West xcenda molec testing sf oct 2011 revised final

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West xcenda molec testing sf oct 2011 revised final

  1. 1. Molecular Markers and Testing Strategiesin Advanced Non-Small Cell Lung Cancer Howard (Jack) West, MD Swedish Cancer Institute Seattle, WA Challenging Cases in Breast & Lung Cancer San Francisco, CA October 22, 2011
  2. 2. Why do molecular testing?•  To improve clinical outcomes –  Give best treatment first (timing of EGFR TKI Rx) –  To provide access to agent (crizotinib for ALK- positive) –  To identify subsets who might benefit from targeted therapy (cetuximab?)•  To facilitate clinical research –  May improve patient outcomes –  Better understanding of molecular oncology
  3. 3. IPASS: Gefitinib vs. Carbo/Paclitaxel as First Line Rx in Asian Never- or Light Ex-Smokers R Carbo/Paclitaxel IV Advanced NSCLC No Prior Systemic Therapy A every 3 weeks Never-/Light Former Smoker N N = 1217 Gefitinib 250 mg/day D•  Primary Endpoint: Progr-Free Survival (PFS)•  Biomarker analysisMok, NEJM 2009
  4. 4. IPASS: Objective Response Rate by EGFR Mutation Status Gefitinib 71.2% Carboplatin / paclitaxel EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p=0.0001 Overall 47.3% EGFR M- odds ratio (95% CI) = 0.04 response (0.01, 0.27), p=0.0013 rate (%) 23.5% 1.1% (n=132) (n=129) (n=91) (n=85) Odds ratio >1 implies greater chance of response on gefitinibMok, NEJM 2009
  5. 5. IPASS Study: OS Overall Population Probability of Survival 1.0 HR: 0.90 (95% CI: 0.79-1.02; P = .109) 0.8 Gefitinib (n = 609) 0.6 Carboplatin/paclitaxel (n = 608) 0.4 0.2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time Since Random Assignment (Mos) EGFR Mutation Positive EGFR Mutation Negative Probability of SurvivalProbability of Survival 1.0 HR: 1.00 (95% CI: 0.76-1.33; P = .990) 1.0 HR: 1.18 (95% CI: 0.86-1.63; P = .309) 0.8 Gefitinib (n = 132) 0.8 Gefitinib (n = 91) Carboplatin/paclitaxel (n = 129) Carboplatin/paclitaxel (n = 85) 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time Since Random Assignment (Mos) Time Since Random Assignment (Mos) Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874.
  6. 6. IPASS Study: PFS by EGFR Status •  EGFR mutation status most predictive, EGFR gene amplification also significantly predictive, but lessFukuoka M, et al. J Clin Oncol. 2011;29:2866-2874.
  7. 7. Prevalence of EGFR MutationsPhenotype of NSCLC Patient Prevalence of EGFR MutationAll 10% to15%Caucasian never-smokers ~35%Asian never-smokers ~65% Jackman DM et al. ASCO 2008 Annual Meeting. Abstract 8035.
  8. 8. MSKCC Continuum of Tobacco Exposure and EGFR Mutations •  Looking for exon 19 or 21 mutations in tumors from 265 pts with detailed smoking historyPham, JCO 2006
  9. 9. Prevalence of EGFR Mutations by Smoking Status: Lung AdenoCa at MSKCC •  Testing for exon 19 or 21 mutation in 2142 adenocarcinomas at MSKCC •  Rate: EGFR mut’ns seen in 52% of never-smokers, 15% of former smokers, and 6% of current smokersD’Angelo, J Clin Oncol 2011
  10. 10. Prospective Trials of EGFR TKIs vs. Chemo in EGFR Mutation (Exons 19, 21) Population RR PFS (mo) OS (mo)Trial N Rx TKI Chemo TKI Chemo TKI ChemoMaemondo Gefitinib vs. 230 74% 31% 10.8 5.4 30.5 23.6NEJ002 Carbo/PacMistudomi Gefitinib vs. 172 62% 32% 9.2 6.3 30.9 N.R.WJTOG3405 Cis/DoceZhao Erlotinib vs. 165 83% 36% 13.1 4.6 N.R. N.R.OPTIMAL Carbo/GemRosell Erlotinib vs. 174 58% 15% 9.4 5.2 N.R. N.R.EURTAC Plat Doublet Maemondo, NEJM 2010; Mistudomi, Lancet Oncol 2010; OPTIMAL, Lancet Oncol 2011; Rosell, ASCO 2011
  11. 11. TORCH Study: Chemo  Erlotinib vs. Erlotinib  ChemoGridelli, ASCO 2010, #7508 Standard arm R Cis/Gemcitabine Erlotinib 150 mg/d Advanced NSCLC No clinical or A x 6 cycles molecular selection N Experimental arm N = 760, Cis/Gemcitabine closed by DSMB D Erlotinib 150 mg/d x 6 cycles Order of therapy matters: get best treatment in at first opportunity
  12. 12. TORCH Study: Efficacy Analysis Efficacy Outcome Erlotinib → Chemo → HR P Chemo Erlotinib (95% CI) Value (n = 380) (n = 380) 1.40 Median OS, mos 7.7 10.9 .002 (1.13-1.73) Median PFS,* mos 2.2 5.7 Not reported Objective response,† % 18 32  With first-line treatment •  CR <1 1 •  PR 9 27 Not reported   With second-line treatment •  CR 1 <1 •  PR 9 6 *Assessment of first-line treatment only. †Intent-to-treat population.Gridelli C, et al. ASCO 2010. Abstract 7508.
  13. 13. KRAS Mutations and Resistance to EGFR Inhibitors RR OS Trial N Agent Wild Type Mutant Wild Type Mutant INTEREST 275 Gefitinib 10% 0% 7.5 mos 7.8 mos Gefitinib or Jackman 116 5% 0% 11.8 mos 13 mos erlotinib Gefitinib or Massarelli 70 10% 0% 9.4 mos 5 mos erlotinib Shepherd 206 Erlotinib 10.2% 5% 7.5 mos 3.7 mos Miller* 101 Erlotinib 32% 0% 21 mos 13 mos*Patients with BAC. Douillard. ASCO. 2008 (abstr 8001); Jackman. ASCO. 2008 (abstr 8035); Massarelli. Clin Cancer Res. 2007;13:2890; Shepherd. ASCO. 2007 (abstr 7571); Miller. J Clin Oncol. 2008;26:1472.
  14. 14. Waterfall Plot of Response on Erlotinib in Advanced BAC, with Molecular Correlates •  Most but not all of the best responders carry EGFR mutations •  Many with minor response and even some with PR have neither EGFR mutation nor EGFR gene amplification •  Several KRAS mutation patients have stable disease or even minor responses (which very likely correlate with modest clinical benefit) •  Selecting on basis of EGFR mutations or FISH positivity would filter out many beneficiaries; selecting by KRAS would also eliminate many w/SD or MRMiller, JCO 2008
  15. 15. INTEREST Trial: A Wide Range of Very Unhelpful Molecular Markers Worldwide trial, second line docetaxel vs. gefitinib, N = 1466 OS DFSDouillard, JCO 2010
  16. 16. EML4-ALK Translocations in NSCLCSoda et al., Nature 448: 561-566, 2007 EML4-ALK frequency: ~4% (64/1709) Primarily adenoCa, minimal or no smoking history Bang, ASCO 2010 #2 (Plenary), then NEJM
  17. 17. 48 yo Female Never Smoker with Stage IV NSCLC Positive for EML4-ALK Pre-Treatment After 2 cycles PF-02341066
  18. 18. 77% of Patients with ALK-positive NSCLC Remain on Crizotinib Treatment •  Duration of treatment (median: 5.7 months) 0–3 mo 13 pts >3–6 mo 29 ptsIndividual patients >6–9 mo 24 pts >9–12 mo 9 pts >12–18 mo 4 pts >18 mo 3 pts •  Reasons for discontinuation –  Related AEs 1 –  Non-related AEs 1 –  Unrelated death 2 –  Other 2 –  Progression 13 0 3 6 9 12 15 18 21 Treatment duration (months) N=82; red bars represent discontinued patients
  19. 19. The Majority of ALK-Positive Patients are Never-Smokers Never smoker Light smoker Smoker ALK-PositiveShaw et al. ASCO 2010
  20. 20. Mutation Status By Smoking History Caucasians 18% 2% ALK EGFR WT/WT ≤10 pack-years >10 pack-years (N=255) (N=232)Shaw et al. ASCO 2010
  21. 21. Mutation Status By Smoking History Asians8% EGFR KRAS ALK WT/WT/WT 1.2% Never-smokers Ever-smokers (N=127) (N=82)Wong et al., Cancer 2009;115:1723-33.
  22. 22. Mutation Status in Asian Never-Smokers N=52Sun et al. JCO 2010;28:4616-20
  23. 23. FLEX: Study Design Adv NSCLC R Cis d1/Vin d1,8 EGFR IHC 1 + No prior Rx A No brain mets N Cis d1/Vin d1,8 (N = 1,125) D + weekly cetuximab •  Stratification •  Primary end point: OS •  – ECOG PS: 0/1 vs. 2 •  – Stage: IIIB (wet) vs. IV •  Secondary end points: PFS, RR, QOL, safetyPirker et al, Lancet 2010
  24. 24. ITT (n=1125) Median OS 1-year survival ▬  CT + cetuximab 11.3 mo 47% (n=557) ▬  CT 10.1 mo 42% Overall survival (%) (n=568) HR=0.871 [95% CI 0.762–0.996]; p=0.044 MonthsPirker, Lancet 2010
  25. 25. EGFR Expression in FLEX StudyO‘Byrne,Lancet Oncol 2011 Low EGFR Expression High EGFR Expression Parameter CT CT + Cetuximab CT CT + Cetuximab Median OS 10.3 9.8 9.6 12.0 (months)
  26. 26. FLEX High EGFR IHC, by HistologyAdenocarcinoma (N = 135) Squamous (N = 144)
  27. 27. NCCN Guidelines (October, 2011)•  Patients with non-squamous advanced NSCLC should be tested for EGFR mutation and ALK rearrangement•  Treatment in this setting should be guided by results of this testing Caveat: NCCN expertise: cancer treatment, independent of cost NCCN non-expertise: health care economics/value of Rx
  28. 28. ASCO Guidelines (Sept, 2011) Re: EGFR inhibitors•  Most patients should not receive EGFR TKI as part of 1st line treatment•  For those with EGFR mut’n, EGFR TKI alone may be recommended•  For patients receiving cis/vinorelbine, cetuximab may be added
  29. 29. ASCO Guidelines (Sept, 2011) Re: Molecular Testing•  ASCO recognizes that most patients with NSCLC may not have any special molecular tests…these molecular tests remain investigational, and selecting treatment based on molecular tests has not been shown to improve a patients’s overall length of live.•  Therefore, ASCO does not recommend using any routine molecular analysis of tumor tissue to guide treatment decisions at this time. For patients with an EGFR mutation, erlotinib or gefitinib may be the best first-line therapy, but may also work well as a second or third-line treatment.•  Larger tissue samples recommended when performing Bx, to facilitate future research and maximize eligibility in trials.
  30. 30. My Conclusions: Clinical Management Decisions•  EGFR TKIs –  EGFR TKI shouldn’t be 1st line Rx in unselected pts. –  If you know EGFR mut’n +, I’d give earlier >> later –  Importantly, EGFR wild type doesn’t mean no benefit from EGFR TKI in maintenance or later•  ALK positivity is KEY to access to crizotinib  major benefit•  EGFR IHC possibly very helpful in selecting for cetuximab
  31. 31. Setting the Balance: Where Do You Fit on the Spectrum?Test enriched Test everyone to population miss NOBODY$5K/pos test Never-smoker, adeno Test 12%, find 40% Adeno (any smoking Hx) Test 45%, find 90% Adeno (any) + non-squam light smokers, Test 67%, find 95% All non-squamous adv NSCLC Test 75%, find 97% All advanced NSCLC Test 100%, find 100% $60K/pos test (All numbers approximate)
  32. 32. My Conclusions: Who To Test?•  Selective vs. everything for everyone? –  I favor a selective approach based on histology & smoking status, not (yet) testing for all patients •  Remember fallibility of histology assignment –  EGFR mut’n pts can still get comparable benefit as maintenance or 2nd line –  Stronger argument for ALK testing (pos = access) –  This is a clinical judgment, with ASCO and NCCN endorsing different conclusions –  The only wrong answer is a dogmatic one

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