Investigative Drug

Investigative Drugpresentation to

Massachusetts College of Pharmacy and Health Science

Oncologic Drugs Advisory Committee

April 12, 2010

A review of Tarceva® and a proposal for an

Investigative Drugthird line monotherapy, for

patients with advanced NSCLC

Presentation preview

• Non Small Cell Lung Cancer is a serious disease

• Patients who live beyond the first stages of the disease have few therapeutic options

• Many available therapeutic options are toxic intravenous therapies

• Tarceva® is an oral monotherapeutic option for second and third stage NSCLC

• Our investigative therapy is also a monotherapy drug for third stage NSCLC

Milon Shah Lung cancer, treatment options, and the chemistry of Tarceva®

Robert Fynn Tarceva® clinical trials

Sandra Brown-Macioci Tarceva® approval process

Kristina Reinold Investigative drug proposal and clinical trial design

Experts available for questions

http://www.cancer.org/docroot/CRI/content/CRI_2_2_1x_How_Many_People_Get_Non-small_Cell_Lung_Cancer.asp?rnav=crihttp://seer.cancer.gov/faststats/selections.php?#Output

Lung Cancer is the leading cancer killer in United States

• Leading cancer killer in men and women in United States (29% of all cancer deaths)

• 219,440 new cases of lung cancer in 2009

• 159,390 deaths from lung cancer

• 5 year survival rate in patients with lung cancer is less than 15.2%

Types of lung cancerThe two main types of lung cancer are:• Small Cell Lung Cancer (SCLC)

– about 10% of all lung cancer patients are of these type

• Non Small Cell Lung Cancer (NSCLC)– about 80-90% of all lung cancer patients are

of these type

Other types of tumors include Lung Carcinoid Tumors, which are slow growing and can be cured by surgery.

http://www.cancer.org/docroot/CRI/content/CRI_2_2_1x_What_Is_Non-small_Cell_Lung_Cancer.asp?sitearea=

Types of Non Small Cell Lung Cancer (NSCLC)

The 3 sub-types of NSCLC differ in size, shape, and chemical composition.

• Adenocarcinoma: • About 40% of lung cancers.• Usually found in the outer part of the lung

• Squamous cell carcinoma: • About 25% to 30% of all lung cancers are this kind. • Usually develops in the middle of the lungs, near a bronchus.

• Large-cell (undifferentiated) carcinoma: • About 10% to 15% of lung cancers are this type. • It can develop in any part of the lung.

http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/patient

Symptoms of NSCLC

• Persistent cough

• Trouble breathing

• Chest discomfort

• Wheezing

• Streaks of blood in sputum

• Hoarseness

• Loss of appetite

• Inexplicable weight loss

• Fatigue

http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/patient

How is NSCLC diagnosed?

• Physical exams• Laboratory tests• Chest x-ray• CT scan• PET scan• Sputum Cytology• Fine-needle

Aspiration (FNA)

http://emedicine.medscape.com/article/279960-diagnosis

Stages of NSCLC

Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.• Stage 0

http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4

Stages of NSCLC

Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.• Stage 0 • Stage IA & IB

http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4http://www.avastin.com/avastin/patient/lung/learn/stages/index.m

Stages of NSCLC

Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.• Stage 0 • Stage IA & IB• Stage IIA & IIB


Stages of NSCLC

Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.• Stage 0 • Stage IA & IB• Stage IIA & IIB• Stage IIIA & IIIB


Stages of NSCLC

Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.• Stage 0 • Stage IA & IB• Stage IIA & IIB• Stage IIIA & IIIB• Stage IV


Treatment Approaches for NSCLC

• Surgery• Radiation Therapy• Chemotherapy• Targeted Therapy• Laser Therapy• Photodynamic Therapy• Cryosurgery• Electrocautery

http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page4

Drug approved for NSCLC treatment

• Alitma®

(pemetrexed)

• Avastin®

(bevacizumab)

• Gemzar®

(gemcitabine)

• Iressa®

(gefitinib)

• Photofrin®

(porfimer)

• Taxol®

(paclitaxel)

• Taxotere®(docetaxel)

• Tarceva® (erlotinib)http://www.empr.com/non-small-cell-lung-cancer-nsclc-drug-treatments/article/123617/

Tarceva® (erlotinib) – the first EGFR oral targeted agent for NSCLC

http://www.roche.com/investors/ ir_update/inv-update-2008-11-14.htm

Tarceva® indication

Tarceva® is prescribed for patients with advanced-stage non-small cell lung cancer (NSCLC) who have received at least one prior chemotherapy regimen

http://www.tarceva.com/patient/taking/how_to_take.jsp

Mechanism of Action of Tarceva®

Pharmacology Category : • Human Epidermal Growth

Factor Receptor Type 1/ Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor

MOA• Inhibits the intracellular

phosphorylation of tyrosine kinase associated with the

epidermal growth factor receptor (EGFR).

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021743s015lbl.pdf http://www.betapharmagroup.com/site/image/egfr.png

http://www.egfr.org/


Chemistry of Tarceva®

• Active ingredient:

Erlotinib hydrochloride• Chemical Name:

N-(3-ethylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine

• Chemical Structure

Tarceva® Clinical TrialsPhase II Trial

Study A248-1007

Phase III Trials• Study BR.21• The Saturn Study

Phase II Clinical Trial assessed efficacy and safety of Tarceva®

• Study A248-1007• A multicenter, open-label, single arm trial• 57 patients received 150mg tablet/day

following the failure of platinum based combination chemotherapy

• Assessed the efficacy and safety of Tarceva® in patients with Stage IIIB or IV, EGFR positive NSCLC

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDF

• Treatment was taken until disease progression or unmanageable toxicity

• Median age of the study was 62 years, with 74% of the patients historically smokers

• 60% of patients were females and 91% were Caucasian

Phase II Clinical Trial treatment and population


• 2 of the patients had complete response (CR)

• 5 had partial response (PR)• The objective response rate was 12.3%

(95% CI:5.1-23.7 %)• The median overall survival was 8.4

months (95% CI:4.8-13.9 months)

Phase II Clinical Trial showed improved response rates


• Multicenter, international, randomized, placebo-controlled, double blinded clinical study

• Designed to compare Tarceva® to a placebo• Enrolled 731 patients• Conducted in 86 study centers in 17 countries• Sites locations included:

1 in USA

27 in Canada

58 (rest of the world)

Phase III Clinical Trial Study BR.21


• Patients ≥ 18 years old with histologically or cytologically confirmed diagnosis of incurable Stage IIIB or IV NSCLC

• Received one but no more than two prior treatment (one of the treatment had to be a combination of chemotherapy)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3

• Adequate renal and hepatic functions

Study BR.21 requirements

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_StatR.PDFhttp://ecog.dfci.harvard.edu/general/perf_stat.html

http://ecog.dfci.harvard.edu/general/perf_stat.html

BR.21 trial process• Dose self-administered in the morning with up to

200ml of water an hour or two after ingestion of food or medications

• Increase in dosage not permitted• Treatment continued until progression of disease

or intolerable toxicityTarceva® arm Placebo arm

488 patients 243 patients

150mg/day tablet orally 150mg/day tablet orally


• The objective endpoint of the study was to compare the Overall Survival (OS) between the two study arm (Tarceva® vs. Placebo)

• Secondary endpoints included:– Progression-free-survival (PFS)– Response Rate– Response Duration– Quality of life (QoL)

OS was BR.21 trial primary endpoint


Efficacy was evaluated by:• Periodic assessments of survival and quality of life (QoL)

scores• Tumor measurement evaluated every 8 weeks • Safety assessed in every 4 weeks

Tarceva® reduced the risk of death by 27%


Eastern Cooperative Oncology Group (ECOG) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_admincorres.PDF

Tarceva® efficacy results

• Evaluation of positive epidermal growth factor receptor (EGFR) (defined as 10% of cells sustaining for EGFR) and negative EGFR

• Status was determined in 33% patients (238)• Tarceva® response rate on positive EGFR was

12% and 3% on negative EGFR

http://www.egfr.org/ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_admincorres.PDF

Tarceva® response rate on patients with positive EGFR


A post marketing Phase III study to evaluate the relationship between EGFR protein expression and clinical outcome:• Compared Tarceva® and Placebo as

maintenance treatment of patients with locally advanced or metastatic NSCLC following 4 cycles of platinum based chemotherapy

• 889 patients enrolled in a global, multicenter, randomized, double blinded, placebo-controlled study

Saturn Study evaluated the effect of EGFR protein and clinical outcome

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdf

Saturn divided into 2 study periods

The chemotherapy run period• Patients received first line platinum based

doublet chemotherapy

The study period • Patients received blinded Tarceva® or Placebo• 438 patients received Tarceva ™• 451 patients received a placebo


Saturn study requirements

• Patients with locally advanced Stage IIIB or metastatic (Stage IV) NSCLC

• Submission of formalin-fixed, paraffin-embedded tumor tissue samples within 3 weeks of starting chemotherapy

• ECOG performance status of 0-1 before and after chemotherapy

• Adequate hematopoietic and end-organ function

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM193921.pdfhttp://ecog.dfci.harvard.edu/general/perf_stat.html

PFS was Saturn study primary endpoint

• The primary objective endpoint for the study was progression-free-survival (PFS) —comparing Tarceva® to Placebo

• Secondary endpoint was Overall Survival (OS)


Saturn study met primary endpoint • Demonstrated a significant improvement in

assessed PFS in the overall population and with EGFR IHC-positive tumors

• PFS Improvements– 41% in overall population– 45% in EGFR IHC-positive population– Median PFS was 11.1 weeks in the

placebo arm vs. 12.3 weeks in the Tarceva® arm


Tarceva(N=438)

Placebo(N=451)

P valueHR/CI

Independent Reviewer

Time to event (weeks)Median (95% CI)

12.3(12.0-15.0)

11.1(7.7-11.9)

P=<0.0001HR 0.71

(0.61-0.84)

Investigator

Time to event (weeks)Median (95% CI)

12.3(12.0-15.0)

11.1(8.1-11.7)

P=<0.0001HR 0.71

(0.62-0.82)

Saturn study time to event results


Most adverse events associated with Tarceva® include rash and diarrhea, which are manageable

Tarceva® safety concerns

• A well tolerated, oral agent to maintain tumor regression from chemotherapy and to prolong time to progression for patients with NSCLC

• Alternative to intravenous maintenance therapy with a high toxicity profile

Tarceva® provides an unmet medical need

Tarceva® approval process

Tarceva® qualifies for Fast Track status

• For use with a serious disease non small cell lung cancer (NSCLC)

• Positively impacts survival, quality of life• Inhibits disease progression• Fills an unmet medical need by showing

superior effectiveness to available therapies

• First EGFR oral targeted agent for NSCLC


Tarceva® qualifies for a Rolling Review

• Fast Track status• Select group of innovative therapies• FDA began reviewing Tarceva®

components in January 2004 and ended in July 2004

http://www.accessmylibrary.com/coms2/summary_0286-20139832_ITM, “OSI, Genentech, Roche begin filing Tarceva rolling NDA”, BioWorld Week January 26, 2004

Tarceva® qualifies for Priority Review

http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/SpeedingAccesstoImportantNewTherapies/ucm128291.htm

• Fast Track status• Significant treatment advancement• Initial submission

• From FDA on November 18, 2004 for treatment of NSCLC after failure of at least 1 chemotherapy regimen

• Tarceva® approved under the Pilot Program for Continuous Marketing Applications

• Tarceva® demonstrated an increase in overall survival in advanced NSCLC patients

Tarceva® receives approval

http://www.osip.com/tarceva

Tarceva® application accepted for an sNDA

• On June 15, 2009, as a first-line maintenance therapy for patients with locally advanced or metastatic NSCLC

• Acceptance based on double-blind trial, SATURN

• Delivers effectiveness comparable to chemotherapy

• Significantly improves QOL without the toxic side effects of chemotherapy such as nausea and vomiting


Tarceva® reviewed by ODAC

• Oncologic Drugs Advisory Committee (ODAC) voted against recommending Tarceva® as a “switch” maintenance therapy

• FDA extended the review action on the sNDA to April 18, 2010

http://cancergrace.org/lung/2009/12/16/odac-says-no-to-maint-erlotinib/http://www.pharmastrategyblog.com/2010/01/fda-extends-review-period-for-tarceva-application-for-firstline-maintenance-use-in-advanced-nonsmall.html

Investigative Drug

• Multi-Tyrosine Kinase Inhibitor

• Inhibits tumor growth and blood supply

• Oral monotherapy

http://www.nelm.nhs.uk/en/NeLM-Area/News/493764/493843/493847 3-23-10

Investigative Drug: Proposed Indication

• Third line therapy for advanced NSCLC• Patients must have been previously

treated with 2 prior chemotherapeutic agents

• Tarceva® is currently the only approved drug for third line therapy


Who makes it to third line therapy?

• Controversy regarding purpose of third-line therapy

• Study done by Dr. Nicholas Girardi at Centre Hospitalier Universitaire de Besançon in France between 2000-2006

• 613 patients received first line chemotherapy for advanced NSCLC

• 173 (28%) went on to receive both second and third line therapy

http://cancergrace.org/lung/2009/11/24/who-benefits-from-third-line-treatment-for-advanced-nsclc 3-15-10

Center for Drug Evaluation & Research (CDER)

Office of Oncology Drug Products (OODP)

Director: Richard Pazdur, MD

Associate for Director of Regulatory Affairs:

Glen Jones, Ph. D

Division of Drug Oncology Products (DDOP)

Director: Robert Justice, MD

Deputy Director: Ann Farrell, MD

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm093910.htm5 April 2010

CDER Approval Statistics

26 new drugs in 2009• 7 biologics• 5 priority review

http://www.fiercebiotech.com/story/fda-approvals-2009/2010-01-25 4-5-10

OODP Statistics• 9 total oncology drugs in 2009

–3 Accelerated Approval• 53 oncology indications approved from July

2005 – December 2007–60 applications in total reviewed–18 indications for new drugs–35 indications for previously approved drugs–9 drugs received accelerated approval–25% of 53 new indications based on overall

survivalhttp://www.drugs.com/news/fda-cancer-approval-rate-highlighted-jnci-22743.html 4-4-10

Oncologic Drugs Advisory Committee (ODAC)

• 13 voters– One non-voter

• General, pediatric, hematologic, immunologic and several other oncology specialties represented

• L.T. Nicole Vesely, Pharm. D., R.Ph., Desingated Federal Official

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/default.htm 4-4-10

Previous ODAC meetings• March 2003 meeting with Astra Zeneca

regarding Iressa™– Confirmatory trial fails to support initial

accelerated approval

• December 2009 meeting with OSI Pharmaceuticals, Inc. regarding Tarceva®

– Inclusion of EGFR-negative population– “Switch Maintenance Therapy” rejected

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_01_01-AstraZeneca-Iressa.pdfhttp://cancergrace.org/lung/2009/12/16/odac-says-no-to-maint-erlotinib/4-4-10

Inclusion Criteria Exclusion Criteria

Stage IIIB or Stage IV NSCLC Brain Metastasis

All forms of NSCLC Bleeding disorders

Received at least two prior lines of therapy

CVA, MI, PE within the last year

At least one platinum-based chemotherapy

ECOG Performance status of 0-1

http://www.clinicaltrials.gov 3-20-10

• EGFR mutations– More likely to occur in:– Asian race– Women– Non-smokers– Patients with adenocarcinoma

• Prior use of tyrosine kinase inhibitors

Stratification

http://www.nelm.nhs.uk/en/NeLM-Area/News/493764/493843/493847 3-23-10http://www.medscape.com/viewarticle/714841 3-25-10

• Confirming less toxicity than chemotherapy

• Focus on dosing• Major focus on hematological effect on

patients• All regimens continue until disease has

progressed or severe toxicity has presented

Phase I: Safety


Phase II: Safety and Efficacy

• Primary endpoint: Overall Objective Response Rate (Partial and Complete Responses)– Shown to be that of 13.1%– 8 month duration of response– Improvement over Tarceva

• Secondary endpoints: Progression-Free Survival (PFS), Overall Survival (OS)

• Of 250 participants two Grade 5 events due to internal hemorrhage


Phase III: Risk vs. Benefit

• Confirmatory Trial for full approval• Investigative Drug vs. Tarceva® • Randomized double-blinded study in

1,200 patients• Improved overall survival


Designations

• Orphan Status?

NSCLC affects more than 200,000 people per year

• Fast Track? – Third line therapy for Stage IIIB and IV

NSCLC – Provides unmet medical need for patients with

serious life-threatening condition – Applied for Fast Track designation in Phase I

T. Class, In-Class Lecture, 1-11-10

Investigative Drug Approval Process

With fast track designation, priority review and accelerated approval may be offered• Priority Review? Has improved objective

response rate over Tarceva® • Accelerated Approval? Surrogate endpoint

of objective response rate in phase II trial reasonably predicts clinical benefit along with 8 month duration of response

T. Class, In-Class Lecture, 1-11-10

Conclusion

Investigative drug provides:• An unmet need• Monotherapy• Improved quality of life for patients with

third stage NSCLC• Alternative therapy to Tarceva®, which

most benefits EGFR positive patients

Who was the director FDA when Tarceva® was granted Fast Track Status?

Richard Padzur

How many drugs were granted Fast Track status the same year as

Tarceva® ?

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/FastTrackApprovalReports/ucm082382.htm

Was Tarceva® granted orphan status?

• No• Greater than 200,000 people are

diagnosed with NSCLC each year in the US

ECOG performance status

The Eastern Cooperative Oncology Group (ECOG) is one of the largest clinical cancer research organizations in the United States, and conducts clinical trials in all types of adult cancers.

http://ecog.dfci.harvard.edu/

http://ecog.dfci.harvard.edu/general/intro.html

Considerations for Future

• Trials conducted in Asian population in Asian countries vs. Asian population in the U.S.

• Lower smoking rate in Asian countries than U.S.

What is a nonsmoker?

A never-smoker is defined as under 100 cigarettes within life

http://www3.interscience.wiley.com/journal/123222528/abstract?CRETRY=1&SRETRY=0 3-30-10

Pediatric Population

Because advanced NSCLC has not shown to affect the pediatric population FDA can waive the requirement to test our investigative drug in children

Confidence Interval

Expected range of outcome: a range of statistical values within which a result is expected to fall with a specific probability

Encarta® World English Dictionary[North American Edition] © & (P) 2009 Microsoft Corporation.All rights reserved. Developed for Microsoft by Bloomsbury Publishing Plc.

Hazard Ratio

How often a particular event happens in one group compare to how often it happens in another group, over time. In cancer clinical trials it measures survival at any point in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less means that survival was better in one of the groups.

http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=618612

Investigative Drug

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