The Personalized Cancer Medicine Initiative at Vanderbilt October 26, 2009 William Pao, MD, PhD Assistant Director, Personalized Cancer Medicine Vanderbilt-Ingram Cancer Center
Cancer in the United States, 2009 New Cases Deaths Lung 219,440 Lung 159,390 Breast 192,370 Colorectal 49,920 Prostate 192,280 Breast 40,170 Colorectal 146,970 Prostate 27,360 Jemal et al 09
Traditional View of Lung Cancer Small Cell Lung Cancer (SCLC) Large Squam Adeno Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Small
30 Yrs Research: Effect of Standard Chemotherapy in NSCLC Has Reached a Plateau 1207 pts Response rate 19% Median TTP 3.7 mos Median OS 8 mos Schiller et al 02
Iressa and Tarceva Related Agents that Target EGFR ATP
Dramatic Response to Gefitinib
EGFR Mutations Associated with Sensitivity to Gefitinib/Erlotinib EGF ligand binding Tyrosine kinase autophos TM K DFG Y Y Y Y 718 745 858 861 964 GXGXXG K DFG L L Exon: 18 19 20 21 22 23 24 LREA G719A/C deletion L858R L861Q Lynch et al 04; Paez et al 04; Pao et al 04
Clinical Predictors NSCLC 10% Female 18% Adenocarcinoma 12% Never smoker 30% Molecular Predictors KRAS mutn <1% EGFR mutn >70% Predictors of Response to Gefitinib/Erlotinib
Probability of progression-free survival Probability of progression-free survival EGFR mutation positive Rnd Ph III Trial: Iressa Pan ASian Study (IPASS: Gefitinib vs Chemo, upfront) EGFR mutation negative 1.0 Gefitinib (n=132) Carboplatin / paclitaxel (n=129) 1.0 Gefitinib (n=91) Carboplatin / paclitaxel (n=85) 0.8 0.6 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib: 97 No. events Chemo: 111 0.8 0.6 HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib: 88 No. events Chemo: 70 0.4 0.4 0.2 0.2 At risk : Gefitinib C/P 0.0 0 4 8 12 16 20 24 Months 132 108 71 31 11 3 0 129 103 37 7 2 1 0 0.0 0 4 8 12 16 20 24 Months 91 21 4 2 1 0 0 85 58 14 1 0 0 0 Gefitinib RR 71% Gefitinib RR 1% Mok et al 09
Fusions Involving the ALK Tyrosine Kinase Define Another Subset of NSCLC (Soda et al 07) 20 ALK EML4 2 6 13 14 15 18 20 KINASE E13a;A20 E20;A20 E6a/b;A20 E14;A20 E2a/b;A20 E13b;A20 E14;A20 E15;A20 E18;A20 KINASE KINASE KINASE KINASE KINASE KINASE KINASE KINASE KINASE V1 V2 V3a/b V4 V5a/b V6 V7 V4 V5
% of best change from baseline One patient had clinical progression and discontinued without radiographic confirmation. Kwak et al PASCO 09 Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK Fusions Tumor Size Change Duration of Response (Weeks) 40 20 0-20 -40 40 8+ 16 20 8+ 12 2+ 13+ 15+ -60-80 2+ 8+ 8+ 23+ 15+ -100 Green - PR Blue - SD Black - PD 4+
Traditional View of Lung Cancer Small Cell Lung Cancer (SCLC) Large Squam Adeno Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Small
Squam 2009: Lung Adenoca- Multiple Molecular Subsets ALK fusion BRAF PIK3CA MEK1 HER2 KRAS EGFR ROS fusion PDGFR amp Large Small Adeno Unknown
2009: Lung Adenoca- Multiple Molecular Subsets ALK fusion ROS fusion BRAF PIK3CA PDGFR amp MEK1 HER2 KRAS EGFR Mutations associated with drug sensitivity G719X, exon 19 del, L858R, L861Q Mutations associated with 1ry drug resistance exon 20 dup Mutations associated with 2ry drug resistance L747S, D761Y, T854A, T790M MET amplification Unknown
Melanoma: Also Comprised of Clinically Relevant Molecular Subsets
(Carvajal et al PASCO 09) Phase II Trial of Imatinib in KIT-Mutant Melanoma
Phase II Trial of BRAF Inhibitor (PLX-4302) in BRAF-Mutant Melanoma (Flaherty, Sosman, Puzanov et al PASCO 09)
%Change From Baseline (Sum of Lesion Size) Interim Best Overall Response in Extension Cohort Patients 100 75 50 25 70% Response Rate (18 PRs and 1 CR) M1a M1b M1c 0-25 -50-75 (RECIST cutoff for PR, 30%) -100 n=27 Evaluable Patients As of 8/21/09
BRAF V600E Melanoma Patient PET Scan at Baseline and Day +15 After PLX4032 Treatment at 960 mg BID
Cancers Driven by Mutant Kinases and Targeted by Specific Kinase Inhibitors Disease Target Kinase inhibitor Chronic myelogenous leukemia BCR-ABL Imatinib Gastrointestinal stromal tumor Mutant KIT or PDGFRa Imatinib Lung adenocarcinoma Mutant EGFR Gefitinib/Erlotinib Lung adenocarcinoma EML4-ALK ALK inhibitors (in development) Melanoma Mutant BRAF BRAF inhibitors (in development) Melanoma Mutant KIT Imatinib
Ongoing Efforts to Sequence Cancer Genomes/Identify Drug Targets
Goals of the VICC PCMI To establish reflex testing of common clinically relevant genetic alterations in lung cancers and melanomas. To develop a clinically-applicable high-throughput molecular genotyping facility for rarer genetic variants. To develop bioinformatic algorithms to report genetic results in the electronic medical record in ways that are clinically useful for practicing oncologists. Collaboration among Depts of Medicine, Pathology, BioInformatics, and VICC Sounds simple, but requires high level of collaboration/coordination
Aim 1 To establish reflex testing of common clinically relevant genetic alterations in lung cancers and melanomas. Melanoma BRAF KIT Lung adenocarcinoma EGFR KRAS ALK
Aim 2 To develop a clinically-applicable highthroughput molecular genotyping facility for rarer genetic variants.
Version 1: 36 Somatic Point Mutations in 8 Genes Relevant totargeted Therapy in Lung Adenocarcinoma EGFR Position AA mutant Nucleotide mutant p.g719c c.2155g>t G719 p.g719s c.2155g>a p.g719a c.2156g>c T790 p.t790m c.2369c>t L858 p.l858r c.2573t>g L861 p.l861q c.2582t>a KRAS G12 G13 Q61 p.g12c p.g12s p.g12r p.g12v p.g12a p.g12d p.g13c p.g13s P.G13R p.g13d p.g13a p.q61k p.q61r p.q61l p.q61h p.q61h c.34g>t c.34g>a c.34g>c c.35g>t c.35g>c c.35g>a c.37g>t c.37g>a c.37g>c c.38g>a c.38g>c c.181c>a c.182a>g c.182a>t c.183a>t c.183a>c BRAF Position AA mutant Nucleotide mutant G469 p.g469a c.1406g>c L597 p.l597v c.1789c>g V600 p.v600e c.1799t>a NRAS Q61 p.q61k p.q61l p.q61r c.181c>a c.182a>t c.182a>g PIK3CA H1047 p.h1047r c.3140a>g E542 p.e542k c.1624g>a E545 p.e545k c.1633g>a MEK1 (MAP2K1) Q56 p.q56n c.167a>c K57 p.k57n c.171g>t D67 p.d67n c.199g>a AKT1 E17 p.e17k c.49g>a PTEN R233 p.r233* c.697c>t
Lung Adenocarcinoma Comprehensive Screen (5 Panels)
NRAS G12 p.g12c p.g12s p.g12r p.g12v c.34g>t c.34g>a c.34g>c c.35g>t p.g12a c.35g>c p.g12d c.35g>a p.g12n c.34_35gg>aa G13 p.g13a c.38g>c p.g13v c.38g>t p.g13r c.37g>t p.g13d c.38g>a Q61 p.q61e c.181c>g p.q61h c.183a>t p.q61h c.183a>c p.q61l p.q61l p.q61l c.182a>t c.181_182ca>tt c.182_183aa>tg p.q61k p.q61k c.181c>a c.180_181ac>ta p.q61p c.182a>c p.q61r p.q61r p.q61r c.182a>g c.180_181ac>ta c.182_183aa>gg Version 1: 45 Somatic Point Mutations in 5 Genes Relevant to Targeted Therapy in Melanoma BRAF Position AA Nucleotide p.v600r c.1798_1799gt>ag p.v600k c.1798_1799gt>aa p.v600e c.1799t>a V600 p.v600e p.v600m p.v600g V600D (call E) c1799_1800 TG>AA c1798g>a c1799t>g c1799_1800 TG>AT CTNNB1 (B-CAT) p.s45p c133t>c S45 p.s45f c134c>t p.s45y c134c>a S37 p.s37f c.110c>t p.s37y c110c>a KIT K642 p.k642e c.1924a>g L576 p.l576p c.1727t>c W557 p.w557r c.1669t>c p.w557r c.1669t>a V559 p.v559a c.1676t>c p.v559d c.1676t>a D816 p.d816h c.2446g>c GNAQ Q209 p.q209p p.q209l p.q209l c.626a>c c.626a>t c.625_626ca>tt
Melanoma Comprehensive Screen (5 Panels) NRAS_G13 (38R) BRAF _V600 (1799) NRAS_Q61 (182) B-CATS45 (134R) B-CAT_S37 (110) NRAS_G13 (37R) BRAF_V600 (1798) NRAS_Q61 (183R) KIT_V559 (1676) B-CAT_S45 (133R) NRAS_G12 (35) KIT_W557 (1669) KIT_L576 (1727) KIT_D816 (2446) GNAQ_Q209 (626) NRAS_G12 (34R) KIT_K642 (1924) NRAS_Q61 (181) A: Green T: Red G: Blue C: Black
PCR-Based Sizing Assays for Insertions/Deletions in Lung Adenocarcinoma H1650: E19del = 15 bp del E20ins = WT H20ins = WT E20i E19d H20i Lung Ca Sample: E19del = WT E20ins = 6 bp ins H20ins = WT H1781: E19del = WT E20ins = 3 bp ins H20ins = WT
Aim 3 To develop bioinformatic algorithms to report genetic results in the electronic medical record in ways that are clinically useful for practicing oncologists. The propensity to prescribe
Current Medical Oncology Provider White Board
Proposed Medical Oncology Provider White Board Demographics Diagnosis/ Stage GW 55AF NSCLC Adenocarcinoma Stage IV Relevant Biomarkers Disease Status EGFR+ Metastatic Erlotinib since 6/7/08 Current Tx CBC Che m Imaging 11:33 11:33 Last CT CAP 8/7/09 Trial Status Consider 2 nd -gen EGFR TKI if POD JD 68WF DS 45WM NSCLC Adenocarcinoma Stage II NSCLC Adenocarcinoma Stage IV KRAS+ Recurrent Metastatic Carboplatin/ Paclitaxel s/p 2 cycles; started 7/15/09 - - Last CT CAP 7/12/09 ALK+ Metastatic Untreated - - Today - pending Consider KRAS trial; unlikely to respond to EGFR TKI Consider ALK trial WP 55M Malignant Melanoma Stage II BRAF+ Recurrent Metastatic PLX-0432 since 08/12/08 - - Last CT CAP 9/22/09 - DS 42M Malignant Melanoma Stage IV KIT+ Metastatic Interferonalfa2b - - Last CT CAP 7/7/09 Consider imatinib
Summary/Future Directions Personalized Cancer Medicine Initiative launched at VICC Multiplex genotyping platforms nearly developed Implementation into CLIA labs planned Reflex testing already initiated for some mutations Consents written Molecular results to be placed in chart Bioinformatics to provide clinical decision support Importantly, PCMI will serve as a template to move forward with other cancers, genetic results
Potential Benefits of Tailoring Therapy According to the Genetic Makeup of Tumors Using EGFR mutations in NSCLC as an example: Make more informed medical decisions Higher probability of desired outcomes Reduced probability of negative side effects Chemo: intravenous, nausea, vomiting, hair loss, neutropenia, kidney failure Iressa/Tarceva: oral, rash, diarrhea
Potential Benefits of Tailoring Therapy According to the Genetic Makeup of Tumors Reduced healthcare costs Standard Approach: 2 cycles carbo/paclitaxel/bevacizumab $29,170 (wait 6 weeks to determine response) followed by 2 cycles of pemetrexed $21,868 (wait 6 weeks to determine response) Total: $51,038 Molecularly Tailored Approach: Multiplex mutation test $2,000 (>70% chance of response if known EGFR mutation) Erlotinib (90d) $13,671 Total: $17,671
Acknowledgements Pao Lab MarKeesa Duke Laurel Fohn Katie Hutchinson Zengliu Su Paula Woods VICC Jennifer Pientepol Pathology Cheryl Coffin Cindy Vnencak-Jones Medicine David Johnson Jeff Sosman Bioinformatics Dan Masys Mia Levy Russ Waitman MGH A. John Iafrate Funding Anonymous Foundation VICC CCSG TJ Martell Foundation