targeted therapy: falso mito o reale innovazione? stefano iacobelli cancer clinic & laboratory...
Post on 15-Jan-2016
218 Views
Preview:
TRANSCRIPT
Targeted therapy: Falso mito o reale innovazione?
Stefano Iacobelli
Cancer Clinic & Laboratory of Molecular Oncology
Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO)
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.
What are Targeted Therapies?
NCI www.cancer.gov
Langer C & Soria JC, Clin Lung Cancer 11: 82-90, 2010
Mechanisms of common Targeted Anticancer Therapies:
mAbs and TKIs
aAgents with antiangiogenic mechanismLi J et al., Targ Oncol 2012
FDA approved TKIs and mAbs for cancer therapy
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.
5-yr OS: 89%5-yr CCR: 87%
Druker BJ et al., N Engl J Med 2006
Results with Imatinib as initial therapy for newly diagnosed chronic-phase CML
The Reality: Targeted Therapy in the Common Solid Tumors
Targeted Therapies Vary in Effectiveness:
The role of the “TARGET”
CML and Breast Cancer
CML Patients
Imatinib
~ 90% Response
All Breast Cancer Patients
Trastuzumab
< 10 % Response
HER2 + Breast Cancer Patients
Trastuzumab
~ 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
• Small mutational load
• Monotherapy is effective
• Resistance rare, late, same pathway
• Multiple mutational drivers
• Large mutational load
• Multi-targeted therapy required
• Resistance common, early
Sledge G, ASCO 2009
Red = amplificationPurple = LOHBlack = mutation
A= Inter- and intra-chromosomal rearrangements
B= LOH and allelic imbalanceC= Copy number variationsD= Single nucleotide variants
CML: A Stupid Cancer NSCLC: A Smart Cancer
• 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
One mutation for every 3 cigarettes!
Lee et al., Nature 465: 473-7, 2010
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)
Somatic mutations of the EGFR gene were found in 15 of 58 unselected tumors from
Japan and 1 of 61 from the US
mPFS 9.7 vs. 5.2 months
Erlotinib vs. standard chemotherapy as first-line treatment for European pts with advanced EGFR-mutation positive NSCLC
- EURTAC phase III study -
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
174 pts with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) enrolled
Thatcher N et al., Lancet 366: 1527-37, 2005
Gefitinib in Refractory Advanced NSCLC
No Benefit
K-Ras mutations in CRC40%
K-Ras mutationsand Benefit from
Cetuximab inAdvanced CRC
mOS 9.5 vs 4.8 months
No difference
Karapetis CS, N Engl J Med 359:1757-65, 2008
Clinical evidence of oncogene addiction
Nagahiro Saijo, Cancer Res Treat. 2012; 44:1-10
The need of a “COMPANION DIAGNOSTIC TEST”
Oncogene addiction describes the phenomenon in which some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities remain dependent on (addicted to) one or a few genes for both maintenance of the malignant phenotype and cell survival.
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)
IHC analysis of ALK in tumor cells (brown)
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)
RT-PCR of EML4-ALK
Kwak EL et al., N Engl J Med 2010
Response to ALK Inhibition and PFS
Kwak EL et al., N Engl J Med 2010; Camidge DR et al., Lancet Oncol 2012
ORR 60.8%
mPFS 9.7 months
CT before and after Crizotinib
Crizotinib 250 mg bid in 28-day cycles
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Vemurafenib 960 mg orally bidDacarbazine 1000 mg/mq d1 q21
Chapman PB et al., N Engl J Med 2011
RR 48% vs. 5%Vemurafenib vs. Dacarbazine
50
100
0
25
75
BC – Using usual selection criteria (EBCTCG)
(100 N0, pre-menopausal pts receiving CT, after 5 yrs follow-up)
83.5 will be alive even w/o CT
13.5 will die despite CT
3 will be alive thanks to CT
Using the 70-gene signature
Only 27% of pts will be overtreated
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 populationsthat 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 Bio-Oncologia (CINBO)
Targeted cancer drugs are expensive and often fail to yeld
clinical benefit
NSCLC
Breast
Breast
Pancreas
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?
GRAZIE PER LA VS ATTENZIONE!!
top related