Companion & Complementary Diagnostics: Clinical and Regulatory Perspectives

Workshop on Companion Diagnostics

January 31, 2017

Jan Trøst Jørgensen, M.Sc.Pharm., Ph.D. Dx-Rx Institute

Fredensborg, Denmark E-mail: jan.trost@dx-rx.dk

Disclosures: Jan Trøst Jørgensen has worked as a consultant for Dako, Agilent Technologies and Euro Diagnostica and has given lectures at meetings sponsored by AstraZeneca, Merck Sharp & Dohme, and Roche.

Jan Trøst Jørgensen

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Companion & Complementary Diagnostics

• Introduction and History • Definitions • Drug-Diagnostic Co-Development • What can be achieved? • Regulatory Aspects • Conclusion and Future Perspectives

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Disease Heterogeneity

Jan Trøst Jørgensen 3

“In order to achieve a more effective pharmacotherapy we need to recognize that most diseases are heterogeneous and thus develop drugs accordingly.”1

1. Jørgensen JT. A challenging drug development process in the era of personalized medicine. Drug Discov Today 2011;16: 891-897

Workshop on Companion Diagnostics - January 31, 2017

Drug-Diagnostic Combinations Oncology

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1970 1980 1990 2000 2010

Tamoxifen Breast Cancer

“A high degree of correlation between response and positive estrogen-receptor assay suggests the value of the diagnostic test as a means to select patients for tamoxifen treatment” Lerner HJ et al. Phase II study of tamoxifen: report of 74 patients with stage IV breast cancer. Cancer Treat Rep. 60,1431-1435 (1976).

HER2 Breast Cancer

Imatinib, Gefitinib, Vemurafenib, Crizotinib, Pertuzumab, Ceritinib,

Pembrolizumab and more

FDA Approves: Trastuzumab + HercepTest

Companion Diagnostics (CDx) US Definition1

A CDx assay is an in vitro diagnostics device that provides information that is essential for the safe and effective use of a corresponding therapeutic product:

1. Identify patients who are most likely to benefit from the therapeutic product

2. Identify patients likely to be at increased as a result of treatment with the therapeutic product risk for serious adverse reactions

3. Monitor response to treatment with the therapeutic product for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness

4. Identify patients in the population for whom the therapeutic product has been adequately studied, and found safe and effective, i.e., there is insufficient information about the safety and effectiveness of the therapeutic product in any other population

1. In Vitro Companion Diagnostic Devices. Guidance Document. FDA, August 6, 2014. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf

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Companion Diagnostics (CDx) Proposed EU Definition1

A device which is essential for the safe and effective use of a corresponding medicinal product:

1. Identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or

2. Identify, before and/or during treatment, patients likely to be at increased risk for serious adverse reactions as a result of treatment with the corresponding medicinal product;

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1. Council of the European Union. (2016) Proposal for a Regulation of the European Parliament and of the Council on in vitro diagnostic medical devices. 911663/16. August 31, 2016. (http://data.consilium.europa.eu/doc/document/ST-11663-2016-INIT/en/pdf)

Complementary Diagnostics (CDx) Preliminary US Definition1

“A test that identify a biomarker-defined subset of patients that respond particularly well to a drug and aid risk/benefit assessments for individual patients, but that are not pre requisites for receiving the drug.”

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1. Theoret M. Biomarkers for PD-1/L1 inhibitors: Regulatory Considerations. Presentation at the EMA-CDDF Joint Meeting, London February 4-5, 2016. (http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2016/04/WC500204586.pdf)

Drugs with US FDA approved complementary diagnostic: • Nivolumab for NSCLC and Melanoma (PD-L1 IHC 28-8 pharmDx) • Atezolizumab for NSCLC and Urothelial Carcinoma (VENTANA PD-L1 (SP142) assay)

Companion & Complementary Diagnostics1

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1. Jørgensen JT. Companion and Complementary Diagnostics: Clinical and Regulatory Perspectives. Trends Cancer 2016; 2: 706-712.

Parallel Development of Drug and Diagnostic

Drug Development

CDx Development

Discovery Research Pre-clinical Clinical

Phase I

Post Approval

Phase

Clinical Phase III

Clinical Phase II

Regulatory Approval

Biomarker Selection

Feasibility Studies

Regulatory Approval

Clinical Validation & Utility

Prototype Assay(s)

Analytical Validation

Post Approval

Phase

Drug-Diagnostic Co-Development1,2 Phase I to III Clinical Development

1. Olsen D, Jørgensen JT. Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects. Front Oncol 2014; 4: 105. 2. US FDA. Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product. Draft Guidance, July 15, 2016.

(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM510824.pdf)

Strong Biomarker Hypothesis

Cut-off Selection & Analytical Validation

Clinical Validation

& Clinical Utility

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Parallel Development of Drug and Diagnostic

Drug Development

CDx Development

Discovery Research Pre-clinical Clinical

Phase I

Post Approval

Phase

Clinical Phase II

Regulatory Approval

Biomarker Selection

Feasibility Studies

Regulatory Approval

Prototype Assay(s)

Analytical Validation

Post Approval

Phase

Drug-Diagnostic Co-Development1,2 Phase I/II Clinical Development

1. Olsen D, Jørgensen JT. Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects. Front Oncol 2014; 4: 105. 2. US FDA. Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product. Draft Guidance, July 15, 2016.

(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM510824.pdf)

Strong Biomarker Hypothesis

Cut-off Selection & Analytical Validation

Clinical Validation

& Clinical Utility

Clinical Validation & Utility

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Immune Checkpoint Inhibitors

1st Line Treatment in NSCLC

• Pembrolizumab/PD-L1 IHC 22C3 pharmDx (KEYNOTE-024) – PD-L1 IHC 22C3 pharmDx is approved as a companion diagnostic – Assay cut-off: 50% PD-L1 expression1

– Treatment: Pembrolizumab (P) vs platinum-based chemotherapy (C), N=3052

– PFS: Median 10.3 mo (P) vs 6.0 mo (C); (HR 0.50, 95% CI 0.37-0.68, P<0.001)

• Nivolumab/PD-L1 IHC 28-8 pharmDx (CheckMate 026)

– PD-L1 IHC 28-8 pharmDx is approved as a complementary diagnostic – Assay cut-off: 5% PD-L1 expression

– Treatment: Nivolumab (N) vs platinum-based chemotherapy (C), N=5413

– PFS: Median 4.2 mo (N) vs 5.9 mo (C); (HR 1.15, 95% CI 0.91-1.45, P=0.25)

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1. Garon EB et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372:2018-28. 2. Reck M al. LBA8_PR - KEYNOTE-024. Abstract presented at ESMO 2016 Congress, October 7 - 11, 2016, Copenhagen, Denmark.

(https://cslide.ctimeetingtech.com/library/esmo/browse/itinerary/5286/2016-10-09#2z94T0v3) 3. Socinski M et al. LBA7_PR - CheckMate 026. Abstract presented at ESMO 2016 Congress, October 7 - 11, 2016, Copenhagen, Denmark.

(https://cslide.ctimeetingtech.com/library/esmo/browse/itinerary/5286/2016-10-09#2z94T0v3)

Drug-Diagnostic Co-Development Enrichment Designs1,2,3

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Enrichment Design (Randomized)

1. Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. Draft Guidance. FDA, December 2012. (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM332181.pdf)

2. US FDA. Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product. Draft Guidance, July 15, 2016. (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM510824.pdf)

3. Jørgensen JT. Companion Diagnostics and Clinical Utility in Oncology - Current Status and Future Aspects . Oncology 2013; 85: 59-68.

Traditional Randomized Design

Enrichment Design (Single Arm)

Workshop on Companion Diagnostics - January 31, 2017

Approved ALK & ROS1 Inhibitors in NSCLC Regulatory Submissions – Efficacy Data1,2,3

50

225

163

255

0 50 100 150 200 250 300

Crizotinib - ROS1(US)/2016

Alectinib (US)/2015

Ceritinib (US)/2014

Crizotinib - ALK(US)/2011

No. of Patients

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1. Gandhi S, Chen H, Zhao Y, et al. First-line treatment of advanced ALK-positive non-small lung cancer. Lung Cancer: Targets and Therapy 2015; 6: 71-82. 2. McKeage K. Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer. Drugs 2015 ; 75: 75-82. 3. Jørgensen JT. The importance of predictive biomarkers in oncology drug development. Expert Rev Mol Diagn. 2016;16: 807-809.

Workshop on Companion Diagnostics - January 31, 2017

Drug-Diagnostic Combinations Objective Response Rates – Oncology1

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1. Jørgensen JT. Clinical application of companion diagnostics. Trends Mol Med. 2015; 21: 405-7.

Workshop on Companion Diagnostics - January 31, 2017

Companion Diagnostics (CDx) Regulatory Aspects1,2,3

• Classification of CDx assays – US: Class III (high risk IVD devices) – EU: General IVD (low risk IVD devices). In the near future Class C*

• Documentation of analytical and clinical validity – US: Review by FDA – EU: Self-certification and CE marking. In the near future review by

independent notified body and national competent authorities and/or EMA

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1. US FDA. Guidance for Industry and FDA Staff. In Vitro Diagnostic (IVD) Device Studies -Frequently Asked Questions. June 25, 2010 (http://www.fda.gov/downloads/MedicalDevices/.../ucm071230.pdf).

2. Council of the European Union. (2016) Proposal for a Regulation of the European Parliament and of the Council on in vitro diagnostic medical devices. 911663/16. August 31, 2016. (http://data.consilium.europa.eu/doc/document/ST-11663-2016-INIT/en/pdf)

3. Pignatti F. et al. Cancer drug development and the evolving regulatory framework for companion diagnostics in the European union. Clin. Cancer Res. 2014; 20: 1458-1468.

*Class C: High individual risk or moderate public health risk, where an erroneous result would put the patient in an imminent life-threating situation or would have major negative impact on outcome

Drug-diagnostics Codevelopment Future Perspectives

0%5%

10%15%20%25%30%35%40%45%50%55%60%65%

Oncology Other Diseases

• Oncology will continue to dominate • Other therapeutic areas:

– Central nervous system diseases – Cardiovascular diseases – Autoimmune diseases

• Drug and biomarker R&D will become a more flexible and iterative process

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Percentage of company pipeline relying on biomarker in late clinical development1

1. Milne CP et al. Market watch: Where is personalized medicine in industry heading? Nat Rev Drug Discov. 2015;14: 812-3.

Summary & Conclusion

• The drug-diagnostic codevelopment model: – Increased drug efficacy – Reduction in time and resources spent1,2,3 – Increased development success rate1,2,3

• Oncology drug development is currently undergoing major changes

• Key requirements for CDx assay development: – A clear intended us – Analytical validity – Clinical validated and demonstrated clinical utility

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1. Falconi A. et al.. Biomarkers and receptor targeted therapies reduce clinical trial risk in non-small-cell lung cancer. J Thorac Oncol 2014; 9: 163-169. 2. Rubinger D.A. et al. Biomarker use is associated with reduced clinical trial failure risk in metastatic melanoma. Biomark Med 2015; 9: 13-23. 3. Jørgensen JT. The importance of predictive biomarkers in oncology drug development. Expert Rev Mol Diagn 2016; 16: 807-809.

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Would like to know more?

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“A bad tumor biomarker test is as bad as a bad drug” Current president of ASCO, Daniel F. Hayes1

1. Hayes D., Raison C. Lessons for tumor biomarker trials: vicious cycles, scientific method & developing guidelines. Expert Rev Mol Diagn 2015; 15:165-169.