Incorporating Genomics into Clinical Care Araba A. Adjei, PhD AACR (SSP) April 4, 2017 Washington, DC. test

Cancer occurs when something goes wrong with our genes ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing Cancer occurs when something goes wrong with our genes DNA is the building block of a gene. Genes are stored in the chromosome A C T T G A G C Basic Genetics 3

Gene Mutation

Chromosomal Aberrations

Somatic mutations: Passengers and Drivers acquired alterations in DNA that occur in body cells other than germ cells (sperm and egg) and therefore not passed on to offsprings alterations in DNA can (but do not always) cause cancer or other diseases Driver mutations somatic mutations within a gene with functional consequences confer selective growth advantage to the cell thus promoting cancer development mutations occur frequently at the same genes, loci, or pathways in different patients

Somatic mutations: Passengers and Drivers Passenger mutations majority of somatic alterations with no functional consequence no positive or negative selective advantage to the tumor; considered to just go along “for the ride” studies suggest “mob mentality”: individually exert small effect; collectively may have enough significant effect to alter the course of cancer progression Oncogene An oncogene is a gene that when mutated or expressed at abnormally-high levels contributes to converting a normal cell into a cancer cell.

Passenger mutations in whole genome sequencing Cancer(s) Protein-coding mutations Driver mutations* 11 breast 115.4 5.1 10 colon 75 4 4 astrocytomas 206 5.5 Acute myeloid leukemia 10 2 26 melanomas 366 Small-cell lung 100 *Classified as drivers in COSMIC database McFarland et al,  PNAS, 2013

Proportion of cancer genes with mutations <10% >10% > 80% Futreal et al, Nat Rev Cancer, 2004

“Driver” Genes as Cancer Targets in TKI therapy EGFR Erlotinib, Gefitinib, Afatinib, Osimertinib EML4-ALK Crizotinib, Alectinib, Ceritinib Bcr-abl Imatinib, Dasatinib, Ponatinib HER2-neu Trastuzumab, Perzutumab B-raf Vemurafenib, Dabrafenib Ret Vandetanib, Cabozantinib Hedgehog Vismodegib Ros-1 Crizotinib MET Crizotinib, Cabozantinib, Tivatinib 9

Paradigm change: from treating clinical characteristics to Genomic – based therapy Drugs that target the molecular mechanisms involved in cancer progression can improve outcome DNA mutations Aberrant proteins Normal Cell Cancer cell

Kinase inhibition in oncogene-addicted NSCLC Erlotinib in NSCLC EGFR mut+ Crizotinib in NSCLC ALK+ ORR: 54–83%; PFS: 12 months Rosell Lancet Oncol 2012 This EGFR mutation predicts response to erlotinib in NSCLC The ALK fusion also predicts response to crizotinib ORR: 50–65%; PFS: 9months Kwak NEJM 2010

Not all “oncogenic” mutations are predictive biomarkers

BRAF Gene Mutations in NSCLC 21 (56.7%) V600E hotspot mutations 16 (43.3%) non-V600E mutations distributed in narrow areas between codons 594 and 606 (exon 15) and 446 and 449 (exon 11) Marchetti A, et al. J Clin Oncol. 2011;9:1669-1674.

Prognostic Significance of BRAF Mutations Litvak AM, et al. J Thorac Oncol. 2014;9:1669-1674.

BRAF V600E Mutant NSCLC: Confirmed Response to Dabrafenib in ≥2nd Line ORR = 33%; N=78 Planchard D, et al. Lancet Oncol 20146

Poor Survival of BRAF mutant CRC Hazard Ratio of 10.6 for OS Less than 1 year OS Tran, Kopetz, et al, Cancer ‘11

Poor Response of BRAFmut CRC to Standard Therapies BRAF wild type Progression at First Restaging Morris et al Clin Colorect Can ‘14

Minimal Efficacy with BRAF or Dual BRAF + MEK Inhibition BRAF inhibition BRAF + MEK inhibition -100 -75 -50 -25 25 50 75 100 %Change From Baseline (Sum of Lesion Size) 5% Response Rate 12% Response Rate Vemurafenib GSK212 + GSK436 Corcoran et al ASCO ‘12, Kopetz et al ASCO ‘10

Genomics-based Therapy is Part of the future Future Directions Repeating molecular analysis can help Drilon CCR 2015 In patients with lung cancer who have tested negative for EGFR, KRAS, ALK and ROS1, adding MET to the panel of mutations to be tested should be very strongly considered and this might be best accomplished as part of multi-gene panels. In fact, the NCCN guidelines have already adopted such recommendations given the powerful observations listed without a formal study in this area. MET∆14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain As the technology, feasibility and costs of NGS improve and become more accessible, NGS as the standard for the evaluation of genomic alterations may prove to be the recommended testing modality and recent technological advances now allow testing for alterations such as MET exon 14 skipping as part of ctDNA-based NGS platforms.

Genomic-based Therapy Current Study Design opened to community oncology programs NCI-Molecular Analysis for Therapy Choice (NCI-MATCH / EAY131) A phase II precision medicine cancer trial Co-developed by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute ECOG: eastern cooperative oncology ACRIN: American college of radiology imaging network; ECOG-ACRIN program merger of the NCI/NCTN (National cancer trials network)program

What is NCI-MATCH? ECOG-ACRIN-NIH-NCI 03/13/2017

NCI-MATCH Objective To determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of the cancer type This is a signal-finding trial—treatments that show promise can advance to larger, more definitive trials ECOG-ACRIN-NIH-NCI

NCI-MATCH Distribution of 1089 Sites Participation Rates by Site Type: NCORPS ~ 90% NCI Cancer Centers ~ 80% ECOG-ACRIN-NIH-NCI 03/13/2017

What do we know about NCI MATCH The clinical trial opened August 12, 2015 with 10 treatment arms Goal was to accrue 3000 patients As new assays were designed treatment arms and patient accrual goals were expanded. Today, patient accrual goal is 6000; treatment arms are 30 Patient Advocates helped design the trial and are overseeing its conduct

Molecular aberrations (gene abnormalities) and 30 treatment arms Drug(s) Abnormality Accrual Goal (Actual) A afatinib EGFR mut 35 (0) B HER2 mut 35 (29) C1 crizotinib MET amp 35 (10) C2 MET exon 14 sk 35 (13) E AZD9291 EGFR T790M 35 (3) F ALK transloc 35 (1) G ROS1 transloc H dabrafenib and trametinib BRAF V600E or V600K 35 (16) I taselisib  PIK3CA mut 70 (68) J trastuzumab and pertuzumab HER2 amp

Gene abnormalities and 30 Treatment Arms Drug(s) Abnormality Accrual Goal (Actual) L TAK-228 mTOR mut 35 (0) M TSC1 or TSC2 mut N GSK2636771 PTEN mut 35 (24) *SUSPENDED* P PTEN loss 35 (35) *FULL* Q ado-trastuzumab emtansine HER2 amp 70 (37) *SUSPENDED* R trametinib BRAF nonV600 35 (24) S1 NF1 mut S2 GNAQ or GNA11 35 (3) T vismodegib SMO or PTCH1 35 (11) U defactinib NF2 loss 35 (18)

Gene abnormalities and 30 Treatment Arms Drug(s) Abnormality Accrual Goal (Actual) V sunitinib malate cKIT mut 35 (2) W AZD4547 FGFR pathway aberrations 70 (42) X dasatinib DDR2 mut 35 (0) Y AZD5363 AKT1 mut 35 (23) Z1A binimetinib NRAS mut Z1B palbociclib CCND1, 2, or 3 amp 35 (21) Z1C CDK4 or CDK6 amp Z1D nivolumab dMMR status 70 (37) Z1E larotrectinib (LOXO-101) NTRK fusions Z1I AZD1775 BRCA1 or BRCA2 mut TOTAL: 1190 (495)

Study participation criteria Adults (18 years and over) solid tumors including rare tumors, lymphoma and myeloma good ECOG performance status able to tolerate being off treatment for 6 weeks ECOG-ACRIN-NIH-NCI 03/13/2017

NCI-MATCH Tumor Gene Testing ECOG-ACRIN-NIH-NCI

Basket Trial – NCI MATCH

NCI-MATCH : SUMMARY …As of March 13, 2017 4702 patients with tumor samples (N=6000) 4125 patients had received their test results 722 patients had a gene abnormality matching an available treatment arm and were further evaluated for specific eligibility 495 patients had enrolled for treatment NOTE: These are strictly numbers reflecting a point in time and cannot be used to calculate overall rates ECOG-ACRIN-NIH-NCI

NCI – MATCH: SUMMARY About 72% of patients who get assigned to a treatment arm actually enroll for treatment The laboratory network completes tumor testing for about 94% of patient cases About 20% of the patients have a gene abnormality which matched the one being studied

Cautionary Note: sequenced tumor Many genetic variants or mutations found when tumor is sequenced. Only a small proportion of the mutations are “actionable mutations” - mutations that are targets for drug therapy (MATCH panel) Most of the mutations received from sequencing are gene variants with UNKNOWN SIGNIFICANCE - not known if they are “actionable”; no known drugs that inhibit their action

Variants of Unknown Significance Gene Substitution Nucleotide Domain ALK G722C 2164G>T Extracellular N709I 2126A>T DDR2 c.554delG (C185fs) F5/8 type C EGFR R377W 1129A>T R962C 2884C>T Kinase E97* 289G>T G203A 608G>C G779V 2336G>T G779C 2335G>T D1014N 3040G>A Cytoplasmic ERBB2 S310Y 929C>A R784H 2351G>A L62V 184C>G S335C 1003A>T D483V 1448A>T KIT K834R 2501A>G

Gene Substitution Nucleotide Domain KRAS Y64N 190T>A Uncharacterized A11T 31G>A GTP binding V14L 40G>T MAP2K1 E255Q 763G>C Kinase PDGFRA Q24L 71A>T Ig-like C2-type 1 S89G 265A>G Y98* 294C>A R293L 878G>T Ig-like C2-type 3 R481M 1442G>T Ig-like C2-type 5 A503S 1507G>T L521M 1561C>A R914L 2741G>T PIK3CA C695F 2084G>T PIK helical Q546H 1638G>C PTEN L186P 557T>C Phosphatase tensin-type RET V53I 157G>A Extracellular R525L 1574G>T

NCI MATCH study conduct at Mayo Clinic Study opened August 2, 2016 in Rochester 113 patients have consented 99 patients have been screened 57 biopsy’s have been done (archived samples were sent for the other patients) 7 matches so far (3 have gone onto treatment) 2 recently MATCHed to the additional arms Proportion MATCHed = 7%

THANKS ! adjei.araba@mayo.edu