDK4 amp

CDK4/6 Inhibitor

Well Differentiated Liposarcoma

CDK4 amp

CDK4/6 Inhibitor

Chordoma

CDKN2A delCDK4/6 InhibitorIntrahepatic CholangiocarcinomaFGFR2-AHCYL1 fusFGFR InhibitorFibroblastic OsteosarcomaCDK4 amp/CDKN2A delCDK4/6 InhibitorBreast, triple negativeBRCA1 p.V1117fsPARP InhibitorBreast, triple negativehigh TMBPD-1 InhibitorLung squamous cell carcinomaKIF5B-RET fusRET TKI

Partial Response

Complete Response

Stable Disease

Time on Treatment (Months)

Diagnosis

Genomic Alteration

Therapy

Exceptional Responder Case Example 1

(rare cancer)38 y.o. female with extraskeletal myxoid chondrosarcoma involving bilateral inguinal regions with lung metastases, diagnosed during pregnancyMi-OncoSeq study:PR-NR4A3 fusion identified (Tier 2, S2)Treatment:Multiple resections (local recurrence), radiationInitiated Tamoxifen - complete response lasting 26 months

10/27/2016 CT Abdomen/Pelvis

4/19/2019 CT Abdomen/PelvisExceptional Responder Case Example 1(rare cancer)

Exceptional Responder Case Example 2

(cancer of unknown primary)63 y.o. female with adenocarcinoma of unknown origin with hepatic, bone and lung metastasesMi-OncoSeq study:Change in Diagnosis: Cholangiocarcinoma (Tier 1, D1)FGFR2-CCDC6 fusion identified (Tier 2, S3)Treatment:Gemcitabine/cisplatin – progressed in 3 monthsPhase I trial with INCB054828, FGFR-inhibitor - partial response lasted 13 months

12/7/2015 CT Chest

2/16/2016 CT ChestExceptional Responder Case Example 2(cancer of unknown primary)

Exceptional Responder Case Example 3

(cancer of unknown primary)56 y.o. male with sarcomatoid carcinoma of unknown origin with large left upper quadrant abdominal massMi-OncoSeq study:PGV in MSH2 (Tier 1, G1*) – Lynch SyndromeMSI High  Elevated Somatic Mutation Burden (Tier 1)Treatment:Surgical resection – recurrence in 3 monthsInitiated treatment with Pembrolizumab - complete response lasting 23 months, now off immunotherapy and on surveillance

9/24/2016 CT Abdomen/Pelvis

4/23/2019 CT Abdomen/PelvisExceptional Responder Case Example 3(cancer of unknown primary)

Reclassification of Cancer of Unknown Primary (CUP)

54%

Pathogenic Germline Variants Observed in MET1000 Cohort (~15.7%)

Cobain et al, JAMA Oncology March 2021

Take home points

Utility of comprehensive integrative sequencing (tumor DNA +matched normal and tumor RNA) in precision oncologyUse of integrative genomic sequencing as a component of SOC in patients with CUP or other rare malignant neoplasmsHigh percentage of advanced cancers (>80%) harbor a clinically actionable alteration-- but in only 13% was a sequencing directed therapy deployedDirected germline testing for inherited cancer predisposition in patients with advanced cancer (1 of 6, matched normal sequencing)Biallelic alterations in pathogenic germline variants (PGVs) were most often seen in DNA damage response genes (i.e., BRCA1/2, ATM) and DNA mismatch repair genes (i.e.,MLH1 and MHS2)

Acknowledgments

Pankaj Vats PhDRashmi Chugh MDFrancis Worden MDDavid C. Smith MDScott M. Schuetze MD, PhDMark M. Zalupski MDVaibhav Sahai MD

Ajjai Alva MD

Anne F. Schott MD

Megan E.V. Caram MDDaniel F. Hayes MDElena M. Stoffel MDMichelle F. Jacobs MS, CGCChandan Kumar-Sinha PhDXuhong Cao MSRui Wang MSDavid Lucas MDYu Ning MSErica Rabban BSJanice BellSandra Camelo-Piragua MDAaron M. Udager MD, PhDMarcin Cieslik PhDRobert J. Lonigro PhDLakshmi P. Kunju MDMoshe Talpaz MDMi-Oncoseq TeamErin Cobain, MDYi-Mi Wu, PhD

Dan Robinson, PhD

SPORE and R35