The VENTANA ALK (D5F3) CDx Assay
The value of a standardized ALK IHC approach
2 1.International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012 http://globocan.iarc.fr/Pages/fact_sheets_population.aspx Accessed March 2015
1
Lung cancer is the most common cancer worldwide
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Cancer-related mortality
Lung cancer remains a leading cause of cancer mortality, globally1
Adenocarcinomas are a distinct sub-type of non-small cell lung cancers (NSCLC)2-4
1. International Agency for Research on Cancer. GLOBOCAN 2012 2. American Cancer Society 2015 3. National Cancer Institute 2015 4. Pao W et al 2011
Lung cancer is a leading cause of death globally
Rapid disease progression of NSCLC
4
Early detection and accelerated treatment is essential. With modern treatment, the average survival for Stage 3 NSCLC is 18 to 22 months versus four to six months with untreated cancer.1
Disease progression of NSCLC is rapid
Stage 1 Stage 4
Mortality
1. Progression of Non Small-Cell Lung Cancer, Oncolink, Accessed February 2016 http://www.oncolink.org/experts/article.cfm?id=1708
Treatment goal in metastatic NSCLC: prolong survival via rapid access to therapy
5 1. American Cancer Society 2015 2. National Cancer Institute 2015 3. Pao W et al 2011
LUNG CANCER
SMALL CELL LUNG CANCER (SCLC)
OTHER TYPES OF LUNG CANCER
10-15%
SQUAMOUS CELL
LARGE CELL
25-30%
10-15%
GEN
ETIC
MU
TATI
ON
S/TR
AN
SLO
CA
TIO
NS
REL
EVA
NT
TO T
REA
TMEN
T D
ECIS
ION
S KRAS
EGFR
ALK
MAPK
PI3K
ADENOCARCINOMA
40%
NON-SMALL CELL LUNG CANCER (NSCLC)
85-90%
MET
2
“With the introduction of targeted therapies that can result in dramatically different outcomes based on subtype, the importance of accurate classification has been amplified.”1
Up to 30% of lung biopsies require adjunct IHC testing after morphologic evaluation.2 IHC and, more specifically, key panels of IHC antibodies, provides the necessary complement in the routine diagnosis and subtyping of lung cancer.3
1. Tacha D, Yu C, Bremer R, Qi W, Haas T. A 6-antibody panel for the classification of lung adenocarcinoma versus squamous cell carcinoma. Appl Immunohistochem Mol Morphol. 2012;20:201-207 2. Rossi, et al. Subtyping Non-Small Cell Lung Cancer. Int J Surg Pathol. 21:326.2013 3. Capelozzi, V.L. Role of immunohistochemistry in the diagnosis of lung cancer. J Bras Pneumol. 2009;35(4):375-382
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IHC is key in stratifying lung cancer
Thyroid Transcription Factor-1 (SP141) Rabbit Monoclonal Primary Antibody
Cytokeratin 5/6 (D5/16B4) Mouse Monoclonal Primary Antibody
Napsin A (MRQ-60) Mouse Monoclonal Primary Antibody
VENTANA p40 (BC28) Mouse Monoclonal Primary Antibody
Lung Carcinoid 40x Squamous Cell Carcinoma 20x
Adenocarcinoma 20x Squamous Cell Carcinoma 20x
Adenocarcinoma vs. Squamous Cell Carcinoma
NSCLC is the most common type of lung cancer, and consequently, the key focus of most diagnostic and therapeutic advances.1
TTF-1, Napsin A, p40, and CK 5/6 have been identified as an accurate and reliable combination of markers for differentiating adenocarcinoma from squamous cell carcinoma.2
1. Capelozzi, V.L. Role of immunohistochemistry in the diagnosis of lung cancer. J Bras Pneumol. 2009;35(4):375-382 2. Zhao, W., et al. ∆Np63, CK5/6, TTF-1 and napsin A, a reliable panel to subtype non-small cell lung cancer in biopsy specimens. Int J Clin Exp Pathol 2014;7(7):4247-4253
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Influential clinical guidelines recommend routine testing for ALK in all lung adenocarcinomas
Testing is required prior to initiating ALK targeted therapy for a patient1-4
• In the event of a positive test result, the patient is eligible for approved ALK targeted therapies, such as XALKORI® (crizotinib).
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1. NCCN. 2015 2. Reck M et al 2014 3.Lindeman N et al 2013 4. Tsao M et al 2013
• National Comprehensive Cancer Network (NCCN)
• International Association for the study of Lung Cancer (IASLC)
• Association for Molecular Pathology (AMP)
• European Society for Medical Oncology (ESMO)
• College of American Pathologists (CAP)
Rapid access to testing is necessary
Patients need a fast, reliable and standardized way to assess eligibility so that the safest and most effective treatments can be promptly delivered1,2
9 1. von Laffert et al 2014 2. Mohammed et al 2011 3. Linderman et al 2013 4. Soloman B et al 2014 5. Schink et al 2014
Expert guidelines recommend results available within 10 days3-4
Only 24% of National Cancer Institute labs meet the CAP/IASLC/AMP 10 day turnaround time recommendation5
Patients with advanced NSCLC need a fast and reliable test to facilitate rapid access to XALKORI® (crizotinib)
Standardized ALK IHC is practical and sustainable
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FISH Testing IHC Testing FISH testing is costly and time consuming and requires sophisticated lab equipment and highly skilled interpretation, which can create a barrier to access3
IHC testing is practical and sustainable: it is affordable, rapid, easy to integrate and accessible to all pathologists3
Often needs to be outsourced, which adds time and expense
High IHC concordance with FISH has been demonstrated across numerous studies, varying levels of sensitivity depending on antibody used3-9
Minimum of 50 assessable tumor cells
No required minimum number of cells
1. Kwak et al 2010 2. Shaw et al 2013 3. Thunnissen et al 2012 4. Ying et al 2013 5. Ali et al 2014 6. Hutarew et al 2014 7. Le Quesne et al 2014 8. Minca et al 2013 9. Wynes et al 2014
Clinical value of the VENTANA ALK (D5F3) CDx Assay
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ALK IHC is able to detect the actual protein that is the target of therapy, compared to other tests that cannot, resulting in detection of patients that can benefit from XALKORI® (crizotinib) therapy.
1. Roche Ventana 2014 2. Thunnissen et al 2012 3. Ying et al 2013 4. Ali et al 2014 5. Hutarew et al 2014 6. Le Quesne et al 2014 7. Minca et al 2013 8. Wynes et al 2014 9. Zhou J et al 2014 10. Peled N et al 2012 11. Sun JM et al 2012
With no minimum sample size, use of the VENTANA ALK (D5F3) Assay can facilitate optimal tissue use1
The VENTANA ALK (D5F3) Assay has demonstrated comparable sensitivity and specificity relative to ALK 2-8
ALK IHC-positive, FISH-negative patients have been identified and may benefit from treatment with crizotinib9-11
1. Roche 2014
The VENTANA ALK (D5F3) CDx Assay stained with OptiView DAB Detection and Amplification is approved to identify patients eligible for treatment with XALKORI® crizotinib)1
VENTANA ALK (D5F3) CDx Assay is a complete system
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Rabbit Monoclonal Negative Control
No ALK Inhibitor
Interpretation Guide
VENTANA ALK (D5F3)
antibody dispenser
VENTANA OptiView DAB IHC Detection
and OptiView Amplification
BenchMark IHC/ISH Series
OR
ALK Inhibitor
• There is no minimum sample size required for the VENTANA ALK (D5F3) CDx Assay, reducing need to resample
• Successful FISH testing requires a minimum of 50 enumerable cancer cells
• This minimum cell count, in addition to difficulties in interpreting FISH results, may lead to uninterpretable results
– A recent study in France found that 20% of cases analyzed by FISH were uninterpretable1
No minimum sample size: VENTANA ALK (D5F3) CDx Assay reduces resampling
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VENTANA ALK (D5F3) CDx Assay on a case where FISH could not be performed due to <50 tumor cells in the sample: • It is positive by IHC
Note small cluster of positive tumor cells
1. McLeer-Florin A et al 2012
Comparison of commercially available tests
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Type
Fully automated
Intended use from package insert
Accessibility Relative costs
Sample requirements Timing
Claims re: XALKORI® (crizotinib)
VENTANA ALK D5F3 CDx Assay
IHC
Detection of the anaplastic lymphoma kinase (ALK) protein
Highly accessible $
No required minimum number of cells
4 hours, in-house testing
Indicated as an aid in identifying patients eligible for treatment with XALKORI® (crizotinib)
ALK-FISH (Vysis, Abbott)
FISH
Detection of rearrangements involving the ALK gene in NSCLC specimens
Not routinely accessible $$$$
Minimum of 50 assessable tumor cells
12+ hours, semi-automated; typically batch or send-out testing
Qualitative test to detect rearrangements involving the ALK gene to aid in identifying those patients eligible for treatment with XALKORI® (crizotinib)
Sources: Vysis product details http://www.abbottmolecular.com/static/cms_workspace/pdfs/US/Vysis_ALK_FISH_Probe_Kit_PI.pdf. Qiagen product details https://www.qiagen.com/gb/products/catalog/assay-technologies/complete-assay-kits/personalized-healthcare/alk-rgq-rt-pcr-kit-ruo/#productdetails
Comparison of commercially available tests
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Routine testing
Simple operation Timing Price
FISH
Other IHC
VENTANA IHC
RT-PCR
Used for screening
ALK+ tumors can be diagnosed
$
$ Fully
automated
12+ hours
4 hours
$$$$
$$$$
Treatment goal in metastatic NSCLC is to prolong survival
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LUNG CANCER
ALK TARGETED THERAPIES
ADENOCARCINOMA
NON-SMALL CELL
LUNG CANCER (NSCLC)
IHC
“Results suggest it's best to get these drugs to patients at the earliest opportunity.”1 - Benjamin Solomon, Peter MacCallum Cancer Centre, Australia
Opportunity: Prolong survival, save costs and make more immediate treatment decisions for advanced NSCLC patients by using the VENTANA ALK (D5F3) CDx Assay
1. Soloman B et al 2014
Health outcome New treatment
Cost New treatment
- Cost
Current treatment
Health outcome Current treatment
-
How to analyze cost/benefit of ALK IHC testing?
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ALK IHC shows potential economic and clinical value
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Accelerate access to care
Impact patient quality of life
Decrease diagnostic costs1
With lower costs and equivalent accuracy, the VENTANA ALK (D5F3) CDx Assay has the potential to improve efficiency and patient quality of life.
1. Roche 2014
Summary: Standardized ALK IHC approach
Clinical guidelines recommend rapid turnaround for earlier targeted therapies1
FISH is widely used but the ALK IHC is an attractive alternative2
The approved VENTANA ALK (D5F3) CDx Assay stained with OptiView DAB Detection and Amp detects the protein that is the target of therapy3
Comparable sensitivity and specificity relative to FISH7-12
No minimum sample size
Accelerates access and impacts patient quality of life13
May decrease diagnostic costs1
19 1. Linderman et al 2013 2. Thunnissen et al 2012 3 Roche et al 2014 4. Ying et al 2013 5. Ali et al 2014 6. Hutarew et al 2014 7. Le Quesne et al 2014 8. Minca et al 2013 9. Wynes et al 2014 10. Zhou J et al 2014 11. Peled N et al 2012 12. Sun JM et al 2012 13. VENTANA ALK (D5F3) Assay Budget Impact Model. Roche 2015 .
References
References
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Abbot Vysis ALK FISH Probe Kit. http://www.abbottmolecular.com/static/cms_workspace/pdfs/US/Vysis_ALK_FISH_Probe_Kit_PI.pdf
Alì, Greta, et al. "ALK Rearrangement in a Large Series of Consecutive Non-Small Cell Lung Cancers: Comparison Between a New Immunohistochemical Approach and Fluorescence In Situ Hybridization for the Screening of Patients Eligible for Crizotinib Treatment." Archives of pathology & laboratory medicine138.11 (2014): 1449-1458
American Cancer Society. Lung cancer (non-small cell). http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer Accessed March 2015
Capelozzi, V.L. Role of immunohistochemistry in the diagnosis of lung cancer. J Bras Pneumol. 2009;35(4):375-382
Hutarew, Georg, et al. "Immunohistochemistry as a screening tool for ALK rearrangement in NSCLC: evaluation of five different ALK antibody clones and ALK FISH." Histopathology 65.3 (2014): 398-407
International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx Accessed March 2015
Kwak, Eunice L., et al. "Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer." New England Journal of Medicine 363.18 (2010): 1693-1703
Le Quesne, John, et al. "A Comparison of Immunohistochemical Assays and FISH in Detecting the ALK Translocation in Diagnostic Histological and Cytological Lung Tumor Material." Journal of Thoracic Oncology 9.6 (2014): 769
Lindeman, Neal I., et al. "Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology." The Journal of Molecular Diagnostics 15.4 (2013): 415-453
McLeer-Florin, Anne, et al. "Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: a French study. "Journal of Thoracic Oncology 7.2 (2012): 348-354
Minca, Eugen C., et al. "ALK Status Testing in Non–Small Cell Lung Carcinoma: Correlation Between Ultrasensitive IHC and FISH." The Journal of Molecular Diagnostics 15.3 (2013): 341-346
References
Mohammed, Nasiruddin, et al. "Rapid Disease Progression With Delay in Treatment of Non–Small-Cell Lung Cancer." International Journal of Radiation Oncology* Biology* Physics 79.2 (2011): 466-472
National Cancer Institute. Non-Small cell lung cancer (PDQ) http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional Accessed March 2015
NCCN. Non-small cell lung cancer Guidelines version 4.2015
Oncolink. Progression of Non Small-Cell Lung Cancer, Oncolink, Accessed February 2016 http://www.oncolink.org/experts/article.cfm?id=1708
Pao, William, and Nicolas Girard. "New driver mutations in non-small-cell lung cancer." The Lancet oncology 12.2 (2011): 175-180
Peled, Nir, et al. "Next-Generation Sequencing Identifies and Immunohistochemistry Confirms a Novel Crizotinib-Sensitive ALK Rearrangement in a Patient with Metastatic Non–Small-Cell Lung Cancer."Journal of Thoracic Oncology 7.9 (2012): e14-e16
Qiagen ALK RT-PCR. https://www.qiagen.com/gb/products/catalog/assay-technologies/complete-assay-kits/personalized-healthcare/alk-rgq-rt-pcr-kit-ruo/#productdetails
Reck M, Reinmuth N, De Ruysscher D et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 25 (Suppl 3) (2014) iii27-iii39
Roche Ventana. (2014). anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody, 1–4 Rossi, et al. Subtyping Non-Small Cell Lung Cancer. Int J Surg Pathol. 21:326.2013
Schink et al. Biomarker testing methods in breast, gastric, and lung cancers: A benchmarking survey of NCI cancer centers. Journal of Clinical Oncology 31.15 (2013) e22093
Shaw, Alice T., et al. "Crizotinib versus chemotherapy in advanced ALK-positive lung cancer." New England Journal of Medicine 368.25 (2013): 2385-2394
Solomon, Benjamin J., et al. "First-line crizotinib versus chemotherapy in ALK-positive lung cancer." New England Journal of Medicine 371.23 (2014): 2167-2177
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References Sun, Jong-Mu, et al. "A Dramatic Response to Crizotinib in a Non–Small-Cell Lung Cancer Patient with IHC-Positive and FISH-Negative ALK." Journal of Thoracic Oncology 7.12 (2012): e36-e38
Tacha D, Yu C, Bremer R, Qi W, Haas T. A 6-antibody panel for the classification of lung adenocarcinoma versus squamous cell carcinoma. Appl Immunohistochem Mol Morphol. 2012;20:201-207
Thunnissen, Erik, et al. "EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations." Virchows Archiv 461.3 (2012): 245-257
Tsao, M. S., F. R. Hirsch, and Y. Yatabe. "IASLC atlas of ALK testing in lung cancer." Aurora, CO, International Society for the Study of Lung Cancer (2013)
VENTANA ALK (D5F3) Assay Budget Impact Model. Roche 2015
von Laffert, Maximilian, et al. "Multicenter ALK Testing in Non–Small-Cell Lung Cancer: Results of a Round Robin Test." Journal of Thoracic Oncology 9.10 (2014): 1464-1469
Wynes, Murry W., Lynette M. Sholl, and Manfred Dietel. "An international interpretation study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators." Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 9.5 (2014): 631
XALKORI Prescribing Information (USA)
XALKORI Summary of Product Characteristics (UK)
Ying, J., et al. "Diagnostic value of a novel fully automated immunochemistry assay for detection of ALK rearrangement in primary lung adenocarcinoma. "Annals of oncology (2013): mdt295
Zhao, W., et al. ∆Np63, CK5/6, TTF-1 and napsin A, a reliable panel to subtype non-small cell lung cancer in biopsy specimens. Int J Clin Exp Pathol 2014;7(7):4247-4253
Zhou, Jianya, et al. "Cell block from malignant pleural effusion might be a valid alternative sample for ALK detection in patients with advanced non small cell lung cancer." Histopathology (2014)
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