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?....
Minuti G et al. Exp Opin Biol Ther 2013; 13(10): 1401-1412
THE “SO LIMITED OTHERS” CONCEPT
Targetable oncogenes in lung ADC
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
El-Deeb et al., Med Res Rev. 2010
FN-III-like repeats
TK domain
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
Structure of ROS
ROS1 Rearrangements in NSCLC
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
Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012
TPM3-ROS1
SDC4-ROS1
CD74-ROS1
EZR-ROS1
LRIG3-ROS1
ROS1
SLC34A2-ROS1
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 advanced/metastatic disease, n (%)
None 6 (14)
1 regimen 18 (43)
>1 regimen 18 (43) aIncludes one patient with adenocarcinoma-favored, poorly differentiated NSCLC
bPatient 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)
Study 1001: Best Tumor Responses in Evaluable Patients with Advanced
ROS1-positive NSCLCa
+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 aExcludes patients with early death (n=2)
*This patient was ALK+ Data as of April 24, 2013
Bes
t ch
ange
fro
m b
asel
ine
(%)
PD
Best overall response
SD
PR
CR
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)
100
80
60
40
20
0
–20
–40
–60
–80
–100
*
Ou S-HI, et al. J Thorac Oncol 2013;8(Suppl 2):S295 (Presentation MO07.03)
Study 1001: PFS in Patients with
ROS1-positive NSCLC (N=42)
Median PFS not reached
26 patients (62%) still in follow-up for progression
Event-free probability: 76% (95%CI: 55–88) at 6 months
100
80
60
40
20
0
0 5 10 15 20 25
PF
S P
rob
ab
ility
Time (months) Censored 95% Hall-Wellner Band
Number
at risk 42 22 12 8 2 1
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
Buttitta, Int J Cancer 2006, Shigematsu, CCR 2005, Arcila CCR 2012, Mazieres JCO 2013
• 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, never-
smokers 52.3%
Mazieres JCO 2013
Therapeutic Perspectives
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
68.2 m
22.9 m
KRAS mutation: PROGNOSTIC, PREDICTIVE OR DRUGGABLE
677 patients with advanced NSCLC and KRAS
mutation seen at the MSKCC between 2005 and 2011
Yu A J Clin Oncol 2013 Abstr 8025
• 2nd most common mutation
in human cancer
• 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
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
Response to Dabrafenib in a V600E mutated
NSCLC patient
Rudin et al. JTO 2013
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)
40 (19.1–63.9)
Disease control rate (CR + PR + SD), % (95% CI)
60 (36.1–80.9)
Planchard et al. ASCO 2013
RET: a new kid on the rock
Incidence of RET fusions
95% CI
[3–27%]
n=5/34
Lipson et al1
Nature 2012 Wang et al2
JCO 2012
Never-Smokers
Pan-Negative
Lung AdenoCAs
Pan-Negative
NSCLCs
Unselected
NSCLCs Inci
denc
e (%
)
Drilon et al Cancer Discovery 2013
KIF5B, CCDC6
1% of lung cancer
Vandetanib, sorafenib, sunitinib, cabozantinib have
RET activity
Met alterations in cancer
• MET gene copy alterations
(amplification or polisomy)
• MET gene mutations
• MET RNA over expression • Met protein overexpression
• Met porttranslational modifications
(e.g. phosphorylation)
RNA DNA Protein
1 2 3 4 5
6 7 8 9 10 11 12
18 17 16 15 14 13
19 20 21 22 X
C-MET receptor tyrosine kinase
• Amplified, mutated, and overexpressed in many tumors
• Associated with worse prognosis in NSCLC
• Met activation, implicated in resistance to EGFR inhibition
• MET inhibitors in NSCLC: ARQ 197 and MetMAb
Erlotinib/placebo v erlotinib/ARQ 197
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 2nd-3rd line
Tissue required
End-point PFS PFS-all pts
PFS in “Met High” pts
MARQUEE TRIAL
MET LUNG TRIAL
NEGATIVE
Crizotinib is a first-in-class, potent and selective ATP
competitive inhibitor of c-Met
Camidge et al. J Clin Oncol 2014 Abstr 8001
Kinase IC50 (nM) mean* Selectivity ratio
Met 8 –
ALK 40–60 5–8X
ROS 55 7X
RON 80 10X
Axl 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
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
Hammerman et al. Cancer Discovery 2011
• Discoidin death receptor 2
(DDR2)
• Mutation in 4% SCC and 1%
NSCC
• Dasatinib has shown
preclinical and clinical
activity
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
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?
BGJ398 AZD4547
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”
Drilon et al. J Clin Oncol 2014 Abstr 8029
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
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