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Advances in treatment of metastaic NSCLC
Aprile 2011 New targets in NSCLC Piano Generale di Emergenza Presidio Ospedaliero di Livorno Viale Alfieri 36 Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy D.Lgs del 9 aprile 2008 n. 81 – Titolo I – Sezione VI Gestione delle emergenze Istituto Toscano Tumori –Livorno, Italy Molecular events in lung cancer Adenocarcinoma Squamous-cell carcinoma EGFR resistance mutations 0.8% HER2 0.9% EGFR 9.5% Unknown 53.8% KRAS 27% ALK 3.7% Barlesi F, ASCO 2013 BRAF 1.7% PI3K 2.6% Paik PK et al, ASCO 2012 Istituto Toscano Tumori – Livorno, Italy ROS1 Translocations in NSCLC Patients with ROS1 rearrangements share many features in common with ALKpositive 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 SDC4 exon 2 SDC4 exon 2 ROS1 exon 32 ROS1 exon 34 Istituto Toscano Tumori – Livorno, Italy ROS1 fusion partners in NSCLC Stumpfova and Janne PA, CCR 2013 Istituto Toscano Tumori – Livorno, Italy Crizotinib: selective inhibitor of ALK, MET and ROS Upstate 102 kinase panel Kinase Met(h) Tie2(h) TrkA(h) ALK(h) TrkB(h) Abl(T315I)(h) Yes(h) Lck(h) Rse(h) [SKY] Axl(h) Fes(h) Lyn(h) Arg(m) Ros(h) CDK2/cyclinE(h) Fms(h) EphB4(h) Bmx(h) EphB2(h) Fgr(h) Fyn(h) IR(h) CDK7/cyclinH/MAT1(h) cSRC(h) IGF-1R(h) Aurora-A(h) Syk(h) FGFR3(h) PKCµ(h) BTK(h) CDK1/cyclinB(h) p70S6K(h) PRK2(h) PAR-1Bα(h) PKBß(h) Ret(h) GSK3ß(h) Flt3(h) MAPK1(h) ZAP-70(h) Abl(h) c-RAF(h) PKD2(h) ROCK-II(h) Rsk3(h) GSK3α(h) CDK5/p35(h) PDGFRα(h) Rsk1(h) SGK(h) CHK1(h) ErbB4(h) Rsk2(h) JNK1α1(h) PKBα(h) Blk(m) CDK3/cyclinE(h) PKCι(h) PKCθ(h) CDK2/cyclinA(h) PAK2(h) PKCßI(h) Pim-1(h) PKCη(h) SAPK4(h) CaMKII(r) MKK7ß(h) CaMKIV(h) CHK2(h) CK2(h) JNK2α2(h) MKK6(h) CK1δ(h) PKCα(h) MAPK2(h) MEK1(h) PKCδ(h) PKCε(h) Plk3(h) PKCßII(h) MSK1(h) PDGFRß(h) PKCζ(h) SAPK3(h) MAPKAP-K2(h) PKA(h) AMPK(r) CDK6/cyclinD3(h) CSK(h) SAPK2a(h) JNK3(h) PKBγ(h) IKKα(h) NEK2(h) % Inhibition 94 103 102 100 100 98 96 95 94 93 93 93 91 90 87 84 80 79 77 73 68 64 58 58 56 54 52 50 50 35 25 24 22 21 21 21 18 17 17 17 16 16 15 14 14 11 10 10 7 6 5 5 5 4 4 3 3 3 3 2 2 2 1 1 1 0 0 -1 -1 -1 -1 -1 -2 -2 -3 -3 -3 -3 -3 -5 -6 -6 -6 -6 -7 -7 -9 -9 -9 -9 -10 -10 -11 -11 Cellular selectivity on 10 of 13 relevant hits Kinase 13 ‘hits’ <100X selective for Met *Measured using ELISA capture method IC50 (nM) Selectivity mean* ratio Met 8 – ALK 40–60 5–8X ROS 55 7X RON 80 10X 294 34X 322 37X Tie2 448 52X Abl 1,159 166X IRK 2,887 334X Lck 2,741 283X Sky >10,000 >1000X VEGFR2 >10,000 >1000X PDGFRβ >10,000 >1000X Axl High probability of ALK, MET and ROS inhibition at clinically relevant doses Bang Y, et al. ASCO 2010 Istituto Toscano Tumori – Livorno, Italy Activity of crizotinib in ROS1+ NSCLC ORR 72%; DCR 90% Shaw AT, et al. NEJM 2014 Istituto Toscano Tumori – Livorno, Italy Median DOR of Crizotinib in ROS1+ NSCLC Median DOR 17.6 mos (95%CI,14.5 – NR) Shaw AT, et al. NEJM 2014 Istituto Toscano Tumori – Livorno, Italy Crizotinib in ROS1+ NSCLC: PFS Median PFS: 19.2 months Shaw A et al, NEJM 2014 Istituto Toscano Tumori – Livorno, Italy Acquired resistance to crizotinib in ROS1 NSCLC Awad MM, et al. NEJM 2013 Istituto Toscano Tumori – Livorno, Italy Second generation ROS1 inhibitors Istituto Toscano Tumori – Livorno, Italy Crizotinib in MET amplified or ROS1 translocated NSCLC: The METROS trial Istituto Toscano Tumori – Livorno, Italy Clinical characteristics of MET amplified NSCLC Characteristic N % Total amplified (ratio ≥2.2) 16 100 Squamous 5 31.2 Non-squamous 11 68.8 Never smokers 0 0 Current/former 15 93.7 Smoking unknown 1 6.3 Cappuzzo F et al., J Clin Oncol 2009 Istituto Toscano Tumori – Livorno, Italy 1,0 1,0 ,8 ,8 ≥4 - <5 copies/cell ,6 <2 copies/cell ≥3 - <4 copies/cell ,4 ≥2 - <3 copies/cell ≥6 copies/cell ≥5 - <6 copies/cell ,2 CUMULATIVE SURVIVAL CUMULATIVE SURVIVAL Survival of Resected NSCLC According to MET Copy Number p=0.0045 ,6 MET <5 copies/cell(N=383) ,4 MET ≥5 copies/cell (N=48) ,2 0,0 Median survival: MET FISH-:47.5 months MET FISH+: 25.8 months 0,0 0 20 40 60 MONTHS 80 100 0 20 40 60 80 100 120 MONTHS Cappuzzo et al., JCO 2009 Istituto Toscano Tumori – Livorno, Italy High levels of MET amplification drive resistance to EGFR-TKIs Gefitinib Resistant MET amplification in HCC827 GR6 Ratio MET/centromere >5 Gefitinib Sensitive NO MET amplification in HCC827 Ratio MET/centromere <2 Modified from Cappuzzo F, et al. Ann Oncol 2008 Istituto Toscano Tumori – Livorno, Italy Sensitivity to anti-Met agents only in presence of high levels of MET amplification Smolen GA et al., PNAS 2006, Tanizaki J et al., JTO 2011 Garcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy Tumor Shrinkage Seen in Intermediate and High MET Cohorts Best percent change from baseline in target tumor lesionsa by patient % Change From Baseline Low MET n=2 Intermediate MET n=6 High MET n=6 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 0 0 0 –20 –20 –20 –40 –40 –60 –60 –80 –80 –80 –100 –100 –100 c –40 c Disease progression Stable disease Partial responseb Complete responseb Threshold for partial response –60 aConfirmed objective responses. investigator assessment. cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment. bBased on Garcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy 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 12-20 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) Istituto Toscano Tumori – Livorno, Italy RET translocation and sensitivity to anti-RET drugs Lipson et al. Nature Med. 2012 Istituto Toscano Tumori – Livorno, Italy RET FISH+ve NSCLC succesfully treated with vandetanib • 58 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 Gautschi O, J Thor Oncol 2013 Istituto Toscano Tumori – Livorno, Italy Activity of cabozantinib in RET + NSCLC Drilon et al, Cancer Discov 2013 Istituto Toscano Tumori – Livorno, Italy HER2 dysregulation in lung cancer Overexpression <10% Amplification <10% Mutation <3% Istituto Toscano Tumori – Livorno, Italy HER2 amplification is not prognostic in resected NSCLC Cappuzzo et al., JTO 2012 Istituto Toscano Tumori – Livorno, Italy High levels of HER2 amplification are responsible for acquired resistance to EGFRTKIs in absence of T790M Takezawa et al., Cancer Discovery 2012 Istituto Toscano Tumori – Livorno, Italy High levels of HER2 amplification are responsible for acquired resistance to cetuximab in colorectal cancer Yonesaka et al Science Transl Med 2011 Istituto Toscano Tumori – Livorno, Italy HER2 mutation exon19 exon20 exon21 YVMA776-779ins GSP781-783ins E A Y V M A G V G S P Y V S R L 770 I A K 785 831 G776V,Cins Istituto Toscano Tumori – Livorno, Italy HER2 Mutations in NSCLC Reference N Race % Never Smoker (%) Female (%) Sasaki 95 Japan 1.0 2.7 3.3 Marchetti 403 Caucasian 2.2 3.1 4.1 Shigematsu 671 All 1.6 3.2 3.6 Stephens 120 Caucasian 4.0 - - Arcila 560 All 5.0* 5.0 2.0 * In EGFR and KRAS wild-type population Istituto Toscano Tumori – Livorno, Italy Trastuzumab efficacy in pretreatred NSCLC patients harboring HER2 mutation Patient # Therapy Best Response 1 Vinorelbine-trastuzumab Partial response 2 Carboplatin-paclitaxel-trastuzumab Stable disease 3 Docetaxel-masatinib Progression 4 Vinorelbine-trastuzumab Partial response 5 Carboplatin-paclitaxel-trastuzumab Partial response 6 Vinorelbine-trastuzumab Partial response 7 Vinorelbine-trastuzumab Stable disease 8 Lapatinib Progression 9 Vinorelbine-trastuzumab Partial response 10 Lapatinib Progression 11 Vinorelbine-trastuzumab Progression 12 Docetaxel-trastuzumab Partial response 13 Vinorelbine-trastuzumab Partial response 14 Vinorelbine-trastuzumab Partial response 15 Vinorelbine-trastuzumab Stable disease 16 Trastuzumab RR: 56.2% Partial response Modified from Mazieres et al. ESMO 2012 Istituto Toscano Tumori – Livorno, Italy 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 Dabrafenib inhibits BRAF V600E Kinase Mode of Action • Reversible, small molecule BRAF inhibitor • ATP competitive RTKs Dabrafenib P P SOS P P Grb2 SHC P P RAS BRAF V600 PI3K/AKT/mTOR pathway BRAF Molecular Activity: • BRAF V600E: IC50 0.65 nM • BRAF WT: IC50 3.2 nM CRAF MEK ERK1/2 Selectivity: • IC50 of 10-100 nM against 8 of 282 human kinases p90RSK MSK1 Proliferation, Growth, Survival Data not registered for darafenib Davies H, et al. Nature. 2002;417:949-954; Platz A, et al. Mol Oncol. 2008;1:395405; 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]. Istituto Toscano Tumori – Livorno, Italy Maximum Percent Reduction at Time of Best Disease Assessment Dabrafenib in V600E BRAF mutated NSCLC: results of a phase II study 50 40 *** 30 20 10 0 *** *** −10 * −20 ** ** ** −30 −40 ** −50 −60 Best Confirmed Response −70 Partial response −80 Stable disease −90 Progressive disease Smoking History * Smoker, ≤ 40 pack years ** ***Smoker, > 40 pack years Nonsmoker * ** * ** * ** ** * −100 Planchard et al. ASCO 2013 Istituto Toscano Tumori – Livorno, Italy 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 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