2. Targeted therapy ???
It is type of medication that blocks growth of cancer cells
by interfering with specific targeted molecules needed for
carcinogenesis and tumor growth, rather than simply
interfering with all rapidly dividing cells.
Expected to be more effective and less harmful to normal
cells
Definition of targeted therapy-NCI Dictionary of cancer terms
9. EGFR in HNSCC
EGFR is detectable by IHC in 90% of HNSCCs
40%-90% of HNSCCs -EGFR over expression.
High levels of EGFR protein expression-worse prognosis
Activating mutations in the EGFR gene (chromosome 7) -
uncommon in HNSCC cases
10. High EGFR gene copy number
-FISH 10%-60% of HNSCC
-prognostic significance-debated
EGFR pathway deregulated also in
Colo-rectal cancer, Lung, Breast and brain
13. Indications
FDA approved
-metastatic colorectal ca , KRAS wild type
-concurrent with RT for LAHNSCC
-Met/rec HNSCC
Under inv-Ca pancreas,Breast,NSCLC
Dose-loading 400mg/m2 over 2hrs
-maintainance-250mg/m2 iv weekly
15. Pregnancy category-D
Level of EGFR expression
No Rx benefit-KRAS mutation codon 12/13
Skin toxicity-surrogate marker of activity
Hypersensitivity
Cardiopulmonary arrest/sudden death
16. Cetuximab as a single agent
RESULTS
-rec/metastatic
platinum refractory
HNSCC
-103 patients
-Cetuximab
Response 17% CR-5%
Median TTP-85 day,
survival -175 days
Cetuximab was well
tolerated
rash (80%), fatigue (24%),
fevers/chills (19%), and nail
changes (15%).
Trigo, et alia,phase II trial,asco 2004
abstract
17. Cetuximab combined with cytotoxic
chemotherapy
EXTREME trial N=424
Rec/met HNSCC
Vermorkan etal
Phase III,RCT
Cis/carbo+5FU+ Cet
NEJM 2008
vs
Cis/carbo+5FU
RR 35% VS 20%
Burtress, et al
Phase III,RCT
-123 patients
-Rec/Met HNSCC
RR 9% vs 26.1%
JCO 2005
-CDDP 100 mg/m2
Q4weeks+Placebo
vs
CDDP 100 mg/m2
Q4weeks +
cetuximab.
mPFS 5.6 vs 3.3
mon
Mos 10.1 vs 7.4 mon
OS ,PFS-ns
-adverse eventslargely similar.
-grade 3 / 4 sepsis in
the cetuximab
plus PF group (4%),
versus PF alone (1%).
CDDP+CET
-90% grade3 -4
toxicity
-Hypomagnesmia
-Hematological
18. Radiotherapy with Cetuximab in LAHNSCC
Phase III, Randomized,
Multicenter
424 Patients
HNSCC ,Stage III/IV(OPx.Lx.HPx)
Measurable disease
KPS>60
randomized
N=213
High dose
radiotherapy
High dose
Radiotherapy
+
Cetuximab
Primary
Duration of locoregional control
Secondary
-Os
-PFS
-ORR
-Safety
N=211
Bonner etal
NEJM 2006
20. Results- Patients
Balanced between both treatment groups with respect
to Compliance
Type of RT chosen
Subsequent neck dissections
Subsequent salvage surgery
Subsequent chemotherapy
24. Results-safety
13 patients discontinued cetuximab
4 due to hypersensitivity post 1st dose
8 due to grade 3 rash
Cetuximab did NOT add to radiation toxicities
including
mucositis, xerostomia, dyphagia, pain, (weight
loss), decreased performance status
26. Study Limitations
Lacked “standard of care” arm
Different RT regimens
Not site specific
Results for hypopharyngeal subgroup
Quality of Life Data
Concomitant boost vs other RT
Late complications
27. 5YEAR UPDATE
RT +CET
RT
Median OS
49·0 months 29·3 months
(95% CI
(20·6–41·4)
32·8–69·5)
5-year OS
45·6%
36·4%
OS (cet with
rash >gr2)
(HR 0·49,
0·34–0·72;
p=0·002).
--------
28. phase II
,RCT, RTOG
0234
-possibly improved
efficacy on the docetaxel
-concomitant boost radiotherapy
(70 Gy total)
3-year overall survival
was 76%.
-with 2 cycles of conc CDDP and
weekly cetuximab
ECOG 3303,
phase II trial
-toxicity to be
Comparable.
-cetuximab +cisplatin /docetaxel
Conc with PORT
phase II trial
Pfister DG
Jco 2010
-resected,
advanced HNSCC
-stopped early due to 2
deaths
cetuximab +
chemoradiation with cisplatin in
LAHNSCC
high rates of grade 3
toxicity
NS-DFS,OS
29. ONGOING TRIALS
RTOG 1016
accelerated-fraction RT +CDDP
Vs accelerated RT + cetuximab
-HPV-associated oropharynx cancer.
RTOG 0920
-intermediate-risk HNSCC following
surgery
-compares postoperative radiation
+/- cetuximab (conc &maintanance)
-stratification based on EGFR
overexpression (IHC)
30. Following the land mark study by “Bonner etal”
Cetuximab was approved by FDA in LA HNSCC
concurrent with RT.
31. Humanised monoclonal
antibodies
Drug
Panitumuma -human IgG2
b (Vectibix)
mAB
-bind
extracellular
domain of the
EGFR
Trial
SPECTRUM trial
-Phase-III
-met/rec HNSCC
-CDDP+5FU+/Panitumumab
-n=657
NCIC Canada
-Phase III trial
LAHNSCC –III/IV
RT+ Conc CDDP
Vs
Acc fraction
RT+Panitumumab
Result
Local PFS-Improved
OS-NS
Benefit-HPV neg
Ongoing
32. Drug
Trial
Zalutumumab -human IgG1 mAB
(HUMax-extracellular
EGFR)
domain of EGFR
Nimotuzuma
b (BIOMAb
EGFR)
-human mab
Result
Hx-EGFr-202 trial
-Phase III,RCT
-Incurable HNSCC
-Failed on std platinum
based regime
-273 patients
-Humax EGFR Vs BSC
•PFS (2yrs)26% vs 7.3%.-SS
-4 arm study
-BEST study IND OO1
-improved overall
survival
•overall survival-NS
-intermediate
affinity to EGFR
-reduce toxicity
1.Michael j etal,ASCO 2010
2. Babu K, . ASCO annual meeting. J Clin
Oncol 28:5530
33. Study Design-Phase II Trial - BEST Study
Nimo 200mg + RT (60 – 66Gy)
Group A
RT (60 – 66Gy)
First
Line, Unresectable,
Stage III/IV SCCHN
Nimo 200mg + RT (60 – 66Gy)
+ CDDP 50mg/w
RT (60 – 66Gy)
Group B
+ CDDP 50mg/w
Patients were allocated at the discretion of the physician to RT alone or
Chemoradiotherapy and then randomized to +/- nimotuzumab
Groups were not stratified
48 months follow up (as of August 2009)
34. Study Design-BEST Study
92 patients
Enrolled (safety pop)
76 patients
1.RT 66gY/33#
Evaluable for Efficacy
Patients that received at least
one dose of nimotuzumab
Protocol compliant with second
image evaluation
2.Nimo- 200mg given
3 days before RT and
then weekly
3.CDDP 50mg/week
R
R
RT
RT + h-R3
CT + RT
CT + RT + h-R3
18 patients
18 patients
20 patients
20 patients
36. Survival Data of ITT Population
After
End of RT
CT+RT
CT+RT+h-R3
n =23 (%)
N=23 (%)
1 year
12 (52.17)
18 (78.26)
0.0633
2 years
9 (39.13)
18 (78.26)
0.0070
30 mths
5 (21.74)
16 (69.57)
0.0011
48 mths
5 (21)
11 (47)
0.0149
After
End of RT
RT
RT+h-R3
n=23 (%)
n=23 (%)
1 year
12 (52.17)
11 (47.83)
0.7681
2 years
5 (21.74)
9 (39.13)
0.1999
30 mths
5 (21.74)
9 (39.13)
0.1999
48 mths
3 (13)
8 (34.7)
0.4278
p-Value
p-Value
37. Panitumumab,Zalutumumab –improve PFS,No OS
Nimotuzumab-?Overall survival improvement
-approved in HNSCC in some
countries(not US FDA)
-Need Phase 3 RCT for confirmation
38. Small Molecule Inhibitors of
EGFR/HER
Gefitinib
Phase II trial
Cohen etal,
JCO 2003
Met/rec HNSCC
Dose-500mg
Response rate
10.6%
phase III study
Stewart JS,JCO
2009
486 patients ,met/rec
HNSCC
Geftinib 250mg
Geftinib 500 mg
Mtx 40mg iv weekly
RR-NS
OS-NS
tumor hge-more
common with
gefitinib
Argiris A asco
2009
phase III ,RCT
met/rec HNSCC
Docetaxel+/-gef
No benefit
Gregoire V,Green
journal,2011
ChemoRT +/- Gef
No benefit
39. Erlotinib
intracellular domain of Met/rec HNSCC
the EGFR
Response rate= 4.3%
Lapatinib
reversible inhibitor of
EFGR &HER2.
ongoing trials-increased CR in
preliminary analysis.
-Monotherapy-no significant activity
.
Afatinib
irreversible inhibitor
of
EGFR and HER2
RCT,phase II
Rec/met HNSCC
Plat refractory ,n=74
Afatinib vs Cet
RR 18 VS 8%
Dacomitinib
irreversible inhibitor of Phase I well tolerated
EGFR (HER1), HER2,
Phase II ongoing
HER3, and HER4
40. RCT do not show any advantage with Gefitinib
Afatinib –some promising response
Other molecules –under study
41. Insulin-like Growth Factor (IGF) Pathway
IGF-1R stimulation induces autophosphorylation with
activation of the Ras/MAP kinase pathway.
Growth and survival are mediated primarily through
downstream activation of PI3K/AKT/mTOR signaling.
Figitumumab (CP-75187)
-human IgG2 monoclonal antibody that binds IGF-1-R.
-dose- 20 mg/kg every 3 weeks
-monotherapy in rec/met HNSCC - no significant
activity
43. Bevacizumab
humanized monoclonal IgG1 antibody
Bind to VEGF-A to inhibit signaling
Reduce new blood vessel formation in primary and mets.
Inhibit blood vessel permeability-incr blood flow to tumor-
Incr drug delivery
44. Bevacizumab trials
Phase II trial
Rec/met HNSCC
N=60
BV +Pemetrxed
RR 30%
Higher gr 3 hemorrages
PhaseI/II
Cohen etal Lancet 2009
Rec/met HNSCC
-well tolerated
BV+Erlotinib
Phase II
DG P Etal JCO 2009
Phase II, RTOG trial 0615
Lee N,ASCO,JCO-2011
LAHNSCC
BV+CDDP+IMRT
LA-Ca NPX
N=44
BV+CDDP+RT
BV+CDDP *3cycle
Prelim-well
tolerated,good efficasy
Final-awaiting
-Fewer distant mets
(prelim)
45. Bevacizumab is well tolerated,with response rate of
30% but need more RCT s to confirm its role.
46.
47. Cediranib
(AZD2171,
Recentin)
TKI -VEGFR1,
met/rec
VEGFR2, and VEGFR3. HNSCC , rec
NSCLC
-monotherapy
mean decr in tumor
size - 25.9%
Sunitinib
(Sutent)
multitargeted receptor Rec/met
TKI-VEGFRs,PDGFR, HNSCC
c-kit, RET, CSF- 1
-monotherapy
receptor, flt3
-minimal activity
significant toxicity
- Tumor ulceration,
fistula bleeding
Sorafenib
(Nexavar
multikinase inhibitor - Monotherapy
VEGF-R, PDGF-R, Raf, 400 mg bid
and c-kit kinase
Met/rec
HNSCC
-minimal activity was Phase II
seen
Williamson
-well tolerated
SK,JCO
2010
Pazopani
b
(Votrient)
multityrosine kinase
inhibitor -VEGFR1,
VEGFR2, VEGFR3, ckit, and PDGFR
RR-6.1%
Phase –II
Lim W Etal
JCO 2010
Ongoing
Phase II
-Monotherapy
800 mg daily
-rec/met NPC
-33 patients
Vandeteni TKI targeting VEGFRs -LAHNSCC
b
and EGFR
-Van+cisplatin
PR- 18%
Phase II
Saura C
etal
JCO 2009
Phase II
Machiels JP
JCO 2010
48. Cediranib is the only molecule showing significant
activity and tolerability comparing other multikinase
inhibitors.
49.
50. Downstream pathways are also explored for treatment
The PI3K/Akt/mTOR pathway plays a central
role in apoptosis, cell
survival, transformation, angiogenesis,and invasion and
metastasis
Mtor activation may occur without EGFR activation in
many head and neck cancers.
51. Src
encodes for a nonreceptor tyrosine kinase
Src family proteins can associate with cellular membranes and
transduce receptor signals (eg, EGFR) to internal signaling
pathways, including PI3K and STAT.
STATs :transcription factors that on phosphorylation migrate
to the nucleus to mediate expression of genes involved in
proliferation, differentiation, and apoptosis
52. DRUG
MOA
TRIAL
RESULTS
XL147
Oral PI3K inh
(SARs 245,408)
XL147, carboplatin and
paclitaxel in 19 patients
with advanced solid
tumors
Phase-I
favorable responses
were described in 2
patients with HNSCC
perifosine
(KRX-040)
oral ,inhibits AKT
activation.
monotherapy in
rec/met HNSCC
no objective response
Everolimus
Mtor inhibitor
oral
Trials ongoing
Temsirolimus Mtor inhibitor
iv
Trials ongoing
Saracatinib
AZD0530
Oral-src TKI
-Dose- 175 mg/d
-no response
-Monotherapy rec/met
(Fury MG,Anticancer res 2011)
HNSCC
Dasatinib
(Sprycel)
Oral TKI-src & BCRABL
-monotherapy
-Rec/met HNSCC
No activity
(Brooks,Cancer 2011)
53. Conclusion:We need more number of well conducted
RCT s to ascertain role of Targeted agents against non
receptor targets.
54. Summary
At present Cetuximab is the only targeted agent that is
approved in Head and neck squamous cell ca
Initial studies targeting other pathways have not yet
yielded clinical applications, they have improved our
understanding of the biology of HNSCC.
There remains much to be discovered
It is clear that molecular-targeted therapies will be a
unavoidable part of the management of HNSCC in future.