Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile LivornoItaly New targets in NSCLC Istituto Toscano Tumori Livorno Italy Molecular events in lung cancer Adenocarcinoma Unknown ID: 1043323
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1. Istituto Toscano Tumori –Livorno, ItalyFederico CappuzzoIstituto Toscano TumoriOspedale CivileLivorno-ItalyNew targets in NSCLC
2. Istituto Toscano Tumori – Livorno, ItalyMolecular events in lung cancerAdenocarcinomaUnknown53.8%KRAS27%EGFR9.5%EGFR resistance mutations0.8%HER20.9%BRAF1.7%PI3K2.6%ALK3.7%Squamous-cell carcinomaBarlesi F, ASCO 2013Paik PK et al, ASCO 2012
3. ROS1 Translocations in NSCLCSDC4 exon 2ROS1 exon 32SDC4 exon 2ROS1 exon 34Istituto Toscano Tumori – Livorno, ItalyPatients with ROS1 rearrangements share many features in common with ALK-positive patients (adenocarcinoma histology, younger age at diagnosis, never or light smokers)Mutually exclusive with EGFR, HER2, KRAS, BRAF mutations and with ALK or translocationPrognostic role is not defined
4. ROS1 fusion partners in NSCLCIstituto Toscano Tumori – Livorno, ItalyStumpfova and Janne PA, CCR 2013
5. Istituto Toscano Tumori – Livorno, ItalyCrizotinib: selective inhibitor of ALK, MET and ROSKinaseIC50 (nM) mean*Selectivity ratioMet8–ALK40–605–8XROS557XRON8010XAxl29434X32237XTie244852XAbl1,159166XIRK2,887334XLck2,741283XSky>10,000>1000XVEGFR2>10,000>1000XPDGFRβ>10,000>1000XCellular selectivity on 10 of 13 relevant hitsUpstate 102 kinase panel13 ‘hits’ <100X selective for MetHigh probability of ALK, MET and ROS inhibition at clinically relevant doses*Measured using ELISA capture methodBang Y, et al. ASCO 2010
6. Activity of crizotinib in ROS1+ NSCLCShaw AT, et al. NEJM 2014Istituto Toscano Tumori – Livorno, ItalyORR 72%; DCR 90%
7. Median DOR of Crizotinib in ROS1+ NSCLCShaw AT, et al. NEJM 2014Istituto Toscano Tumori – Livorno, ItalyMedian DOR 17.6 mos (95%CI,14.5 – NR)
8. Istituto Toscano Tumori – Livorno, ItalyShaw A et al, NEJM 2014Crizotinib in ROS1+ NSCLC: PFSMedian PFS: 19.2 months
9. Acquired resistance to crizotinib in ROS1 NSCLC Istituto Toscano Tumori – Livorno, ItalyAwad MM, et al. NEJM 2013
10. Istituto Toscano Tumori – Livorno, ItalySecond generation ROS1 inhibitors
11. Crizotinib in MET amplified or ROS1 translocated NSCLC: The METROS trialIstituto Toscano Tumori – Livorno, Italy
12. Clinical characteristics of MET amplified NSCLCCharacteristicN%Total amplified (ratio ≥2.2)16100Squamous531.2Non-squamous1168.8Never smokers00Current/former1593.7Smoking unknown16.3Cappuzzo F et al., J Clin Oncol 2009Istituto Toscano Tumori – Livorno, Italy
13. Survival of Resected NSCLC According to MET Copy Number<2 copies/cell≥2 - <3 copies/cell≥3 - <4 copies/cell≥4 - <5 copies/cell≥5 - <6 copies/cell≥6 copies/cell1008060402001,0,8,6,4,20,0MONTHSCUMULATIVE SURVIVALMET <5 copies/cell(N=383)MET ≥5 copies/cell (N=48)1201008060402001,0,8,6,4,20,0MONTHSCUMULATIVE SURVIVALp=0.0045Median survival:MET FISH-:47.5 monthsMET FISH+: 25.8 months Cappuzzo et al., JCO 2009Istituto Toscano Tumori – Livorno, Italy
14. High levels of MET amplification drive resistance to EGFR-TKIsMET amplification in HCC827 GR6Ratio MET/centromere >5NO MET amplification in HCC827Ratio MET/centromere <2Gefitinib ResistantGefitinib SensitiveModified from Cappuzzo F, et al. Ann Oncol 2008Istituto Toscano Tumori – Livorno, Italy
15. Smolen GA et al., PNAS 2006, Tanizaki J et al., JTO 2011Sensitivity to anti-Met agents only in presence of high levels of MET amplificationGarcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy
16. Tumor Shrinkage Seen in Intermediate and High MET CohortsaConfirmed objective responses.bBased on investigator assessment.cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment.Best percent change from baseline in target tumor lesionsa by patientLow METn=2Intermediate METn=6High METn=6100806040200–20–40–60–80–100100806040200–20–40–60–80–100Disease progressionStable diseasePartial responsebComplete responseb% Change From Baseline100806040200–20–40–60–80–100Threshold for partial responseccGarcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy
17. Istituto Toscano Tumori – Livorno, ItalyRET rearrangements in lung adenocarcinoma11,294,741-bp pericentric inversion on chromosome 10 generating a new gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RETMutually exclusive with EGFR, HER2, KRAS, BRAF mutations and with ALK or ROS1 translocationExclusively identified in moderately to poorly differentiated adenocarcinomas with solid predominant subtype, younger age never or light smokers and with a particular pattern of metastatic spread (lymph nodes)
18. RET translocation and sensitivity to anti-RET drugsLipson et al. Nature Med. 2012Istituto Toscano Tumori – Livorno, Italy
19. Istituto Toscano Tumori – Livorno, ItalyRET FISH+ve NSCLC succesfully treated with vandetanib Gautschi O, J Thor Oncol 201358 y-o man, past smoker (5 pck/yr)ADC, stage IV for supraclavicular, mediastinal, retroperitoneal and inguinal nodes abdominal, Pre-treated with standard carboplatin-pemetrexed for 2 cycles with evidence of progression Second-line* Vandetanib 300 mg daily* Patient unsuitable for standard chemotherapy due to recent myocardial infarction
20. Drilon et al, Cancer Discov 2013Istituto Toscano Tumori – Livorno, ItalyActivity of cabozantinib in RET + NSCLC
21. HER2 dysregulation in lung cancerOverexpressionAmplificationMutation<10%<10%<3%Istituto Toscano Tumori – Livorno, Italy
22. HER2 amplification is not prognostic in resected NSCLCCappuzzo et al., JTO 2012Istituto Toscano Tumori – Livorno, Italy
23. Takezawa et al., Cancer Discovery 2012Istituto Toscano Tumori – Livorno, ItalyHigh levels of HER2 amplification are responsible for acquired resistance to EGFR-TKIs in absence of T790M
24. Yonesaka et al Science Transl Med 2011Istituto Toscano Tumori – Livorno, ItalyHigh levels of HER2 amplification are responsible for acquired resistance to cetuximab in colorectal cancer
25. HER2 mutation770831785G776V,CinsGSP781-783insE A Y V M A G V G S P Y V S R L I A KYVMA776-779insexon19 exon20 exon21 Istituto Toscano Tumori – Livorno, Italy
26. HER2 Mutations in NSCLCReferenceNRace%Never Smoker (%)Female (%)Sasaki95Japan1.02.73.3Marchetti403Caucasian2.23.14.1Shigematsu671All1.63.23.6Stephens120Caucasian4.0--Arcila560All5.0*5.02.0* In EGFR and KRAS wild-type populationIstituto Toscano Tumori – Livorno, Italy
27. Trastuzumab efficacy in pretreatred NSCLC patients harboring HER2 mutationPatient #TherapyBest Response1Vinorelbine-trastuzumabPartial response2Carboplatin-paclitaxel-trastuzumabStable disease3Docetaxel-masatinibProgression4Vinorelbine-trastuzumabPartial response5Carboplatin-paclitaxel-trastuzumabPartial response6Vinorelbine-trastuzumabPartial response7Vinorelbine-trastuzumabStable disease8LapatinibProgression9Vinorelbine-trastuzumabPartial response10LapatinibProgression11Vinorelbine-trastuzumabProgression12Docetaxel-trastuzumabPartial response13Vinorelbine-trastuzumabPartial response14Vinorelbine-trastuzumabPartial response15Vinorelbine-trastuzumabStable disease16TrastuzumabPartial responseModified from Mazieres et al. ESMO 2012RR: 56.2%Istituto Toscano Tumori – Livorno, Italy
28. BRAF mutations in NSCLCDetectable in up to 5% of lung adenocarcinomas using high sensitive methodsV600E is the most frequent mutation (up to 60% of all BRAF mutations)V600E more frequent in female and in micropapillary featuresNon-V600E mutations associate with smoking exposure with no prognostic effectMarchetti et al, JCO 2011Istituto Toscano Tumori – Livorno, Italy
29. Mode of ActionReversible, small molecule BRAF inhibitor ATP competitiveMolecular Activity:BRAF V600E: IC50 0.65 nM BRAF WT: IC50 3.2 nM Selectivity:IC50 of 10-100 nM against 8 of 282 human kinasesDavies H, et al. Nature. 2002;417:949-954; Platz A, et al. Mol Oncol. 2008;1:395-405; Karasarides M, et al. Oncogene. 2004;23:6292-6298; Curtin JA, et al. N Engl J Med. 2005;353:2135-2147; Flaherty K, et al. J Clin Oncol. 2009;27 [abstract 9000]; Kefford R, et al. J Clin Oncol. 2010;28 [abstract 8503].PI3K/AKT/mTORpathwayRTKsSOSGrb2SHCPPPPProliferation, Growth, SurvivalMEKp90RSKMSK1PPBRAFCRAFBRAFV600ERK1/2RASDabrafenibDabrafenib inhibits BRAF V600E Kinase Istituto Toscano Tumori – Livorno, ItalyData not registered for darafenib
30. −40−50−60−90−1005040302010−10−20−30−70−800******************************Stable disease Partial response Progressive disease Best Confirmed Response**NonsmokerSmoker, ≤ 40 pack yearsSmoker, > 40 pack years****Smoking HistoryMaximum Percent Reduction at Time of Best Disease AssessmentDabrafenib in V600E BRAF mutated NSCLC: results of a phase II studyPlanchard et al. ASCO 2013Istituto Toscano Tumori – Livorno, Italy
31. Dabrafenib in BRAF mutated NSCLC: 2014 updateBRAF V600E mutations 1.5% of NSCLC, mutually exclusive to other driver alterationsPhase II dabrafenib in NSCLC p harboring V600E mut78 previously treated p; median age 66 yrs, 50% female, 15% ECOG 2, 37% never-smoker32% PR / 24% SD > 12 weeks / 29% PD / 14% NEDisease control rate: 51% independent review vs 56% investigator Median duration of response 11.8 moPFS 5.5 moSafety profile manageablePlanchard et alesmo 2014Istituto Toscano Tumori – Livorno, Italy
32. ConclusionsCrizotinib is an emerging effective treatment in ROS1+ or MET amplified NSCLCMET amplification could be detected in NSCLC generally not considered for biomarker assessmentRET translocation is a rare event but already druggable with available agents Strategies against HER2 mutations should be extensively investigatedDrugs available for metastatic melanoma could represent a new option for BRAF mutated NSCLCIstituto Toscano Tumori – Livorno, Italy