OTRAS DIANAS MOLECULARES TRATABLES Rosario García Campelo Servicio de Oncología Médica Complejo Hospitalario Universitario A Coruña, CHUAC
A propósito de un caso. Mujer 34 años Fumadora ocasional < 10 paq/año Dx de Adenocarcinoma de pulmón ctxn3m1b, estadio IV EGFR WT ALK WT PE tras CDDP+Pemetrexed PE tras Docetaxel PS 0-1 Y ahora qué?...
THE SO LIMITED OTHERS CONCEPT Targetable oncogenes in lung ADC Minuti G et al. Exp Opin Biol Ther 2013; 13(10): 1401-1412
The so low frecuency Mostly non-overlapping Never/ light smokers (exceptions: KRAS, BRAF) Growing understanding of resistance mechanisms Gerber D et al. Educational Book ASCO 2014
Rationale for targeting the ROS receptor tyrosine kinase FN-III-like repeats TK domain Structure of ROS ROS overexpression in brain, lung, gastric, breast, and liver tumors/cell lines ROS mutations in colon and kidney cancer cell lines ROS fusions identified in cancer Glioblastoma: FIG-ROS1 NSCLC: SCL34A2-, CD74-, FIG-, SDC4-,TPM3-, ERZ-,LRIG3-ROS1 Cholangiocarcinoma: FIG-ROS1 Drosophila homolog: sevenless Drosophila ligand homolog: son of sevenless Growth of cell lines with ROS fusion genes inhibited by crizotinib El-Deeb et al., Med Res Rev. 2010
ROS1 Rearrangements in NSCLC TPM3-ROS1 SDC4-ROS1 SLC34A2-ROS1 CD74-ROS1 EZR-ROS1 Present in ~1% of NSCLC cases (also found in some GBMs and cholangiocarcinomas) Enriched in younger never or light smokers with adenocarcinoma histology No overlap with other oncogenic drivers LRIG3-ROS1 ROS1 Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012
Study 1001: Clinical Characteristics of Patients with ROS1-positive NSCLC Characteristic Crizotinib (N=42) Age, years Median (range) 52 (31 77) Sex, n Male/female 19/23 Smoking history, n (%) Never 33 (79) Former 9 (21) Race, n (%) Caucasian 21 (50) Asian 18 (43) Other 3 (7) Histology, n(%) Adenocarcinoma 41 (98) a ECOG PS, n (%) 0 21 (50) 1 20 (48) 2 1 (2) b Prior regimens for None 6 (14) advanced/metastatic 1 regimen 18 (43) disease, n (%) >1 regimen 18 (43) a Includes one patient with adenocarcinoma-favored, poorly differentiated NSCLC b Patient had an ECOG PS of 1 at screening and 2 on cycle 1 day 1 Ou S-HI, et al. J Thorac Oncol 2013;8(Suppl 2):S295 (Presentation MO07.03)
Best change from baseline (%) Study 1001: Best Tumor Responses in Evaluable Patients with Advanced ROS1-positive NSCLC a 100 80 60 40 20 0 20 40 60 80 36 evaluable patients; 2 CRs and 20 PRs Overall response rate: 61% (95% CI: 44 77) Disease control rate: 81% (8 weeks), 67% (16 weeks) Best overall response * PD SD PR CR 100 +Treatment ongoing; duration of response/sd is from first documentation of tumor response/first dose to the time of PD or death. For ongoing patients, duration of response/sd is from first documentation of tumor response/first dose to last available on-treatment scan Duration is in weeks a Excludes patients with early death (n=2) *This patient was ALK+ Data as of April 24, 2013 Ou S-HI, et al. J Thorac Oncol 2013;8(Suppl 2):S295 (Presentation MO07.03)
PFS Probability Study 1001: PFS in Patients with ROS1-positive NSCLC (N=42) 100 80 Median PFS not reached 26 patients (62%) still in follow-up for progression Event-free probability: 76% (95%CI: 55 88) at 6 months 60 40 20 0 Number at risk 0 5 10 15 20 25 42 22 12 8 2 1 Censored 95% Hall-Wellner Time Band (months) Ou S-HI, et al. J Thorac Oncol 2013;8(Suppl 2):S295 (Presentation MO07.03)
Epidemiology HER2 mutation 403 stage I-III adenocarcinomas in caucasian patients: mutation in 9 (2.2%). 78% in frame duplications insertions in exon 20 Frequency higher in females and in never smokers 394 adenocarcinoma, HER2 mutations preferentially in oriental ethnicity (3.9% vs 0.7%) All HER2 mutations were in-frame insertions in exon 20, significantly more frequent in never smokers and adenocarcinoma 6% of EGFR/KRAS/ALK-negative specimens More frequent among never-smokers but no associations with sex, race, or stage HER2 mutation was not associated with concurrent HER2 amplification 3.800 p: HER2 mut in 1.7%, all insertions in exon 20, 69% women, neversmokers 52.3% Buttitta, Int J Cancer 2006, Shigematsu, CCR 2005, Arcila CCR 2012, Mazieres JCO 2013
Therapeutic Perspectives 68.2 m 22.9 m 22 patients receiving anti HER2 therapy ORR: 50% DCR 82% Median PFS: 5.1m DCR Trastuzumab based therapies (n= 15): 96% DCR Afatinib based therapy (n=4): 100% No responses to lapatinib or to masatinib Mazieres JCO 2013
KRAS mutation: PROGNOSTIC, PREDICTIVE OR DRUGGABLE 2nd most common mutation in human cancer 677 patients with advanced NSCLC and KRAS mutation seen at the MSKCC between 2005 and 2011 Lung Cancer: mutation at codon 12,13, 61 Smokers: G12C,G12V A greater oncogenic potential for KRas G12V compared to other mutations Non smokers: G12D Yu A J Clin Oncol 2013 Abstr 8025
MEKi (Selumetinib or Trametinib) plus docetaxel for KRAS mutant advanced NSCLC Jänne, Lancet Oncol 2013 Gandara D et al. J Clin Oncol 2013 Abstr 8028
LY2835219 (Abemaciclib): a cell cycle inhibitor CDK4 and CDK6 Goldman et al. J Clin Oncol 2014 Abstr 8026
DIRECT KRAS G12C INHIBITORS Lim SM et al. Angew Chem Int Ed 2014
SUMMARIZE OF CURRENT STRATEGIES TARGETING KRAS MUT NSCLC PATIENTS Vasan et al. Clin Cancer Res 2014
1046 NSCLC 4.9% ADC 0.3% SCC More common in current /former smokers V600 56.8% (more diverse mutation profile than in melanoma) V600 more prevalent in females: 8.6% vs 0.9% V600 showed agressive histotype and shorter PFS and OS
Activity of BRAF inhibitors in BRAF mut NSCLC patients Best response n=20 Complete response (CR), n (%) 0 Partial response (PR), n (%) 8 (40) Stable disease (SD), n (%) 4 (20) Progressive disease, n (%) 6 (30) Not evaluable, n (%) 2 (10) Response rate (confirmed CR/PR), % (95% CI) Disease control rate (CR + PR + SD), % (95% CI) 40 (19.1 63.9) 60 (36.1 80.9) Response to Dabrafenib in a V600E mutated NSCLC patient Rudin et al. JTO 2013 Planchard et al. ASCO 2013
Incidence (%) RET: a new kid on the rock KIF5B, CCDC6 Incidence of RET fusions Never-Smokers Pan-Negative Lung AdenoCAs Vandetanib, sorafenib, sunitinib, cabozantinib have RET activity Pan-Negative NSCLCs 1% of lung cancer Unselected NSCLCs 95% CI [3 27%] n=5/34 Lipson et al 1 Nature 2012 Wang et al 2 JCO 2012 Drilon et al Cancer Discovery 2013
Met alterations in cancer 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X DNA RNA Protein MET gene copy alterations (amplification or polisomy) MET gene mutations MET RNA over expression Met protein overexpression Met porttranslational modifications (e.g. phosphorylation)
C-MET receptor tyrosine kinase Amplified, mutated, and overexpressed in many tumors Associated with worse prognosis in NSCLC MARQUEE TRIAL Met activation, implicated in resistance to EGFR inhibition MET inhibitors in NSCLC: ARQ 197 and MetMAb MET LUNG TRIAL Erlotinib/placebo v erlotinib/arq 197 NEGATIVE Erlotinib/placebo v erlotinib/metmab Met inhibitor TKI, daily PO Mab, Iv q 3W Trial phase, design Randomised Phase II, Placebo Randomised Phase II, Placebo N pts 167 128 Eligibilitty > 1 prior line 2 nd -3rd line Tissue required End-point PFS PFS-all pts PFS in Met High pts
Crizotinib is a first-in-class, potent and selective ATP competitive inhibitor of c-met Kinase IC50 (nm) mean* Selectivity ratio Met 8 ALK 40 60 5 8X ROS 55 7X RON 80 10X 294 34X Axl 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 Camidge et al. J Clin Oncol 2014 Abstr 8001
Squamous cell lung cancer: The forgotten one A significant minority of NSCLC No effective targeted therapy Lack of efficacy or toxicity for Pemetrexed Bevacizumab Some KRAS and PIK3CA mutations Ongoing systematic genomics efforts The Cancer Genome Atlas
Dominant Mutations in Lung Cancer Some time ago KRAS EGFR EML4-ALK BRAF PIK3CA ERBB2 Other Lung adenocarcinoma Lung squamous cell carcinoma
Genetic alterations in SCC 2014 Perez-Moreno et al. CCR 2012
Dasatinib shrinks DDR2-mutant tumors in vivo Discoidin death receptor 2 (DDR2) Mutation in 4% SCC and 1% NSCC Dasatinib has shown preclinical and clinical activity Hammerman et al. Cancer Discovery 2011
FGFR1 amplification occurs in 20% of primary squamous-cell lung cancers Weiß et al. Science Trans Med 2010
Targeting FGFR1 in SCC FGFR-amplified NSCLC BGJ398 AZD4547 Nogora et al. J Clin Oncol 2014 Abstr 8034 Paik et al. J Clin Oncol 2014 Abstr 8035 Not a true driver? Cutoff for amplification? Tumor heterogeneity?
Clinical application of molecular subsets is not easy, however...
A propósito de un caso. PE tras CDDP+Pemetrexed PE tras Docetaxel 34 años, PS 0-1 No muestra tumoral disponible para análisis molecular Y ahora qué?... Re-biopsia adenopatía retroperitoneal: Kras negativo BRAF- FISH HER2 negativo Ros negativo MET: 3 (+) 65% (positivo) por IHQ
H&E IHQ MET
The complex history of other genomic alterations in our daily practice The Cancer Biomarker Problem Rebiopsies procedures at different moments of the disease evolution New technologies (NGS, WGS ) Are we using the right biomarker? Cost What should I do if after all this effort I find a genetically defined NSCLC patient?
EMERGING TECHNOLOGIES FOR TUMOR GENOMIC PROFILING MacConaill L E JCO 2013;31:1815-1824
NGS to identify genomic alterations in pan negative lung cancer patients 1 genomic alteration identified in 94% of patients Tumor tested was obtained from the same procedure as tumor used for non-ngs testing in 71% of cases Drilon et al. J Clin Oncol 2014 Abstr 8029
LCMC: Molecular characterization network and associated clinical trials
Some notes to conclude many targets, many drugs A pletora of new agents in the horizon that target specific molecularly defined patients, let s say PERSONALIZED THERAPY: Establish molecular profile Availability of tumor tissue Newer technologies allow testing all of these mutations at the same time Some of these genetic alterations have a low incidence, but Every single patient is unique: it s worthwhile