Presentation is loading. Please wait.

Presentation is loading. Please wait.

Istituto Toscano Tumori –Livorno, Italy Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy New targets in NSCLC.

Similar presentations


Presentation on theme: "Istituto Toscano Tumori –Livorno, Italy Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy New targets in NSCLC."— Presentation transcript:

1 Istituto Toscano Tumori –Livorno, Italy Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy New targets in NSCLC

2 Istituto Toscano Tumori – Livorno, Italy Molecular events in lung cancer Adenocarcinoma Unknown 53.8% KRAS 27% EGFR 9.5% EGFR resistance mutations 0.8% HER2 0.9% BRAF 1.7% PI3K 2.6% ALK 3.7% Squamous-cell carcinoma Barlesi F, ASCO 2013 Paik PK et al, ASCO 2012

3 ROS1 Translocations in NSCLC SDC4 exon 2ROS1 exon 32 SDC4 exon 2ROS1 exon 34 Istituto Toscano Tumori – Livorno, Italy Patients 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 translocation Prognostic role is not defined

4 ROS1 fusion partners in NSCLC Istituto Toscano Tumori – Livorno, Italy Stumpfova and Janne PA, CCR 2013

5 Istituto Toscano Tumori – Livorno, Italy Crizotinib: selective inhibitor of ALK, MET and ROS Kinase IC50 (nM) mean* Selectivity ratio Met8– ALK40–605–8X ROS557X RON8010X Axl 29434X 32237X Tie244852X Abl1,159166X IRK2,887334X Lck2,741283X Sky>10,000>1000X VEGFR2>10,000>1000X PDGFRβ>10,000>1000X Cellular selectivity on 10 of 13 relevant hits Upstate 102 kinase panel 13 ‘hits’ <100X selective for Met High probability of ALK, MET and ROS inhibition at clinically relevant doses *Measured using ELISA capture method Bang Y, et al. ASCO 2010

6 Activity of crizotinib in ROS1+ NSCLC Shaw AT, et al. NEJM 2014 Istituto Toscano Tumori – Livorno, Italy ORR 72%; DCR 90%

7 Median DOR of Crizotinib in ROS1+ NSCLC Shaw AT, et al. NEJM 2014 Istituto Toscano Tumori – Livorno, Italy Median DOR 17.6 mos (95%CI,14.5 – NR)

8 Istituto Toscano Tumori – Livorno, Italy Shaw A et al, NEJM 2014 Crizotinib in ROS1+ NSCLC: PFS Median PFS: 19.2 months

9 Acquired resistance to crizotinib in ROS1 NSCLC Istituto Toscano Tumori – Livorno, Italy Awad MM, et al. NEJM 2013

10 Istituto Toscano Tumori – Livorno, Italy Second generation ROS1 inhibitors

11 Crizotinib in MET amplified or ROS1 translocated NSCLC: The METROS trial Istituto Toscano Tumori – Livorno, Italy

12 Clinical characteristics of MET amplified NSCLC CharacteristicN% Total amplified (ratio ≥2.2)16100 Squamous531.2 Non-squamous Never smokers00 Current/former Smoking unknown16.3 Cappuzzo F et al., J Clin Oncol 2009 Istituto 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/cell ,0,8,6,4,2 0,0 MONTHS CUMULATIVE SURVIVAL MET <5 copies/cell(N=383) MET ≥5 copies/cell (N=48) ,0,8,6,4,2 0,0 MONTHS CUMULATIVE SURVIVAL p= Median survival: MET FISH-:47.5 months MET FISH+: 25.8 months Cappuzzo et al., JCO 2009 Istituto Toscano Tumori – Livorno, Italy

14 High levels of MET amplification drive resistance to EGFR-TKIs MET amplification in HCC827 GR6 Ratio MET/centromere >5 NO MET amplification in HCC827 Ratio MET/centromere <2 Gefitinib ResistantGefitinib Sensitive Modified from Cappuzzo F, et al. Ann Oncol 2008 Istituto Toscano Tumori – Livorno, Italy

15 Smolen GA et al., PNAS 2006, Tanizaki J et al., JTO 2011 Sensitivity to anti-Met agents only in presence of high levels of MET amplification Garcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy

16 Tumor Shrinkage Seen in Intermediate and High MET Cohorts a Confirmed objective responses. b Based on investigator assessment. c Two 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 lesions a by patient Low MET n=2 Intermediate MET n=6 High MET n= –20 –40 –60 –80 – –20 –40 –60 –80 –100 Disease progression Stable disease Partial response b Complete response b % Change From Baseline –20 –40 –60 –80 –100 Threshold for partial response c c Garcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy

17 RET rearrangements in lung adenocarcinoma 11,294,741-bp pericentric inversion on chromosome 10 generating a new gene fusion joining exons 1-15 of KIF5B to exons of RET Mutually exclusive with EGFR, HER2, KRAS, BRAF mutations and with ALK or ROS1 translocation Exclusively 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 drugs Lipson et al. Nature Med Istituto Toscano Tumori – Livorno, Italy

19 RET FISH+ve NSCLC succesfully treated with vandetanib Gautschi O, J Thor Oncol 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 2013 Istituto Toscano Tumori – Livorno, Italy Activity of cabozantinib in RET + NSCLC

21 HER2 dysregulation in lung cancer Overexpression Amplification Mutation <10% <3% Istituto Toscano Tumori – Livorno, Italy

22 HER2 amplification is not prognostic in resected NSCLC Cappuzzo et al., JTO 2012 Istituto Toscano Tumori – Livorno, Italy

23 Takezawa et al., Cancer Discovery 2012 Istituto Toscano Tumori – Livorno, Italy High levels of HER2 amplification are responsible for acquired resistance to EGFR- TKIs in absence of T790M

24 Yonesaka et al Science Transl Med 2011 Istituto Toscano Tumori – Livorno, Italy High levels of HER2 amplification are responsible for acquired resistance to cetuximab in colorectal cancer

25 HER2 mutation G776V,Cins GSP ins E A Y V M A G V G S P Y V S R L I A K YVMA ins exon19 exon20 exon21 Istituto Toscano Tumori – Livorno, Italy

26 HER2 Mutations in NSCLC ReferenceNRace%Never Smoker (%) Female (%) Sasaki95Japan Marchetti403Caucasian Shigematsu671All Stephens120Caucasian4.0-- Arcila560All5.0* * In EGFR and KRAS wild-type population Istituto Toscano Tumori – Livorno, Italy

27 Trastuzumab efficacy in pretreatred NSCLC patients harboring HER2 mutation Patient #TherapyBest Response 1Vinorelbine-trastuzumabPartial response 2Carboplatin-paclitaxel-trastuzumabStable disease 3Docetaxel-masatinibProgression 4Vinorelbine-trastuzumabPartial response 5Carboplatin-paclitaxel-trastuzumabPartial response 6Vinorelbine-trastuzumabPartial response 7Vinorelbine-trastuzumabStable disease 8LapatinibProgression 9Vinorelbine-trastuzumabPartial response 10LapatinibProgression 11Vinorelbine-trastuzumabProgression 12Docetaxel-trastuzumabPartial response 13Vinorelbine-trastuzumabPartial response 14Vinorelbine-trastuzumabPartial response 15Vinorelbine-trastuzumabStable disease 16TrastuzumabPartial response Modified from Mazieres et al. ESMO 2012 RR: 56.2% Istituto Toscano Tumori – Livorno, Italy

28 BRAF mutations in NSCLC Detectable in up to 5% of lung adenocarcinomas using high sensitive methods V600E is the most frequent mutation (up to 60% of all BRAF mutations) V600E more frequent in female and in micropapillary features Non-V600E mutations associate with smoking exposure with no prognostic effect Marchetti et al, JCO 2011 Istituto Toscano Tumori – Livorno, Italy

29 Mode of Action Reversible, small molecule BRAF inhibitor ATP competitive Molecular Activity: BRAF V600E: IC nM BRAF WT: IC nM Selectivity: IC 50 of nM against 8 of 282 human kinases Davies H, et al. Nature. 2002;417: ; Platz A, et al. Mol Oncol. 2008;1: ; Karasarides M, et al. Oncogene. 2004;23: ; Curtin JA, et al. N Engl J Med. 2005;353: ; Flaherty K, et al. J Clin Oncol. 2009;27 [abstract 9000]; Kefford R, et al. J Clin Oncol. 2010;28 [abstract 8503]. PI3K/AKT/mTOR pathway PI3K/AKT/mTOR pathway RTKs SOS Grb2 SHC P P P P P P P P Proliferation, Growth, Survival MEK P P P P BRAF V600 BRAF V600 ERK1/2 RAS Dabrafenib Dabrafenib inhibits BRAF V600E Kinase Istituto Toscano Tumori – Livorno, Italy Data not registered for darafenib

30 −40 −50 −60 −90 − −10 −20 −30 −70 −80 0 * * * * * ** *** ** Stable disease Partial response Progressive disease Best Confirmed Response ** Nonsmoker Smoker, ≤ 40 pack years Smoker, > 40 pack years *** * Smoking History Maximum Percent Reduction at Time of Best Disease Assessment Dabrafenib in V600E BRAF mutated NSCLC: results of a phase II study Planchard et al. ASCO 2013 Istituto Toscano Tumori – Livorno, Italy

31 Dabrafenib in BRAF mutated NSCLC: 2014 update BRAF V600E mutations 1.5% of NSCLC, mutually exclusive to other driver alterations Phase II dabrafenib in NSCLC p harboring V600E mut o 78 previously treated p; median age 66 yrs, 50% female, 15% ECOG 2, 37% never-smoker o 32% PR / 24% SD > 12 weeks / 29% PD / 14% NE o Disease control rate: 51% independent review vs 56% investigator o Median duration of response 11.8 mo o PFS 5.5 mo o Safety profile manageable Planchard et alesmo 2014 Istituto Toscano Tumori – Livorno, Italy

32 Conclusions Crizotinib is an emerging effective treatment in ROS1+ or MET amplified NSCLC MET amplification could be detected in NSCLC generally not considered for biomarker assessment RET translocation is a rare event but already druggable with available agents Strategies against HER2 mutations should be extensively investigated Drugs available for metastatic melanoma could represent a new option for BRAF mutated NSCLC Istituto Toscano Tumori – Livorno, Italy


Download ppt "Istituto Toscano Tumori –Livorno, Italy Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy New targets in NSCLC."

Similar presentations


Ads by Google