Leading the Way to Precision Care: Molecular Diagnostics and Therapeutics in Lung Cancers Mark G Kris, MD Memorial Sloan Kettering New Amsterdam USA
Molecular Therapeutics in Lung Cancers Financial Disclosures AstraZeneca - Consultant Additional Disclosures I was born a medical oncologist but was raised by thoracic surgeons I am a chemotherapy guy who has gone molecular
Molecular Therapeutics in Lung Cancers Introduction Revolution: targeting oncogenic drivers in lung cancers Growing opportunities from multiplex NGS testing New agents disrupt current standards: EGFR and ALK New Targets: NTRK, NRG, MET Expanding the use of targeted therapies Adjuvant Neoadjuvant Oligometastases and oligoprogression Intersection of targeted therapies with immunotherapeutics New research directions
Stage IV Lung Adenocarcinomas: Drug Therapy 1975-2018 Response Rate 1 Year Survival 2 Year Survival No Chemotherapy 0% 10% 0% Single Agent 15% 20% 10% Two Drugs (Pemetrexed + Cisplatin) 25% 50% 18% Three Drugs 35% 35% 20% Two Drugs plus Bevacizumab 35% 51% 23% Pembrolizumab with >50% PD-L1 45% 70% Osimertinib with EGFR Exon 19/21 Mutation Alectinib with ALK Rearrangement Crizotinib with ROS1 Rearrangement 80% 90% 72% 83% 84% 75% 72% 85% 74%
Initial Gefitinib Investigators Meeting 14 July 1996 Jose Baselga Eric Rowinsky
Results with Gefitinib 250 mg Daily 6 FEB 2002 11 FEB 2002
Lung Cancer Mutation Consortium LCMC2 Oncogenic Drivers Aisner Clin Cancer Research 2018 N=423
LCMC1: Survival with the five most frequent oncogenic drivers SURVIVAL 0.0 0.2 0.4 0.6 0.8 1.0 group=alk group=doub group=egfr(o) group=egfr(s) group=kras 0 1 2 3 4 5 YEARS Altered Gene N Median Survival (95% CI) EGFR (sensitizing) 140 4.0 years (2.7 to 5.4) Kris and Johnson JAMA 2014 EGFR (other) 50 3.3 years (2.2 to 6.2) ALK 73 4.3 years (3.0 to NA) KRAS 231 2.4 years (1.9 to 3.6) Drivers in Two Genes 32 2.0 years (1.6 to 4.6)
Marc Ladanyi Looking for a Target on Every Tumor Science 2009; 326: 218-220 www.science mag.org
Evolution of Multiplexed Testing Platforms Now-Gen MSK LC-MAP 8 genes Point mutations only Next-Gen MSK IMPACT 468 genes Point mutations plus deletions, insertions, amplifications Comparable cost
MSK-IMPACT DNA from FFPE Tumor and Normal cells Integrated Mutation Profiling of Actionable Cancer Targets Capture DNA for 410 cancer genes* Won H, et al., Journal of Visualized Experiments, Oct 2013 Cheng D, et al., J Mol Diagnostics, March 2015 Next-gen Sequencing (500-1000 x) Align to genome and analyze *As of February 2017 468 genes Somatic Mutations (Tumor-Normal Pairs): Base Substitutions Small Indels Copy Number Alterations Select Rearrangements
Landscape of Lung Cancers by NGS XXX XXX XXX XXX XXX XXX XXX Jordan Cancer Discov 2017
MSK-IMPACT : determinants of success Ryma Benayed
NGS Testing Using Cell free DNA from Plasma DNA fragments of 120-200bp with half life of ~2 hours Real-time, non-invasive, multilesions Cheaper because it does not require a biopsy Often very low amount of ctdna in the sea of wild type DNA - Needle in a farm Specific to tumor Diaz J Clin Oncol 2016
Concordance: Forty two patients had concurrent tissue NGS (42/86, 49% of MSK patients) Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) DNA isolated from tumor tissue and matched normal peripheral blood subjected to hybridization capture and deep-coverage NGS to detect somatic mutations in 468 cancer related-genes Mean overall coverage of sequencing depth ranged from 500 1000X. Concordance Tissue vs Plasma 40/42 (95%) Plasma vs Tissue 26/42 (62%)
NGS results in patients with lung adenocarcinomas with no drivers with non-ngs testing Genomic alteration/s identified with no targeted therapy option No genomic alteration identified Sales Genomic alteration with targeted therapy in NCCN guidelines EGFR G719A BRAF V600E SOCS5-ALK CLIP4-ALK CD74-ROS1 KIF5B-RET KIF5B-RET CCDC6-RET Tumor from same procedure as tumor subjected to non-ngs testing yes yes yes yes yes yes no yes Patient s clinical course recently started erlotinib, response evaluation pending subsequently passed away disease shrinkage (<30%) with crizotinib partial response to crizotinib recently started crizotinib, response evaluation pending partial response to cabozantinib disease shrinkage (<30%) with cabozantinib candidate for cabozantinib after progression on chemotherapy 29% (n=9/31) 6% (n=2/31) 39% (n=12/31) 26% (n=8/31) Drilon Clin Cancer Res 2015 Genomic alteration with targeted agent available on or off a clinical trial CDKN2A Loss EGFR L747P EGFR exon 18 del (n=2) EGFR exon 20 ins ERBB2 L755F FGFR1 T141R KRAS G12C KRAS Q61H MDM2 Amp (n=3) Targeted therapeutic (clinicaltrials.gov number) with potential activity available at institution CDK4/6 inhibitor (NCT01237236) erlotinib, afatinib pan-erbb inhibitor (NCT01858389) pan-erbb inhibitor (NCT01858389) pan-erbb/mtor inhibitor (NCT01953926) FGFR inhibitor (NCT01948297) ERK inhibitor (NCT01781429) ERK inhibitor (NCT01781429) MDM2 inhibitor (NCT01877382)
IFCT: Frequency of molecular alterations in six genes from 18,679 analyzed samples: overall population Barlesi Lancet 2016
Gallant Cancer Discov 2015
EGFR-KDD kinase domains (GLY 696-PRO 1370) Gallant Cancer Discov 2015
5 DECEMBER 2017
Strategies to Improve Outcomes in Patients with EGFR-mutant Lung Cancers Arbour and Riely Cancer 2018 (in press)
Components of care for patients with lung cancers with oncogenic drivers Targeted Therapies: Target Dependent and Independent Immunotherapy Surgery Angiogenesis Radiation Clinical Trials Chemotherapy
Small Cell Transformation + MET Amplification (1%) Small cell (1%) MET Amplification (3%) HER2 Amplification (8%) Unknown 18% The Stale Pie: Mechanisms of acquired resistance with 1 st and 2 nd generation EGFR TKIs T790M Alone 60% T790M + Small Cell (2%) T790M + MET Amplification (3%) T790M + HER2 Amplification (4%) Yu Clin Cancer Res 2013
Published online 7 May 2015 Acquired resistance to osimertinib and other 3rd generation agents in patients with acquired resistance to 1 st or 2 nd generation EGFR TKIs Published online 4 May 2015 Published online 1 May 2015
Genetic alterations associated with acquired resistance to osimertinib Target-dependent C797S G724S L718Q G796S/R/D L792F/H/Y The Pie in the Oven Target-independent MET amplification HER2 amplification HER2 exon 20 insertion EGFR amplification KRAS amplification KRAS G12S BRAF V600E MEK1 G128V JAK2 V617F FGFR3-TACC3 fusions small cell transformation
31 AUGUST 2017
TRK fusions found in diverse types of cancers Brain cancers (glioma, GBM, astrocytoma) Salivary (MASC) Thyroid cancer Lung cancer Secretory breast cancer Pancreatic Cholangiocarcinoma GIST Common cancer with low TRK fusion frequency Rare cancer with high TRK fusion frequency Colon Melanoma Sarcoma (multiple) Gliomas Thyroid cancer Infantile fibrosarcoma Congenital nephroma Spitz nevi Sarcoma (multiple) Estimated 1,500 5,000 patients harbor TRK fusion-positive cancers in the United States annually Hyman, LBA2501 32
Maximum change in tumor size (%) Larotrectinib efficacy regardless of tumor type 50 93.2 40 30 * 20 10 0-10 -20-30 -40-50 -60-70 -80-90 -100 Thyroid Colon Melanoma Soft tissue sarcoma Lung GIST Appendix IFS Breast Salivary gland Cholangiocarcinoma Pancreas # Hyman, LBA2501 33
Science 2017
Garber Science 2017
CD74- NRG1 Fusion Activation of HER3-HER2 Autocrine Juxtacrine Fernandez-Cuesta Clin Can Res 2014
HER3 Inhibitors Fernandez-Cuesta Clin Can Res 2014
NRG1 Fusion Response to anti HER3 MAb 86 man with lung adenocarcinoma with CD74-NRG1 fusion detected by MSK-IMPACT. baseline week 11 Alexander Drilon MD, Thoracic Oncology Service
Ado-trastuzumab emtansine for patients with HER2 mutant lung cancers ORR was 44% (8/18, 95% CI 22-69%), study met primary endpoint.
Adjuvant Osimertinib EGFR-mutant Lung Cancers Proposed Phase III Study Design Stage IB IIIA EGFRm NSCLC (exon 19 del or L858R) Complete surgical resection No adjuvant chemotherapy Adjuvant chemotherapy N=660 Randomisation stratification: prior adjuvant chemotherapy, mutation type, stage 1:1 Osimertinib 80mg QD 3 year treatment Placebo 1 yr: DFS 2 yr: OS Trials are designed with Power = 90%, 2-sided alpha = 0.05 Based on enrolment rate of 23 patients/month, to be confirmed by detailed feasibility Assumes 35% death rate at time of DFS (50% maturity)
EGFR Resectable IB-IIIB (8 th ed) Enroll with local genotyping or ctdna LCMC 4.0 Neoadjuvant Precision Multimodality Therapy Osimertinib (Bivona) Crizotinib (Doebele) T-cell checkpoint inhibitor Chemotherapy Scans, Repeat ctdna Major pathologic response rate Correlates in persister cells Adjuvant therapy -investigator s choice followed by personalized strategies per future research studies
DNA Sequence Not The Whole Story DNA Sequencing Copy Number Changes Fusion Proteins Epigenome Gene expression profiling Proteome Thomas Lynch, MD
T-Cell Checkpoint Inhibitors in Patients with EGFR-mutant Lung Cancers Patients with EGFR-mutant lung caners excluded from pivotal clinical trials scant data Tumors with EGFR mutations generally have a low mutational burden. PR in 4%, PD-L1 >50% in 11%, high level TILs in 2% (Gainor Clin Cancer Res 2016) No consensus on what to do if a patient tumor has both EGFR mutation and PD-L1 > 50%. Some data Recommend frank discussion with the patient.favor PD-L1 drug 1 st.
WES is a challenge to apply as a diagnostic tool but targeted NGS is routinely used now and good estimate Variety of tumor types Same DNA libraries for both NSCLC only (Same tumor tissue in 80% cases) Zahir, Benayed, Nature Medicine 2017 Rizvi H, Sanchez-Vega, JCO [in press]
Direct use of TMB from targeted sequencing as a biomarker Rizvi H, Sanchez-Vega, JCO [in press]
Lessons learned from molecular revolution: Toward precision immunotherapy Don t discard low response rates in unselected patients just need to find the right population of people to give it to. Beatty, ASCO 2017
YES1 amplification: a new mechanism of acquired resistance to all EGFR kinase inhibitors in EGFR-mutant lung cancers YES1 is a Src family kinase (SFK) that phosphorylates YES1-associated protein 1 (YAP1), a Hippo pathway effector implicated in resistance to multiple targeted therapies Overexpression of YES1 a resistance mechanism in the EGFR-mutant PC9 lung adenocarcinoma cells by two different approaches: 1) generation of osimertinib-resistant cells through gradual dose escalation and 2) a forward transposon mutagenesis screen to recover afatinib-resistant PC9 derivatives Cells overexpressing YES1 exhibited resistance to all 3 generations of EGFR TKIs but sensitivity to SFK inhibitors Analysis of MSK-IMPACT data for 136 cases of acquired resistance to EGFR TKIs revealed 4 cases with YES1 amplification, 3 of which lacked other mechanisms of resistance Ichihara, Cancer Research 2017, Fan (MSK) submitted for publication
Characterization of drug-tolerant persister cells and adaptive resistance mechanisms in patients with EGFR-mutant lung adenocarcinomas treated with erlotinib or osimertinib MSK IRB #17-290 first on-treatment scan at 4 2 weeks Scan* subsequent scans every 8 2 weeks Scan* Scan* Scan* Day 0 Week 2 4 6 8 10 12 14 16 18 20 22 24 26 28 TKI Therapy baseline scan & pre-treatment biopsy scan showing initial clinical response (ICR) 4 weeks biopsy of ICR* sample for pathology sample for whole-exome sequencing, RNAseq sample for pathology sample for wholeexome sequencing, RNAseq, and PDX Helena Yu, PI
Bending the survival curve in lung cancers Hellmann JAMA Oncology 2015 Stage IV Lung cancers - Today All Lung cancers - Tomorrow
There are no Good Prognosis Lung Cancers 8 th Edition T Stage (all N0M0) Primary Size (cm) N (%) 5 Year Survival Clinical Stage 5 Year Survival Pathological Stage T1a 0.1-1 785 (8) 92% 92% T1b 1.1-2 3157 (31) 83% 86% T1c 2.1-3 2469 (24) 76% 81% T2a 3.1-4 1944 (19) 67% 74% T2b 4.1-5 612 (6) 60% 65% T3 5.1-7 814 (8) 52% 57% T4 >7 403 (4) 38% 47% Rami-Porta J Thorac Oncol 2015
Components of Care for the Therapy for Lung Cancers Angiogenesis Clinical Trials Immunotherapy Targeted Rx Surgery Radiation Chemotherapy
Molecular Therapeutics in Lung Cancers Conclusions The discovery of oncogenic drivers and the identification of drugs to target them has transformed the care of persons with lung cancers Multiplex NGS testing at diagnosis permits the selection of the best initial targeted and immunotherapies New trial designs can accelerate progress across diseases Disease agnostic therapies have arrived more are on the way New therapies and paradigms have radically changed research priorities. Time to reboot. As we search for cures, we must meet the challenge to bring the best drug at the best time to each patient with lung cancer today
2005 2012 Kris Kris XXXXXXXXXXXXXXXXX Here's my sequence...
Response to Vemurafenib BRAF V600E Mutant Lung Cancer baseline 6 weeks on vemurafenib
When there are thousands of starfish and only one of you. What difference can you make throwing just one back in the water?
You can sure made a difference to this one