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Genotype-Driven Lung Cancer Treatment AAAS-FDLI Colloquium on Personalized Medicine October 27, 2009 William Pao, MD, PhD Assistant Director, Personalized.

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Presentation on theme: "Genotype-Driven Lung Cancer Treatment AAAS-FDLI Colloquium on Personalized Medicine October 27, 2009 William Pao, MD, PhD Assistant Director, Personalized."— Presentation transcript:

1 Genotype-Driven Lung Cancer Treatment AAAS-FDLI Colloquium on Personalized Medicine October 27, 2009 William Pao, MD, PhD Assistant Director, Personalized Cancer Medicine Vanderbilt-Ingram Cancer Center Nashville, TN

2 Disclosure Information I have the following financial relationships to disclose: Patent licensed to MolecularMD for EGFR T790M testing Consulting for MolecularMD

3 Day 0 Case Report 55 yo Caucasian woman 9 pk-yr smoking history s/p RLL and LUL lobectomies for lung adenocarcinoma 2 years later, recurrence with bilateral pulm nodules Progression on systemic chemotherapy

4 Jemal et al 09 Cancer in the United States, 2009 New CasesDeaths Lung219,440Lung159,390 Breast192,370Colorectal49,920 Prostate192,280Breast40,170 Colorectal146,970Prostate27,360

5 Adeno Squam Large Small Lung Cancer Facts –Risk factors 10% never smokers (<100 cigarettes in a lifetime) 50% former smokers –NSCLC has 4 stages St I-IIIA – potentially curable by surgery But 60% diagnosed at incurable stages (IIIB/IV) NSCLC histologies: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma

6 5-Year Overall Survival (Clinical Stage) Goldstraw et al 07

7 30 Yrs Research: Effect of Standard Chemotherapy in Metastatic NSCLC Has Reached a Plateau 1207 pts Response rate – 19% Median TTP – 3.7 mos Median OS – 8 mos Schiller et al 02

8 Gefitinib and Erlotinib – Related Quinazoline EGFR-TKIs OSI-774 Erlotinib Tarceva ATP ZD1839 Gefitinib Iressa

9 KK PI3K AKT Survival Grb-2 SOS RAS RAF MEK MAPK Proliferation Ligand Ligand-binding domain PTEN mTORSTAT 3/5 Schematic of EGFR Signaling Pathway Gefitinib & erlotinib block signaling here

10 Phase I/II/III Results Phase I - gefitinib –Unexpected objective regressions in 10/100 patients with NSCLC Phase II - gefitinib –10/28% RRs in US/Japan for gefitinib – 2003 FDA approval (2 nd - line) Phase III – erlotinib vs placebo –9% vs <1% RR; 6.7 vs. 4.7 mo OS – 2004 FDA approval (2 nd -line) Mild side effects –acneiform rash and diarrhea Baselga et al 02; Herbst et al 02; Ranson et al 02; Nakagawa et al 03; Fukuoka et al 03; Kris et al 03; Shepherd et al 05

11 Dramatic Response to Gefitinib

12 Day 04 months Case Report 55 yo Caucasian woman 9 pk-yr smoking history s/p RLL and LUL lobectomies for lung adenocarcinoma 2 years later, recurrence with bilateral pulm nodules Progression on systemic chemotherapy Response to erlotinib

13 Who Responds to Gefitinib or Erlotinib (2003)? No clear association with EGFR expression Clinical predictors –Female –Never smoker –Adenocarcinoma – esp. bronchioloalveolar subtype –Japanese (Miller et al JCO 04; Fukuoka et al JCO 03) Are there molecular predictors of sensitivity?

14 KDFG L L Tyrosine kinase 745 K DFG YYYY TM EGF ligand bindingautophos GXGXXG 858 LREA 861 Exon: EGFR Mutations Associated with Sensitivity to Gefitinib/Erlotinib G719A/CL858RdeletionL861Q Lynch et al 04; Paez et al 04; Pao et al 04

15 Prospective Trials of EGFR-TKIs in NSCLC StudyAgentRR%PFS*OS* Patients with EGFR mutant tumors (1 st line) Paz-AresErlotinib31/388213NR MorikawaGefitinib13/2065NR SunagaGefitinib16/217713NR SutaniGefitinib21/ InoueGefitinib12/167510NR AsahinaGefitinib12/16759NR SequistGefitinib17/ ** Total122/16474 Unselected Populations (2 nd line) ISELGefitinib77/ BR.21Erlotinib38/ *measured in months; **includes 5 atypical mutations; NR – not reached

16 Rnd Ph III Trial: Iressa Pan ASian Study (IPASS: Gefitinib vs Chemo, upfront) EGFR mutation positiveEGFR mutation negative HR (95% CI) = 0.48 (0.36, 0.64) p< No. events gefitinib: 97 No. events Chemo: 111 Gefitinib (n=132) Carboplatin / paclitaxel (n=129) HR (95% CI) = 2.85 (2.05, 3.98) p< No. events gefitinib: 88 No. events Chemo: Gefitinib C/P Probability of progression-free survival At risk : Probability of progression-free survival Gefitinib (n=91) Carboplatin / paclitaxel (n=85) Months Gefitinib RR 71% Gefitinib RR 1% Mok et al 09

17 Are There Molecular Predictors of Resistance to EGFR-TKIs? Primary resistance –Tumors that are refractory to treatment with either gefitinib or erlotinib –The majority of patients –Are these all EGFR wildtype tumors?

18 KK PI3K AKT Survival Grb-2 SOS RAS RAF MEK MAPK Proliferation Ligand Ligand-binding domain PTEN mTOR STAT 3/5 1 = both EGFR and HER2 Mutations in the ERBB Pathway in NSCLC

19 KRAS Mutations in NSCLC: A Negative Predictor for Response to EGFR TKIs RetrospectiveDrugNResponsesRR (%) Pao 05G/E900 Tsao (BR.21) 06E2015 Fujimoto 06G600 Van Zandwijk 06G300 Han 06G900 Hirsch (ISEL) 06G600 Massarelli 07G/E1600 Subtotal6911 ProspectiveDrugNResponsesRR (%) Miller 06E1900 Giaccone 06E1000 Jackman 07E600 Subtotal3500 Total10411

20 Predictors of Response to Gefitinib/Erlotinib Clinical Predictors NSCLC10% Female18% Adenocarcinoma12% Never smoker30% Molecular Predictors KRAS mutn<1% EGFR mutn>70%

21 How to Select EGFR-TKI Therapy? Scenario EGFR Mutation KRAS Mutation Treatment 1 +- Gefitinib or Erlotinib 2 -- Trial of drug? 3 -+ Alternative agents 4 ++ Likely contamination 50% of never smokers with adenoca have EGFR mutations 19% of former smokers with adenoca have EGFR mutations 4% of current smokers with adenoca have EGFR mutations 15% of never smokers have KRAS mutations Pham et al 06

22 Day 04 months25 months Case Report 55 yo Caucasian woman 9 pk-yr smoking history s/p RLL and LUL lobectomies for lung adenocarcinoma 2 years later, recurrence with bilateral pulm nodules Progression on systemic chemotherapy Response to erlotinib Acquired resistance

23 Day 04 months25 months Case Report Growing bone lesionGrowing lung lesion

24 Drug Contact Residues Are Commonly Affected (T790M, T854A) Adapted from Yun et al 07; Bean et al 08 92% 4%

25 MET Amplification Occurs in ~20% of Cases, With or Without T790M Mutations Engelman et al 07; Bean et al 07

26 Day 04 months25 months Case Report Exon 19 del Erlotinib T790M no MET BIBW2992?

27 Is this unique? Are there other examples?

28 EML4 ALK KINASE V1 V2 V3a/b V4 V5a/b V6 V7 V4 V5 Fusions Involving the ALK Tyrosine Kinase Define Another Subset of NSCLC (Soda et al 07)

29 Tumor Responses to PF for NSCLC Evaluable Patients with ALK Fusions – Kwak et al PASCO One patient had clinical progression and discontinued without radiographic confirmation.

30 Adeno Squam Large Small Traditional View of Lung Cancer Small Cell Lung Cancer (SCLC) Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma Squamous cell carcinoma Large cell carcinoma

31 Adeno Squam Large Small KRAS Unknown 1987: KRAS Mutations in Lung Adenoca

32 Adeno Squam Large Small KRAS Unknown EGFR 2004: EGFR Mutations Identified

33 Adeno Squam Large Small KRAS Unknown EGFR HER2 BRAF ALK fusion PIK3CA MEK1 ROS fusion PDGFR amp 2009: Lung Adenoca- Multiple Molecular Subsets

34 KRAS Unknown EGFR HER2 BRAF ALK fusion PIK3CA MEK1 ROS fusion PDGFR amp 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 2009: Lung Adenoca- Multiple Molecular Subsets

35 Molecularly Tailored Therapy MutationPrediction EGFR exon 19 del/L858RSens to EGFR TKIs KRASRes to EGFR TKIs EGFR T790M/D761Y/T854ARes to EGFR TKIs; sens to new TKIs? MET amplificationSens to MET TKIs MEK1Sens to MEK inhibitors HER2Sens to HER2 TKIs BRAFSens to BRAF inhibitors ALK fusionsSens to ALK inhibitors PDGFR amplification Sens to PDGFR inhibitors PIK3CAPIK3CA inhibitors? ROS fusionSens to ROS inhibitors?

36 PositionAA mutantNucleotide mutant G719 p.G719Cc.2155G>T p.G719Sc.2155G>A p.G719Ac.2156G>C T790 p.T790Mc.2369C>T L858 p.L858Rc.2573T>G L861 p.L861Qc.2582T>A EGFR G12 p.G12Cc.34G>T p.G12Sc.34G>A p.G12Rc.34G>C p.G12Vc.35G>T p.G12Ac.35G>C p.G12Dc.35G>A G13 p.G13Cc.37G>T p.G13Sc.37G>A P.G13Rc.37G>C p.G13Dc.38G>A p.G13Ac.38G>C Q61 p.Q61Kc.181C>A p.Q61Rc.182A>G p.Q61Lc.182A>T p.Q61Hc.183A>T p.Q61Hc.183A>C KRAS NRAS Q61 p.Q61Kc.181C>A p.Q61Lc.182A>T p.Q61Rc.182A>G H1047 p.H1047Rc.3140A>G E542 p.E542Kc.1624G>A E545p.E545Kc.1633G>A PIK3CA Q56 p.Q56Nc.167A>C K57 p.K57Nc.171G>T D67p.D67Nc.199G>A MEK1 (MAP2K1) E17p.E17Kc.49G>A AKT1 R233p.R233*c.697C>T PTEN PositionAA mutantNucleotide mutant G469 p.G469Ac.1406G>C L597 p.L597Vc.1789C>G V600 p.V600Ec.1799T>A BRAF Version 1 SNaPShot: 36 Somatic Point Mutations in 8 Genes Relevant to Targeted Therapy in Lung Adenocarcinoma + PCR-based sizing assays for EGFR ex 19 dels, EGFR ex 20 inss, HER2 20 inss + ALK assessment

37 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 Day 0

38 Successes/Limitations Successes Molecular subsets of NSCLC defined Greater likelihood of expected outcomes Can prioritize treatment regimens –Will be necessary as more agents become available Can rationally develop trials Cost savings Limitations Some small molecular subsets (~1% = 2,100 pts) Diagnostic molecular assays labor-intensive May take 2-3 weeks to get result Different mutns assessed by different technologies –Translocations/ Pt mutns/insertions/deletions RR/PFS vs OS Practicing oncologists not familiar with various tests

39 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


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