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!!