Targeted therapy:
Falso mito o reale innovazione?
Stefano Iacobelli
Cancer Clinic & Laboratory of
Molecular Oncology
Consorzio Interuniversitario Nazionale per la BioOncologia (CINBO)
What are Targeted Therapies?
 Targeted cancer therapies are drugs or other
substances that block the growth and spread of cancer
by interfering with specific molecules involved in
tumor growth and progression.
 Targeted cancer therapies that have been approved for
use in specific cancers include drugs that interfere with
cell growth signaling or tumor blood vessel
development, promote the specific death of cancer
cells, stimulate the immune system to destroy specific
cancer cells, and deliver toxic drugs to cancer cells.
NCI www.cancer.gov
Mechanisms of common Targeted Anticancer Therapies:
mAbs and TKIs
Langer C & Soria JC, Clin Lung Cancer 11: 82-90, 2010
FDA approved TKIs and mAbs for cancer therapy
aAgents
with antiangiogenic mechanism
Li J et al., Targ Oncol 2012
Myth: Imatinib Mesylate, “Proof of
Principle” for Targeted Therapy
• Imatinib Mesylate targets the bcr-abl TK very
specifically.
• Bcr-abl is the root cause of CML, essentially a
“monogenetic disease”
Before Imatinib, only 30% of patients with CML
survived for even five years after being
diagnosed.
Results with Imatinib as initial therapy for newly
diagnosed chronic-phase CML
5-yr CCR: 87%
5-yr OS: 89%
Druker BJ et al., N Engl J Med 2006
The Reality: Targeted Therapy in the
Common Solid Tumors
CML and Breast Cancer
Targeted Therapies Vary in Effectiveness:
The role of the “TARGET”
CML Patients
All Breast
Cancer Patients
HER2 + Breast
Cancer Patients
Imatinib
Trastuzumab
Trastuzumab
~ 90% Response
< 10 % Response
~ 35% Response
The Ideal Target
 Driving mutation in a
 “ Dumb ” tumor that is
 Easily druggable
 and the mutation is really common
Stupid and Smart Cancers
Stupid Cancers
Smart Cancers
•
Single dominat mutation
•
Multiple mutational drivers
•
Small mutational load
•
Large mutational load
•
Monotherapy is effective
•
•
Multi-targeted therapy
required
Resistance rare, late, same
pathway
•
Resistance common, early
Sledge G, ASCO 2009
CML: A Stupid Cancer
NSCLC: A Smart Cancer
One mutation for every 3 cigarettes!
A= Inter- and intra-chromosomal
rearrangements
B= LOH and allelic imbalance
C= Copy number variations
D= Single nucleotide variants
• Driven by a single chromosomal
translocation (BCR-ABL)
• Success with the first drug that came
along
• That doesn’t work?
- Use an "ib" targeting the same
kinase domain
Red = amplification
Purple = LOH
Black = mutation
Lee et al., Nature 465: 473-7, 2010
Somatic mutations of the EGFR gene were
found in 15 of 58 unselected tumors from
Japan and 1 of 61 from the US
Somatic mutations were identified in the
tyrosine kinase domain of the EGFR gene
in 8 of 9 patients with gefitinib-responsive
lung cancer, as compared with none of the
seven patients with no response (P<0.001)
Erlotinib vs. standard chemotherapy as first-line treatment for
European pts with advanced EGFR-mutation positive NSCLC
- EURTAC phase III study 174 pts with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) enrolled
mPFS 9.7 vs. 5.2 months
 Erlotinib 150 mg daily
 Standard chemotherapy:
cisplatin 75 mg/m(2) d1 + docetaxel 75 mg/m(2) d1 or gemcitabine 1250 mg/m(2) d 1,8 q21
Rosell R et al., Lancet Oncol 2012; 13:239-46
Gefitinib in Refractory Advanced NSCLC
No Benefit
Thatcher N et al., Lancet 366: 1527-37, 2005
40%
K-Ras mutations in CRC
No difference
K-Ras mutations
and Benefit from
Cetuximab in
Advanced CRC
mOS 9.5 vs 4.8 months
Karapetis CS, N Engl J Med 359:1757-65, 2008
Clinical evidence of oncogene addiction
The need of a “COMPANION DIAGNOSTIC TEST”
Nagahiro Saijo, Cancer Res Treat. 2012; 44:1-10
Recently, 2 targeted therapies were approved by FDA with a
companion diagnostic to identify enriched subpopulations of
patients that are more likely to respond to the drug
Parkinson DR et al., Clin Cancer Res 2012
Diagnosis of an EML4-ALK-Positive NSCLC in a single patient
Adenocarcinoma (H&E)
Kwak EL et al., N Engl J Med 2010
IHC analysis of ALK in
tumor cells (brown)
RT-PCR of EML4-ALK
Panel A: The green probe hybridizes to the region immediately 5’ to ALK, and the red probe to the 3’ region. The
separation of red and green probes indicates a chromosomal rearrangement of ALK. The probe used was the Vysis
LSI ALK Dual Color, Break Apart Rearrangement Probe (Abbott Molecular)
Response to ALK Inhibition and PFS
ORR 60.8%
Crizotinib 250 mg bid in 28-day cycles
mPFS 9.7 months
CT before and after Crizotinib
Kwak EL et al., N Engl J Med 2010; Camidge DR et al., Lancet Oncol 2012
Chapman PB et al., N Engl J Med 2011
Improved Survival with
Vemurafenib in Melanoma
with BRAF V600E Mutation
RR 48% vs. 5%
Vemurafenib vs. Dacarbazine
Vemurafenib 960 mg orally bid
Dacarbazine 1000 mg/mq d1 q21
BC – Using usual selection criteria (EBCTCG)
(100 N0, pre-menopausal pts receiving CT, after 5 yrs follow-up)
100
83.5 will be alive even w/o CT
13.5 will die despite CT
3 will be alive thanks to CT
75
50
Using the 70-gene signature
Only 27% of pts will be overtreated
25
0
Conclusions
 The outcome of CML was transformed by targeted therapy: median
survival increased from about 4 yrs to 20-25 yrs
 Solid tumors are more complex than CML
 Therefore the outcomes in CML are an aberration, and we are not
likely to see such a transformation in outcomes in solid tumors
 Only a co-development strategy that identifies biomarkers of
response and treats only vulnerable tumors will be defensible going
forward
 Development strategies that administer therapies to populations
that are not selected or are selected with methodologies not validated,
must become a strategy of the past.
Molecular Diagnostics:
The next step
Stefano Iacobelli
Cancer Clinic & Laboratory of
Molecular Oncology
Consorzio Interuniversitario Nazionale per la BioOncologia (CINBO)
Targeted cancer drugs are expensive
and often fail to yeld clinical benefit
NSCLC
Breast
Pancreas
Breast
Provocative statement 1:
Drug companies cannot afford NOT to have a
molecular diagnostic division
 Tissue samples for MDx will become ever smaller as
diagnosis improves, requiring concentration of MDx testing
in single large central services laboratories
These MDx companies that offer the broadest range of
diagnostic tests will receive the samples available for MDx
If co-development of drug and companion MDx test
will become the norm and integral part of FDA/EMA
regulatory process, any company that does not control
the entire chain of events will be vulnerable.
Provocative statement 2:
Biomarker discovery should start before Phase 1
 Too often, companies start to think about biomarkers
when the drug has falled in phase 3 (the Iniparib scenario)
 Candidate biomarkers of response should be identified
while a compound is in research phase, validated in phase 1
and 2 trials and used as an enrollment criterion in phase 3
Provocative statement 3:
No tissue, no trial!
 Is it ethical to make biopsies mandatory for
participation in trials or should we realize high consent to
biopsies through patient education?
Provocative statement 4:
Heathcare insurers will not pay for Rx without
companion Dx in the future
 Future drug reimbursement will depend on quality of
life years gained
 How much are payers willing to pay for a MDx test
that rules out half of the patient population for a €
100,000 targeted therapy?