5Platinum-based doublet chemotherapy q3wks x 4 cycles* EURTAC Study DesignStage IIIB/IV NSCLCEGFR exon 19 deletion or exon 21 L858R mutation (DNA sequencing/Genescan and Taqman)ChemonaiveECOG PS 0–2Measurable or evaluable diseaseErlotinib 150 mg/dayPDStratificationMutation typeECOG PS (0 vs 1 vs 2)RPlatinum-based doublet chemotherapy q3wks x 4 cycles*PDSecondary endpointsObjective response rateOverall survival (OS)Location of progressionSafetyEGFR mutation analysis in serumQuality of lifePrimary endpointProgression-free survival (PFS)US FDA approval May 14, 2013Cobas® EGFR Mutation Test41 mutations in Exons 18, 19, 20 and 21ECOG = Eastern Cooperative Oncology Group; PS = performance status; PD = progressive disease*Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1; cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8; carboplatin AUC6 d1 / docetaxel 75mg/m2 d1; carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,855
6Primary endpoint: PFS in ITT population (updated analysis 26 Jan 2011) 1.00.80.60.40.2Erlotinib (n=86)Chemotherapy (n=87)HR=0.37 (0.25–0.54)Log-rank p<0.0001PFS probability5.29.7Time (months)Patients at riskErlotinib ChemoData cut-off: 26 Jan 2011US FDA approval May 14, 2013
7Study design US FDA approval July 12, 2013 Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)EGFR mutation in tumor(central lab testing; Therascreen EGFR29* RGQ PCR)Randomization 2:1Stratified by:EGFR mutation (Del19/L858R/other)Race (Asian/non-Asian)Afatinib 40 mg/day†Cisplatin + Pemetrexed75 mg/m mg/m2i.v. q21 days, up to 6 cyclesPrimary endpoint: PFS (RECIST 1.1, independent review)‡Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO§, safety, PK*EGFR29:19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I.†Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related G3 or prolonged G2 AE. ‡Tumor assessments: q6 weeks until Week 48 and q12 weeks thereafter until progression/start of new therapy.§Patient-reported outcomes: Q-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and q3 weeks until progression or new anti-cancer therapy.US FDA approval July 12, 2013Yang JC, et al.
8EGFR Gene Mutations in Adenocarcinoma Lung Cancer Therascreen ®EGFR (29) RGQ PCR Kit
9PFS: Common mutations (Del19/L858R) Independent review – patients with Del19/L858R (n=308) 1.0Afatinib n=204Cis/pem n=104PFS event, n (%)130 (64)61 (59)Median PFS (months)13.66.9Hazard ratio (95% confidence interval)0.47 (0.34–0.65) p<0.00010.80.6Progression-free survival (probability)51%0.40.221%0.0Progression-free survival (months)Number at risk Afatinib Cis/PemUS FDA approval July 12, 2013Yang JC, et al.
11RADIANT Study Results Hierarchical testing rendered all secondary endpoints non-significant.
12LUX-Lung clinical trials and eligibility TreatmentLine of treatmentMutation testLUX-Lung 2Phase IIN=129AfatinibFirst- and second-line (after chemo)Direct sequencing (central)LUX-Lung 3Phase IIIN=345Afatinib vs. Pemetrexed/ cisplatinFirst-lineEGFR29* (central)LUX-Lung 6N=364Afatinib vs. Gemcitabine/ cisplatin*EGFR mutations detected by TheraScreen EGFR29 test:Common: 19 deletions in exon 19 and L858R in exon 21Uncommon: 3 insertions in exon 20, L861Q, T790M, G719S, G719A and G719C, S768I
13EGFR mutation-positive patients in LUX-Lung trials Del19 n=408L858R n=330Uncommon n=100LUX-Lung 2Phase IIN=129n=52n=54n=23LUX-Lung 3Phase IIIN=345n=170n=138n=37LUX-Lung 6N=364n=186n=40Patients with uncommon mutations treated with afatinibUncommon n=75n=23n=26n=26
15Tumour shrinkage in patients with uncommon mutations Independent review (n=67†)*De novo T790M (n=14):T790M alone(*), T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719XExon 20 insertions (n=20)Other (n=33):L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R,S768I, L861P, P848L, R776H+L858R, L861Q+Del19, K739_1744dup6**†8 patients were not included due to insufficient data
16EGFR TKI resistance mechanisms T790M+ EGFR- TKI failures 2nd/3rd line NSCLCAn area of high unmet medical needThere are no current proven treatment options for these patients. Chemotherapy or EGFR-TKIs are used, but their benefit isn’t provenEGFR TKI resistance mechanismsAZD9291 or CO1686“Patients with EGFR-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) after a median of months. In half of these cases, a second EGFR mutation, T790M, underlies acquired resistance”Oxnard, et al. Clin Cancer Res Dec 6, 2010
17Clinical activity AZD9291 in T790M+ Fast Track status granted by FDA in October 2013Breakthrough Therapy Designation submission early February 2014Best % change from baseline in target lesions in central testing T790M+T790M+ Response Rate* = 64% (95% CI 53%-74%)For the 89 T790M+ evaluable patients there are57 PRs (35 confirmed), 28 SDs, 4 PDsPopulation: T790M+ patients with observed or imputed target lesion data (n=89)*Confirmed+ unconfirmed responseImputations and exclusionsTwo patients with a BOR of PD are imputed as +20% increase as no follow up assessments for target lesions (E , E , both died prior to first scan).No patients are excludedResponse ongoing for 34/35 T790M+ patients with confirmed PRD Discontinued treatment* ImputedT790M status is assigned by central testing of a recent tumour sampleIndependent review of scans is underway as per FDA request 41/43 confirmed so farPreliminary data, data cut off 16th January 2014
19FISH Assay for ALK Rearrangement* Telomere2p23 regionCentromerep25.2p25.2ALK 29.3p24.3p24.3t(2;5) ALK genebreakpoint regionp24.1p24.1p23.2p23.2p22.3p22.3p22.1p22.1EML4 42.3p16.3p16.3p16.1p16.13’5’p14p14p13.2p13.2p12p12~250 kb~300 kbq12.1q12.1q12.3q12.3Break-apart FISH assay for ALK-fusion genes1q14.1q14.1q14.3q14.3q21.2q21.2q22.1q22.1q23.2q22.2q22.2q23.2q24.1q24.1q24.3q24.3q31.3q31.3q32.1q32.3q33.2q32.1q32.3q33.2Non-split signalq34q34Split signalq36.1q36.3 q37.2q36.1q36.3 q37.2ALK break-apart FISH assay [Courtesy John Iafrate, Massachusetts General Hospital]*Assay is positive if rearrangements can be detected in ≥15% of cells FISH = fluorescence in situ hybridization1Shaw AT et al. J Clin Oncol 2009;27:4247–4253
20Crizotinib: First-in-human/Patient Trial Cohort 5 (n=6)300 mg BID2 DLTs: grade 3 fatiguePart 1:Dose escalationCohort 6 (n=9)250 mg BID MTD/RP2DCohort 4 (n=7)200 mg BIDCohort 3 (n=8)200 mg QD1 DLT: grade 3 ALT elevationPart 2:Molecularly enriched cohorts(ALK and c-MET)Cohort 2 (n=4)100 mg QDEnrolling patients with ALK-positive NSCLC after preliminary observation of impressive activity in a few patientsData from database April 7, 2010Data presented for 82 patients, study ongoingCohort 1 (n=3)50 mg QDALT = alanine aminotransferase
21Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC 604020–20–40–60–80–100Progressive diseaseStable diseaseConfirmed partial responseConfirmed complete responseMaximum change in tumor size (%)–30%US FDA accelerated approval Aug 26, 2011Full approval Nov 21, 2013**Partial response patients with 100% change have non-target disease present
25Study Design – LDK378 (Ceritinib) Dose-Escalation PhaseAdvanced ALK-rearranged malignanciesNCTCompletedn=59Dose escalation started at 50 mg/dayEscalate to MTD (750 mg/day)Primary objective: determination of MTDSecondary objectives: characterize safety, PK, and antitumor activityPatients received treatment until disease progression, unacceptable toxicity, or withdrawal of consentContinuous oral dosing 21-day cyclesExpansionPhaseALK-rearranged NSCLCOther ALK-activated tumorsAdditional n=71 enrolledCrizotinib naiveCrizotinib pretreatedShaw AT et al. N Engl J Med. 2014;370:
27BRAF-Mutations in NSCLC harbor BRAF V600E-mutations W. Pao, N. GirardLancet Oncology,February 2011A. Marchetti et al., J. Clin. Oncol. 29, 1, 20111,046 NSCLC samplesFrequency of BRAF-mutations 3.5%BRAF-mut. in 4.9% adeno- and 0.3% SCC57% BRAFV600E-mutations43 % non-activating BRAF mutations697 NSCLC-adeno. ca. SamplesFrequency of BRAF-mutations 3%50% BRAFV600E-mutations50% non-activating BRAF mutationsP. Paik et al., J. Clin. Oncol. 29, 2046, 2011% of NSCLCharbor BRAF V600E-mutations
28BRF113928: Initial Study Design Single arm, Phase II, open labelGreen-Dahlberg 2-stage: H(0): ORR ≤ 10% versus H(1): ORR ≥30%NSCLC (Adenocarcinoama)BRAFV600E-mutation≥ 2nd Linedabrafenib150 mg twice dailyN = 40Primary objective: Investigator-assessed ORRSecondary objectives: PFS, duration of response, OS, safety and tolerability, population PK
29Interim Analysis (ASCO 2013) US FDA granted BreakthroughTherapy Jan 13, 2014Investigator based response assessments demonstrated:7PRs (5 confirmed—duration 29 and 49 weeks for 2 pts and remaining 3 patient 6+ to 24+ weeks)1 stable disease4 progressive diseasePlanchard et. al ASCO Annual Meeting Proceedings
30Rationale for the Combination Sustained target inhibition to observe more prolonged and durable anti-tumor effectDelay and potentially prevent the development of resistancePrevent/delay hyperproliferative lesions and secondary malignancies (Cu SCC)RASBRAF V600BRAF WTmutBRAFBRAFi+MEKiMEKpERKProliferation, survivalInvasion , Metastasis
31Molecular Subsets Adenocarcinoma Lung Cancer MAP2K1NRASROS1 fusionsKIF5B-RETAKT1PIK3CABRAFHER2ALKFusionsEGFRKRASUnknown1. Mascaux C et al. Br J Cancer 2005;92:131–9; 2. Winton et al. N Engl J Med 2005;352:2589–97; 3. Eberhard et al JCO 2005;23:5900–9; 4. Pao et al. PLOS Medicine (1): e17; 5. Pao et al. Nat Med 2012;18:349–51; 6. Kris et al. ASCO 2011
32Copy number alterations Point mutations & indels Gene expression Structural variantsTranslocationsFusionsInversionCopy number alterationsAmplificationsDeletionsLOHPoint mutations & indelsMissenseNonsenseSplice siteFrameshiftGene expressionOutlier expressionIsoform usagePathways & signaturesWild type AGTGAMutant AGAGAAdapted from: Roychowdhury et al. Sci Transl Med; 20122
33Conclusion Future Directions Molecular selection of patients improves therapy outcomes for patients with advanced adenocarcinoma of the lungFuture DirectionsExtent patient selection and targeted therapies to squamous cell and earlier stages of NSCLC (i.e. RADIANT)Next generation sequencing neededMolecular characterization of resistanceDevelopment of a structure to conduct studies in uncommon molecular selected populations (BRAF, HER2, RET, etc)Clinical integration of tumor genomic and proteomic testing to better direct therapy for NSCLC (Gerber)