Disclosures Institutional Research Grants: Roche- Genentech, - PDF document

11/5/19 Emerging Role of Liquid Biopsy in Precision Medicine: Non-Small Cell Lung Cancer as a Model David R. Gandara, MD University of California Davis Comprehensive Cancer Center 1 Disclosures • Institutional Research Grants: Roche- Genentech, Novartis, Merck • Consultant/Advisory Board: AstraZeneca, Celgene, CellMax, FujiFilm, Roche-Genentech, Guardant Health, Inivata, IO Biotech, Lilly, Merck, Samsung Bioepis 2 1

11/5/19 100 patients with Advanced Stage Non-Small Cell Lung Cancer (NSCLC): They all look alike, but they are not NSCLC 3 100 patients with Advanced Stage Non-Small Cell Lung Cancer (NSCLC): 56 y/o female They all look alike, but they are not Former Smoker Adenoca 43 y/o female MET ex14 mt Never-Smoker Adenoca EGFR mt 55 y/o male 65 y/o male Former Smoker Current Smoker Adenoca Adenoca ROS1 fusion BRAF V600E mt 52 y/o male Former Smoker 34 y/o female Adenoca Never Smoker Squamous ALK fusion In 2019 most Oncologist would agree that these are different malignancies. HER2 mt SqCC Non-SqCC In 2019 most Oncologists would agree that these patients need different therapies 4 2

11/5/19 Evolution & Expanding List of Guideline Recommendations for Genomic Testing in NSCLC “The NCCN NSCLC Guidelines Panel strongly endorses broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC).” Genomic Alteration (i.e. driver event) Available targeted agents with activity against driver event in lung cancer* EGFR mutations osimertinib, erlotinib, gefitinib, afatinib, dacomitinib ALK rearrangements alectinib, brigatinib, ceritinib, crizotinib, lorlatinib HER2 mutations ado-trastuzumab emtansine, afatinib BRAF V600E mutations dabrafenib + trametinib, vemurafenib MET amplification/mutation crizotinib ROS1 rearrangements crizotinib, ceritinib RET rearrangements cabozantinib, vandetanib NTRK rearrangements entrectinib, larotrectinib NCCN Clinical Practice Guidelines. NSCLC. v3.2019. 5 Growing Number of Oncogene-driven NSCLCs with Active Targeted Therapies RET : Pending: NTRK : HER2 mutation Cabozantinib: LOXO-292: Larotrectinib HER2 mutation: RR=40% RR=77% 71% RR ~15% RR -Afatinib; Alectinib BLU-667: ~20% -Dacomitinib RR = 50% 44% -Ado Trastuzumab ROS1 : 70% RR to Crizotinib -Ceritinib BRAF (V600E): >60% RR to BRAF + MEK inhibitor combo ALK : 65% RR to crizotinib; ~70% RR to 2 nd -gen TKI; Ceritinib in resistant cancers Alectinib 1 st line MET ex14: 30-40% RR Crizotinib KRAS G12C EGFR : RR>70% Cabozantinib AMG510 to 1st-2nd–Gen TKIs; ~60% RR to 3rd-Gen TKIs 48% (11/23) MET ex14 in resistant cancers responders Capmatinib 60% RR Tepotinib 59% RR Gandara: Lung Cancer Summit. ESMO19 6 3

11/5/19 Schema for Multidisciplinary Integration of Biomarker Testing in Advanced Stage NSCLC: Looking for “Actionable” Oncogenes Referring Physician Identify Patient Pathologist Pulmonologist Multidisciplinary Interventional Radiologist Team Histology Evaluation Oncologist Surgeon (Tumor Board) Determine Identify Biopsy Therapy Target Lesion Molecular Biomarker Treat Med Oncologist Testing Thoracic Surgeon Radiation Oncologist T Pulmonologist r When When Determine Radiologist Progression e Progression New Therapy Pathologist à Re-Biopsy a à Re-Biopsy Plasma ctDNA Plasma ctDNA t Adapted from: Raez, Gandara et al Clin Lung Cancer 2016 7 Evolution of Biomarker Testing in NSCLC: Past, Current & Future Empiric Approach (Past) (Compound-Based Therapy): 1. Histomorphological Clinical-histologic factors to select Diagnosis: drugs for individual patients Cancerous 2. Molecular Diagnosis: Macro- or Extract tumor Archival FFPE tumor Archival cancer Micro-dissection nucleic acids: specimens specimens of Tumors DNA and RNA Representative technologies: Current Approach (Target-Based Therapy V1.0): Single Biomarker Tests: • Sanger DNA Sequencing Single gene molecular testing for decision-making in • RT-PCR individual patients • FISH • IHC Multiplex, Hot Spot Mutation Tests: Evolving Approach (Target-Based Therapy V2.0): • PCR-based SNapShot • PCR-based Mass Array SNP Multiplexed molecular tests with increased sensitivity • Sequenom & output for decision-making in individual patients Initial High-Throughput Technologies: • SNP/CNV DNA microarray • RNA microarray Near-Future Approach (Patient-Based Therapy): Next Generation Sequencing (NGS): • Whole Genome or Exome capture Genomic profiling by high throughput next generation Sequencing (DNA) sequencing for decision-making in individual patients • Whole or Targeted Transcriptome Sequencing (RNA) à Plasma ctDNA by NGS for Genomics & TMB from Li, Gandara et al: J Clin Oncol , 2013 • Epigenetic profiling 8 4

11/5/19 Terminology: Liquid Biopsy CTCs (circulating tumor cells) ctDNA (circulating tumor DNA) cfDNA (cell-free DNA) Liquid biopsy (blood sample) Crowley E, et al. Nat Rev Clin Oncol 2013;10:472–484. 9 What can Liquid Biopsy provide in November 2019 for NSCLC? Tumor Genomics & blood-based Tumor Mutational Burden (investigational) Advantages of plasma ctDNA over Tumor biopsy or re-biopsy: • Indicated when tumor tissue not available or high risk (or “plasma-first” situations) • Reflects shed tumor DNA into plasma from all tumor sites, providing a “global perspective” • May abrogate the issue of tissue heterogeneity and undergenotyping due to small sample • Can determine mechanism of resistance without biopsy, to guide subsequent therapy • Can be repeated serially (longitudinal assessment) for response & early progressive disease • Relatively non-invasive & high acceptance rate by patients • Detection of Minimal Residual Disease (i.e. after surgical resection) 10 5

11/5/19 Patient with Advanced Treatment-naïve NSCLC Molecular profiling on all with non squamous, non squamous component, or if clinical features may suggest a molecular driver NO Surgical specimen is available Tissue biopsy specimen is sufficient for molecular testing YES NO YES Perform molecular analysis a Perform molecular analysis a on on tissue biopsy specimens b ; Perform molecular analysis a liquid biopsy (ctDNA); NGS is on surgical specimen b ; NGS is preferred c ; Treat with preferred c SOC therapy based on NGS is preferred c ; Treat presence or absence of with SOC therapy based on presence or absence of oncogenic driver; Perform Therapeutic PD-L1 IHC as needed oncogenic driver; Perform Therapeutic target target positive PD-L1 IHC as needed negative Treat with SOC Tissue re-biopsy therapy based on presence of oncogenic driver Perform molecular analysis a on tissue biopsy specimens b ; NGS is preferred c ; Treat with SOC therapy based on presence or absence of oncogenic driver; Perform PD-L1 IHC as needed From Rolfo, Gandara et al: J Thorac Onc 2018 . a EGFR, ALK, ROS1, and BRAF at minimum, but panel if available. b Strongly suggest tissue sparing to facilitate participation in clinical trials. c While NGS is preferred, based on availability, other validated assays are acceptable. 11 Patient with NSCLC progressive or recurrent disease during therapy Perform molecular analysis a on liquid biopsy (ctDNA) Targetable Targetable resistance mutation resistance mutation absent present Tissue re-biopsy Treat with SOC therapy based on presence of oncogenic driver Feasible Not Feasible Perform molecular analysis a Evaluate the potential benefit on tissue biopsy specimen b ; of other therapy for marker NGS is preferred c ; Treat with unknown or best supportive SOC therapy based on care presence or absence of oncogenic driver; Perform PD-L1 IHC as needed from Rolfo, Gandara, et al: J Thorac Onc 2018 . a cobas/ddPCR for EGFR mutation NGS preferred for ALK and ROS1. b Strongly suggest tissue sparing to facilitate participation in clinical trials. c While NGS is preferred, based on availability, other validated assays are acceptable. 12 6

11/5/19 High Circulat ating Tumor (ct ct)D )DNA Det etect ection Rat ate ac across Multiple Can ancer Ty Types (N=21,807) NSCLC Guardant360 plasma NGS assay for detection of somatic alterations in 21,807 cancer patients 85% detection rate across all cancers 93% SCLC 87% NSCLC Median VAF: 0.41% (range 0.03-97.6) Zill, Mack, Gandara, Landman et al, CCR 2018 13 PENN2 Study: Response to Targeted Therapy is Independent of Plasma Mutation Allelic Fraction Progression of Disease Partial Response n=42; R=-0.121; p=0.45 Aggarwal et al: JAMA Oncol 2018 14 7