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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 Cancer Medicine Vanderbilt-Ingram Cancer Center Nashville, TN
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Disclosure Information
I have the following financial relationships to disclose: Patent licensed to MolecularMD for EGFR T790M testing Consulting for MolecularMD
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Case Report Day 0 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
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Cancer in the United States, 2009
New Cases Deaths Lung 219,440 159,390 Breast 192,370 Colorectal 49,920 Prostate 192,280 40,170 146,970 27,360 Jemal et al ‘09
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Lung Cancer Facts Risk factors NSCLC has 4 stages
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) Squam NSCLC histologies: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Large Adeno Small
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5-Year Overall Survival (Clinical Stage)
Goldstraw et al ‘07
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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
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Gefitinib and Erlotinib – Related Quinazoline EGFR-TKIs
ZD1839 Gefitinib Iressa OSI-774 Erlotinib Tarceva ATP
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Schematic of EGFR Signaling Pathway
Ligand K Ligand-binding domain RAS Gefitinib & erlotinib block signaling here RAF Grb-2 PI3K MEK SOS MAPK PTEN AKT Proliferation mTOR STAT 3/5 Survival
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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 (2nd-line) Phase III – erlotinib vs placebo 9% vs <1% RR; 6.7 vs. 4.7 mo OS – 2004 FDA approval (2nd-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
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Dramatic Response to Gefitinib
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Case Report Day 0 4 months 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
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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?
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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
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Prospective Trials of EGFR-TKIs in NSCLC
Study Agent RR % PFS* OS* Patients with EGFR mutant tumors (1st line) Paz-Ares Erlotinib 31/38 82 13 NR Morikawa Gefitinib 13/20 65 Sunaga 16/21 77 Sutani 21/27 9 15 Inoue 12/16 75 10 Asahina Sequist 17/26 12 21** Total 122/164 74 Unselected Populations (2nd line) ISEL 77/959 8 3 6 BR.21 38/427 2 7 *measured in months; **includes 5 atypical mutations; NR – not reached
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Rnd Ph III Trial: Iressa Pan ASian Study (IPASS: Gefitinib vs Chemo, upfront)
EGFR mutation positive EGFR mutation negative Gefitinib (n=132) Carboplatin / paclitaxel (n=129) Gefitinib (n=91) Carboplatin / paclitaxel (n=85) 1.0 1.0 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib: 97 No. events Chemo: 111 HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib: 88 No. events Chemo: 70 0.8 0.8 0.6 0.6 Probability of progression-free survival Probability of progression-free survival 0.4 0.4 0.2 0.2 0.0 0.0 4 8 12 16 20 24 4 8 12 16 20 24 Months Months At risk : Gefitinib 132 108 71 31 11 3 91 21 4 2 1 C/P 129 103 37 7 2 1 85 58 14 1 Gefitinib RR 71% Gefitinib RR 1% Mok et al ‘09 16
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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?
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Mutations in the ERBB Pathway in NSCLC
Ligand K Ligand-binding domain RAS 3 1 = both EGFR and HER2 1 4 RAF 2 Grb-2 PI3K MEK SOS MAPK PTEN AKT Proliferation mTOR STAT 3/5 Survival
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KRAS Mutations in NSCLC: A Negative Predictor for Response to EGFR TKIs
Retrospective Drug N Responses RR (%) Pao ’05 G/E 9 Tsao (BR.21) ’06 E 20 1 5 Fujimoto ’06 G 6 Van Zandwijk ’06 3 Han ’06 Hirsch (ISEL) ’06 Massarelli ’07 16 Subtotal 69 Prospective Miller ’06 19 Giaccone ’06 10 Jackman ‘07 35 Total 104
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Predictors of Response to Gefitinib/Erlotinib
Clinical Predictors NSCLC 10% Female 18% Adenocarcinoma 12% Never smoker 30% Molecular Predictors KRAS mutn <1% EGFR mutn >70%
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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
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Case Report Day 0 4 months 25 months 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
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Case Report Day 0 4 months 25 months Growing bone lesion
Growing lung lesion
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Drug Contact Residues Are Commonly Affected (T790M, T854A)
92% 4% 4% Adapted from Yun et al ’07; Bean et al ‘08
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MET Amplification Occurs in ~20% of Cases, With or Without T790M Mutations
Engelman et al ’07; Bean et al ‘07
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Case Report Day 0 4 months 25 months Exon 19 del T790M no MET
Erlotinib BIBW2992?
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Is this unique? Are there other examples?
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Fusions Involving the ALK Tyrosine Kinase Define Another Subset of NSCLC
(Soda et al ‘07) 20 ALK KINASE EML4 KINASE V1 KINASE V2 KINASE V3a/b KINASE V4 KINASE V5a/b KINASE V6 KINASE V7 “V4” KINASE KINASE “V5”
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Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK Fusions – Kwak et al PASCO ‘09
40 8+ 16 20 8+ 12 2+ 13+ 2+ 8+ 15+ 8+ 23+ 15+ 4+ One patient had clinical progression and discontinued without radiographic confirmation.
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Traditional View of Lung Cancer
Small Cell Lung Cancer (SCLC) Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Squam Large Adeno Small
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1987: KRAS Mutations in Lung Adenoca
Squam Large Adeno Unknown Small
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2004: EGFR Mutations Identified
KRAS Squam Large Adeno Unknown Small
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2009: Lung Adenoca- Multiple Molecular Subsets
ALK fusion ROS fusion BRAF PIK3CA PDGFR amp MEK1 HER2 KRAS EGFR Squam Large Adeno Unknown Small
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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
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Molecularly Tailored Therapy
Mutation Prediction EGFR exon 19 del/L858R Sens to EGFR TKIs KRAS Res to EGFR TKIs EGFR T790M/D761Y/T854A Res to EGFR TKIs; sens to new TKIs? MET amplification Sens to MET TKIs MEK1 Sens to MEK inhibitors HER2 Sens to HER2 TKIs BRAF Sens to BRAF inhibitors ALK fusions Sens to ALK inhibitors PDGFRa amplification Sens to PDGFR inhibitors PIK3CA PIK3CA inhibitors? ROS fusion Sens to ROS inhibitors?
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Version 1 SNaPShot: 36 Somatic Point Mutations in 8 Genes Relevant to Targeted Therapy in Lung Adenocarcinoma EGFR BRAF Position AA mutant Nucleotide mutant G719 p.G719C c.2155G>T 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 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 c.181C>A p.Q61L c.182A>T p.Q61R c.182A>G KRAS G12 p.G12C c.34G>T p.G12S c.34G>A p.G12R c.34G>C p.G12V c.35G>T p.G12A c.35G>C p.G12D c.35G>A G13 p.G13C c.37G>T p.G13S c.37G>A P.G13R c.37G>C p.G13D c.38G>A p.G13A c.38G>C Q61 p.Q61K c.181C>A p.Q61R c.182A>G p.Q61L c.182A>T p.Q61H c.183A>T c.183A>C 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 + PCR-based sizing assays for EGFR ex 19 dels, EGFR ex 20 ins’s, HER2 20 ins’s + ALK assessment
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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 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
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Successes/Limitations
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 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
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Acknowledgements Pao Lab VICC Pathology Medicine Bioinformatics MGH
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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