Giorgio V. Scagliotti Università di Torino Dipartimento di Oncologia giorgio.scagliotti@unito.it
Politi K & Herbst R. Clin. Cancer Res. 2015; 21:2213
Breast Colorectal Gastric/GE Junction Tumor Type Head and neck cancer Melanoma Non-small cell lung cancer (nonsquamous) GIST ER/PR, HER2 Biomarker KRAS, NRAS, BRAF, MSI HER2 HPV* (ISH) or p16 expression* BRAF V600E EGFR mt, ALK fusion, ROS1 CKIT, PDGFRA mt**, succinate dehydrogenase for wt GIST * For prognostication only ** e.g., D842V imatinib resistant
Darzi A. World Ecomonic Forum, November 2012
Hanahan D & Weinberg RA Cell 2011; 144:646
Garber K. J Natl Cancer Inst 2007;99:264-269
Assumption : Treatment T is effective for condition C, as defined by testing positive for biomarker B, where B is determined by diagnostic assay A. A biomarker, hypothesized to play a crucial role in the disease pathway A diagnostic assay, used to determine a patient s biomarker status; and A therapeutic agent, intended to be more effective for patients who are biomarker-positive.
TCGA, Nature, 2014: Alice Berger, William Lee By including amplification of MET and ERBB2, MET exon 14 splicing mutations, RIT1 mutations, and NF1 loss-of-function mutations, the driverpositive group increases to 75% of cases
RTK/Ras/Raf pathway in lung adenocarcinoma: KRAS, EGFR, NF1, BRAF, MET, ERBB2, RIT1, RAF1 Common squamous cell cancer genes including NFE2L2, FAT1, NOTCH1 Campbell et al., submitted
Patients who get benefit from molecular diagnosis
Kris M. et al. JAMA 2014; 311:1998
Biankin AV, Hudson TJ Hum. Genet. 2011; 130: 79-91 Emerging Molecular Taxonomy Prevalence of Phenotypes
EGFR mutant ALK rearranged Tanizaki J., WCLC 2015
Linear evolution pattern Branched evolution pattern Hiley et al. Genome Biology 2014 15:453
Crowley E et al. Nat Rev Clin Oncol. 2013;10(8):472-84.
Early detection Assessment of molecular heterogeneity Monitoring of tumor dynamics Identification of genetic determinants for targeted therapy Evaluation of early treatment response Monitoring of minimal residual disease Real time assessment of evolution of resistance
Diaz LA & Bardelli A. J. Clin. Oncol. 2014; 32: 579-586
Plasma ddpcr Turn around time (TAT): 3 days (range 1-7) Tissue genotyping TAT: Newly diagnosed: 12 days (range 1 54) EGFR acquired resistance: 27 days (range 1-146) Sacher et al JAMA Oncology 2016
TIGER-X: 331 of 417 were T790M+ by central tissue genotyping; 189 of 242 were T790M+ by plasma genotyping; and 136 of 169 were T790M+ by urine genotyping Four of 14 pts who were T790M+ in plasma but T790M in tissue responded; 3 of 7 pts who were T790M+ in urine but T790M in tissue responded Shrinkage of target lesions correlated with higher T790M:activating mutation ratio in plasma (p=0.006) n (T790M +) 500 mg BID 625 mg BID Tissue Plasma Urine Tissue Plasma Urine 156 61 50 175 128 86 ORR, % 25.0 27.9 32.0 39.4 33.6 40.7 95% CI mdor, mo 18.4-32.6 17.1-40.8 19.5-46.7 32.1-47.1 25.5-42.5 30.2-51.8 9.0 9.0 9.0 7.9 6.7 8.0 95% CI 4.6-11.0 4.4-11.0 2.6-11.0 5.6-9.2 4.8-9.0 6.8-11.2 Correlation plasma/tissue 81.5% Correlation urine/tissue 83.8% Plasma and urine EGFR analyses complement tissue biopsies in EGFR TKI resistant NSCLC CI, confidence interval; mo, months; NR, not reached Wakelee HA, et al. ASCO 2016. Abstract #9001
Oxnard GR et al. J Clin Oncol 2016; 34:3375-3382.
Jamal-Hanjani M et al. Clin. Cancer Res. 2015; 21:1258
Targeted Therapy Chemotherapy OX40 GITR CD137 Activating receptors CD28 CD27 HVEM T cell Inhibitory receptors LAG-3 CTLA-4 PD-1 B7-1 TIM-3 BTLA VISTA Cell Therapies Vaccines Agonistic antibodies T cell stimulation Blocking antibodies Adapted from Mellman I et al. Nature. 2011;480:481 489.
Progression during or after platinum therapy Chemotherapy EGFR TKI Antiangiogenics Immune checkpoint inhibitors Nintedanib 7,a Ramucirumab Docetaxel 3 8 Pemetrexed 4 Erlotinib 5 Afatinib 6 (+ docetaxel) (+ docetaxel) Nivolumab 9 Pembrolizumab 10,b If not given previously May be inferior to chemotherapy in WT patients If docetaxel not given previously Not suitable for squamous NSCLC Only approved for squamous NSCLC Only approved for adenocarcinoma Only approved for patients whose tumors express PD-L1 a Approved in EU only; b Approved in US only 1. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.4.2016 2. Reck M et al. Ann Oncol 2014;25(Suppl 3):27-39
Tumor cells: -Mutation load -Neoantigens -Genomic instability -Mutation immune molecules -Resistance Immune cells: -TCR seq -Amount/clones -Specificity -Antigens Mutation load and change with therapies Class I and Class II neoantigens Allelic frequency and expression of neoantigens Association with genetic makeup and oncogenic signaling Expression of immune inhibitory targets Clonal TCR selection and affinity
Molecular characterization before 1. line trx and in certain situation at PD (EGFR+) / ALK+? NGS recommended and preferred! Approved: EGFR, ALK, ROS, BRAF Recommended: MET, RET, HER2, KRAS Plasma T 790 accepted (sensitivity?) ALK-IHC accepted for treatment. ROS-IHC accepted for screening, but positivity verification with FISH PD-L1 testing, but with its own guidelines 25
DEFLeCT rapresents the key infrastructure of the Hub for Precision & Predictive Medicine (H4PPM) a public-private initiative that aims to merge partners and expertise to develop and support new products and services 28
Academic Partners Healthcare facilities H4PPM Pharma industries Research projects Diagnostic industries 29
Keep pace with genome discovery Use genomics tools in pre-clinical studies Consortia based molecular screening Smaller studies in pre-selected population Genotype based basket studies (agnostic of site of origin) Regulatory involvement- NGS as a companion diagnostic Use of genomic tools to refine patient selection using extreme responders Registry mechanisms- drug genome database