7/10/2017
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`Quick Minutes
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`U.S. Food and Drug Administration
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`Notice: Archived Document
`
`The content in this documentis provided on the FDA’s website for reference purposes
`only. It was current when produced, but is no longer maintained and may be outdated.
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`Summary Minutes of the
`Oncologic Drugs Advisory Committee
`December 16, 2009
`Location: Hilton Washington DC North/Gaithersburg, The Ballrooms, 620 Perry Parkway,
`Gaithersburg, Maryland
`
`All external requests for the meeting transcripts should be submitted to the CDER, Freedom of
`Informationoffice.
`
`These summary minutes for the December16, 2009 Meeting of the Oncologic Drugs Advisory
`Committee of the Food and Drug Administration were approved on
`___January 11, 2010
`
`I certify that I attended the December 16, 2009 meeting of the Oncologic Drugs Advisory
`Committee of the Food and Drug Administration and that these minutes accurately reflect
`whattranspired.
`
`/s/
`
`Nicole Vesely, Pharm.D.
`Designated Federal Official, ODAC
`
`/s/
`
`Wyndham Wilson, M.D.
`Acting Committee Chair
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`The Oncologic Drugs Advisory Committee of the Food and Drug Administration, Center for Drug Evaluation
`and Research met on December 16, 2009 at the Hilton Washington DC North/Gaithersburg, The Ballrooms, 620
`Perry Parkway, Gaithersburg, Maryland. Prior to the meeting, members and invited consultants were provided
`copies of the background material from the FDA andthe sponsor. The meeting wascalled to order by
`Wyndham Wilson, M.D. (Acting Committee Chair); the conflict of interest statement was read into the record
`by Nicole Vesely, Pharm.D. (Designated Federal Official). There were approximately 200 personsin
`attendance. There were three speakers for the Open Public Hearing session.
`
`Issue: On December 16, 2009, during the morning session, the committee met to discuss supplemental new
`drug application (SNDA) 021-743/S-016, TARCEVA(erlotinib) tablets, by OSI Pharmaceuticals, Inc. The
`proposedindication (use) for this productis first-line maintenance, monotherapy(first-choice, single drug)
`treatment in patients with a form of lung cancer called non-small cell lung cancer (NSCLC)thatis either
`locally advanced(has spread regionally within the lung and/or within chest lymph nodes) or metastatic (has
`spread beyondthe lung), and who havenotprogressed (including those patients with stable disease) on first-line
`treatment with platinum-based chemotherapy (a regimen including a platinum drug(cisplatin or carboplatin)
`plus another chemotherapy drug).
`
`Attendance:
`
`Oncologic Drug Advisory Committee MembersPresent (Voting):
`Ralph Freedman, M.D., Ph.D., William Kelly, D.O., Michael Link, M.D., Gary Lyman, M.D., M.P.H. Virginia
`Mason, R.N. (Consumer Representative), Ronald Richardson, M.D., Mikkael Sekeres, M.D., M.S., Margaret
`Tempero, M.D., Wyndham Wilson, M.D. (Acting Chair)
`
`Special Government Employee Consultants (Temporary Voting Members):
`Thomas Fleming, Ph.D., Steven H. Krasnow, M.D. Brent Logan, Ph.D., Pamela Moffitt (Patient
`Representative)
`
`Non-voting Participants:
`Richard Hubbard, M.D. (Acting Industry Representative)
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`Oncologic Drugs Advisory Committee MembersNotPresent:
`S. Gail Eckhardt, M.D.
`Jean Grem, M.D., F.A.C.P
`Patrick Loehrer, Sr., M.D.
`
`FDAParticipants (Non-Voting):
`Richard Pazdur, M.D., Robert Justice, M.D., John Johnson, M.D., Martin Cohen, M.D., Somesh
`Chattopadhyay, Ph.D.
`
`Designated Federal Official:
`Nicole Vesely, Pharm.D.
`
`Open Public Hearing Speakers:
`Peter Matloff
`
`Maureen Rigney, LICSW, Director of Community and Support Services, Lung Cancer Alliance
`Susan C. Mantel, Executive Director, Uniting Against Lung Cancer
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`2
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`Page 4
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`The agenda wasasfollows:
`
`Call to Order
`Introduction of Committee
`
`Wyndham Wilson, M.D.
`Acting Chair, ODAC
`
`Conflict of Interest Statement
`
`Nicole Vesely, Pharm.D.
`Designated Federal Official, ODAC
`
`Sponsor Presentation
`Introduction and Regulatory History
`
`OSI Pharmaceuticals, Inc.
`Karsten Witt, MD
`Senior Vice President
`
`Oncology Development
`OSI Pharmaceuticals,Inc.
`
`Federico Cappuzzo, MD
`Rationale for NSCLC Maintenance
`Therapy & SATURN:Study Design Principal Investigator, SATURN
`Professor and Vice Director
`
`Department of Medical Oncology
`Istituto Clinico Humanitas IRCCS
`
`Rozzano, Italy
`
`SATURN: Efficacy and Safety Results Angela Davies, MD
`Vice President
`
`Clinical Development
`OSI Pharmaceuticals,Inc.
`
`Paul Bunn,Jr., MD
`Dudley Professor
`University of Colorado CRIREEEEtter! 035-004
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`Lung Cancer: Maintenance Therapy
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`Concluding Remarks
`
`FDAPresentation
`
`Aurora, Colorado USA
`
`Karsten Witt, MD
`Senior Vice President
`
`Oncology Development
`OSI Pharmaceuticals, Inc.
`
`(sNDA) 021-743/S-016
`Martin Cohen, M.D.
`Medical Officer, Division of Drug Oncology
`Products
`
`(DDOP), OODP, OND, CDER, FDA
`
`Questionsto the Presenters
`
`Open Public Hearing
`
`Questions to the ODAC and ODACDiscussion
`
`Page 5
`
`Question to the Committee:
`
`Thefull question is included after the vote below for completeness.
`
`Question (VOTE)
`
`* The study was not optimally designed to demonstrate that maintenance therapy with erlotinib after
`
`initial chemotherapyis better than therapy with erlotinib at disease progression
`
`* Results of the study demonstrated a modest improvement in OS.
`
`VOTE: Based onthese results, should Erlotinib be approved for the proposed indication?
`
`PROPOSED INDICATION
`
`“Tarceva monotherapyis indicated asfirst-line maintenance treatment in patients with locally advanced or
`metastatic NSCLC who havenot progressed (including stable disease) on first-line treatment with platinum-
`based chemotherapy.”
`
`Vote:
`
`Yes=1
`
`No=12
`
`Abstain = 0
`
`¢ Members hadissues that there was only onetrial with a marginalfavorable survival
`
`improvement andfelt that this study had design flaws andlimitations because patients in the
`control arm were not offered Tarceva at disease progression.
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`¢ Members had difficulty determining whether maintenance treatment was as good as treatment at
`relapse based on the data presented.
`
`¢ Members agreed that the overall survival benefit was modest with most questioning whetherthis
`
`simply reflected access to Tarceva in the treatment arm. It was mentionedthat with other
`products currently on the marketthat the barforfuture products for review is higher.
`
`¢ It was noted that the study had a modest overall survival.
`
`¢ It was felt that the subgroupsthat would benefitfrom maintenance therapy neededto be studied
`
`further and defined. Some members questioned the use of Tarceva in patients who were EGFR
`(IH©) negative and those patients with squamouscell carcinoma.
`
`Please see the transcriptfor detailed discussion.
`
`The meeting adjourned @ approximately 2:30 p.m.
`
`Page 6
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`Question for the
`Oncologic Drugs Advisory Committee Meeting
`December16, 2009
`
`NDA 21743/S016
`
`Tarceva®(erlotinib) tablets oral
`Applicant: OSI Pharmaceuticals, Inc.
`
`PROPOSED INDICATION
`
`“Tarceva monotherapyis indicatedas first-line maintenance treatment in patients with locally advanced or
`metastatic NSCLC whohavenot progressed (including stable disease) onfirst-line treatment with platinum-
`based chemotherapy.”
`
`BACKGROUND
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`Onerandomizedtrial is submitted, comparing Erlotinib with Placebo (randomized 1:1) as maintenance
`treatment in 889 patients with locally advanced or metastatic NSCLC whohavenotprogressed after 4
`cycles offirst-line treatment with platinum-based chemotherapy. Patients were stratified prior to
`randomization, using the adaptive method of Pocock and Simon,to ensure balance between treatment
`groups for EGFRprotein expression by IHC (EGFRPositive versus EGFR Negative versus EGFR
`Undetermined); Stage of disease at start of chemotherapy(IIIb versus IV); ECOG PS (0 versus1);
`Chemotherapy regimen (gemcitabine pluscisplatin versus carboplatin plus docetaxel versus other);
`Smokingstatus (current smoker[includes patients who had stopped smoking within a year] versus former
`smoker versus never smoked); and Region (North America, South America, Western Europe, Eastern
`Europe, South East Asia and Africa). All patients were required to provide a tumor sample for analysis of
`EGFRprotein expression by IHC. Treatment was continued until progression, death or unacceptable
`toxicity.
`
`The protocol specified co- primary endpoints are progression-free survival (PFS)in all patients and PFS in
`the EGFR (IHC)Positive subgroup. At a Special Protocol Assessment on 4/20/05 the FDA indicated that
`“To demonstrate the value of maintenance targeted therapy superiority of survival will have to be
`demonstrated”. The study was conductedentirely outside of the United States.
`
`Erlotinib is superior to Placebo for both co-primary endpoints, i.e., PFS in all patients and PFS in the EGFR
`(IHC)Positive subgroup. Using the protocol-specified unadjusted Log Rank Test, Erlonitib is also superior
`to Placebo for overall survival (OS) in all patients and in the EGFR (IHC)Positive subgroup. Using the
`Stratified Log Rank Test, Erlotinib is not superior to Placebo for OS.
`
`A confirmatory OSanalysis was performed, censoring at the date of first open-label Erlotinib or second or
`further line Tyrosine Kinase Inhibitor (TKI) treatment. The HRin this analysis is 0.80 versus 0.81 in ITT
`analysis. The LR in this analysis is p=0.0087 versus p=0.0088 in the ITT analysis.
`
`PFS and OSresults are shown in Table 1.
`
`Page 7
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`Table 1 PFS and OSResults
`
`PLACEBO
`N
`
`ERLOTINIB
`N
`
`DIFFERENCE
`IN MEDIANS
`
`Median (Mo)
`
`Median (Mo)
`
`(Mo)
`
`HR (95% CT)
`LR P Value
`
`Unadjusted
`
`Progression-Free Survival
`All Patients
`
`+
`EGER (HC +)
`EGER(IHC) —
`
`EGFR Mutation +
`(PFS Cut-Off)
`EGFR Mutation +
`(OS Cut-Off)
`
`
`
`N=451
`2.6
`N=313
`2.6
`N=59
`2.1
`N=27
`3.0
`N=27
`3.0
`
`N=438
`2.8
`N=308
`2.8
`N=62
`2.5
`N=22
`10.3
`N=22
`11.0
`
`02
`
`.
`0.2
`0.4
`
`74
`‘
`8
`
`0.71 (0.62,0.82)
`p<0.0001
`0.69 (0.58,0.82)
`p<0.0001
`0.77 (0.51,1.14)
`p=0.1768
`0.10 (0.04,0.25)
`p<0.0001
`0.23 (0.12,0.45)
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`0.8
`
`1
`
`'
`
`1.8
`
`0.5
`
`02
`-0.
`
`11
`
`23
`.
`
`02
`
`15
`
`32
`,
`
`0.78 (0.63,0.96)
`p=0.0182
`
`0.81 (0.70,0.95)
`p=0.0088
`0.85 (0.71,1.02)
`p=0.0839 *
`0.77 (0.64,0.93)
`p=0.0063
`0.91 (0.59,1.38
`p=0.6482
`1.01 (0.47-2.16)
`p=0.9870
`0.77 (0.61,0.97)
`p=0.0243
`0.77 (0.61,0.97)
`p=0.0249
`0.86 (0.68,1.10)
`p=0.2369
`0.85 (0.57,1.27)
`p=0.4219
`0.79 (0.64,0.96)
`P=0.0194
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`7/10/2017
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`EGER Mutation —
`PFS Cut-Off)
`Overall Survival
`All Patient:
`atients
`
`All patients
`Stratified LR
`
`EGFR(IHC +
`(
`EGER(IHC -)
`
`)
`
`+
`
`EGRF Mutation
`ation
`.
`EGRF Mutation —
`
`Ad
`
`enoca
`
`Squamous
`q
`Other NSCLC
`
`Non-Squamous
`
`*Stratified LR Test
`
`N=189
`2.0
`
`N=451
`11.0
`N=451
`11.0
`N=313
`11.0
`N=59
`11.1
`N=27
`23.8
`N=189
`10.2
`N=198
`11.6
`N=194
`Wd
`N=59
`9.1
`N=257
`10.5
`
`N=199
`2.8
`
`N=438
`12.0
`N=438
`12.0
`N=308
`12.8
`N=62
`10.6
`N=22
`23.6
`N=199
`11.3
`N=205
`13.9
`N=166
`113
`67
`10.6
`N=272
`13.7
`
`6
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`Page 8
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`Figure 1 PFSin All Patients
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`Applicant Figure
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`Page 9
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`Figure 2 PFS in EGFR (IHC)Positive Subgroup
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`Applicant Figure
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`Page 10
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`Figure 3 OSin All Patients
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`Page 11
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`Figure 4 OS in EGFR (IHC) Positive Subgroup
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`Applicant Figure
`
`Main Issue
`
`The main issue concernsother available treatment options for patients in this randomizedtrial. Both single
`agent Erlotinib and Docetaxel are approved for treatment of NSCLCafter failure of prior chemotherapy.
`Erlotinib and Docetaxel havea statistically significant improvement in median survival over Placebo of 2-3
`monthsin this setting, compared to a 1 month improvement in median survivalin the Erlotinib versus
`Placebo maintenancetrial (See Table 2). In both the Erlotinib and Docetaxeltrials after failure of prior
`chemotherapy, the treated population is more difficult than in the Erlotinib maintenancetrial. This is
`because the population includes both responders and non-respondersto initial chemotherapy, while the
`Erlotinib maintenancetrial includes only respondersorstable disease. In addition, Pemetrexed wasrecently
`approved for maintenance therapy of non-squamouscell NSCLC in patients who did not progress on
`platinum-basedinitial chemotherapy based on a 5 month improvementin median survival (See Table 5).
`This raises the question whether treatment with single agent Erlotinib or Docetaxel after progression or
`Pemetrexed maintenancetherapyare better options than treatment with Erlotinib as maintenance.
`
`Table 2 NSCLC After Failure of Prior Chemotherapy
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`10
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`Page 12
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`Median Survival TopeORanxkex Vedee-012Diff in Hazard Ratio
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`Erlotinib
`Placebo
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`Docetaxel
`BSC
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`(mo)
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`6.7
`4.7
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`75
`4.6
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`Quick Minutes
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`Medians
`(mo)
`2
`
`(95% CD
`
`Unadjusted
`
`0.73 (0.61-0.86)
`
`<0.001
`
`2.9
`
`0.56 (0.35-0.88)
`
`0.01
`
`Other Issues
`
`Although Erlonitib is superior to Placebo in the maintenancestudy, the findings in some subgroups may be
`issues for the wording of any approvedindication or other sections in the packageinsert. Thefirst issue is
`that the OS HR in the EGFR (IHC) Negative subgroupis 0.91. Notably in the Erlotinib advanced NSCLC
`trial after failure of at least one prior chemotherapy regimen, the OS HRof Erlonitib versus Placebo was
`1.01 in the EGFR (IHC) Negative subgroup (See Table 3). Thus Erlonitib appears to have at best a weak OS
`effect in this subgroup. This raises the question whether the EGFR (ICH) Negative subgroup should be
`included in any approval.
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`11
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`Table 3 NSCLC EGFR (IHC) Negative Subgroup
`
`Median
`Survival
`(mo)
`
`Diff in
`Medians
`(mo)
`
`Hazardratio
`(95%CI)
`
`Log Rank P
`Value
`Unadjusted
`
`10.6
`11.1
`
`5.35
`75
`
`-0.5
`
`0.91 (0.59-1.38)
`
`0.6482
`
`-2.15
`
`1.01 (0.7-1.6)
`
`0.958
`
`Maintenance
`
`Erlotinib
`Placebo
`
`Failure at least one
`
`prior chemotherapy
`Erlotinib
`Placebo
`
`The secondissueis that in the squamouscell subgroup of the Erlotinib maintenancetrial the Erlonitib
`effect on OS is very modest with median OS Erlotinib 11.3 months and Placebo 11.1 months, HR 0.86
`(0.68,1.10), p=0.2369. Pemetrexedis the only drug approved for maintenance treatment of patients with
`locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based
`first-line chemotherapy. Pemetrexed is approved for maintenanceonly in the non-squamouscell subgroup
`(Approved 7/2/09). In the trial with all histological subgroups the median OS wasPlacebo 10.6 months and
`Pemetrexed 13.4 months, HR=0.79 (0.65, 0.95), LR p=0.012. In the squamouscell subgroup median OS
`was Placebo 10.8 months and Pemetrexed 9.9 months, HR 1.07 (0.77,1.50), LR p=0.23 (See Table 4). This
`raises the question whether the squamouscell subgroup should be included in any approval. However, when
`Erlotinib was compared with Placebo after NSCLC progression on prior chemotherapy,in the squamous
`cell subgroup the HR=0.67 (0.5-0.9) favoring Erlotinib.
`
`Table 4 SquamousCell Subgroup Maintenance Rx
`
`Median
`Survival
`(mo)
`11.3
`11.1
`
`9.9
`10.8
`
`Diff in
`Medians
`(mo)
`0.2
`
`Hazard Ratio
`(95% CI)
`
`0.86 (0.68-1.10)
`
`Log Rank P
`Value
`Unadjusted
`0.2369
`
`-0.9
`
`1.07 (0.77-1.50)
`
`0.23
`
`Erlotinib
`Placebo
`
`Pemetrexed
`Placebo
`
`In the Erlotinib Maintenancetrial in the non-squamouscell subgroup median OS was Placebo 10.5 months
`and Erlotinib 13.7 months, HR 0.79 (0.64-0.96). In the Pemetrexed Maintenancetrial in the non-squamous
`cell subgroup OS wasPlacebo 10.3 months and Pemetrexed 15.5 months, HR 0.7 (0.56-0.88) (See Table 5).
`This raises the question whether any Erlotinib approval should be limited to only the non-squamouscell
`subgroup.
`
`Table 5 Non-SquamousCell Subgroup Maintenance Rx
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`Median
`Survival
`(mo)
`13.7
`10.5
`
`15.5
`10.3
`
`Diff in
`Medians
`(mo)
`3.2
`
`Hazard Ratio
`(95% CI)
`
`0.79 (0.64-0.96)
`
`Log Rank P
`Value
`Unadjusted
`0.0194
`
`5.2
`
`0.70 (0.56-0.88)
`
`0.0020
`
`Erlotinib
`Placebo
`
`Pemetrexed
`Placebo
`
`Thethird issue is that although Erlotinib has a large improvement in PFS (HR=0.10) in the EGFR
`Mutation Positive subgroup,this is not reflected in OS (HR=1.01) (See Table 6). This disparity may be
`partly accountedfor by the lack of mature survival data in the EGFR Mutation Positive subgroup (55%
`dead) becauseof the longer survival in this subgroup. However, it seems unlikely the results will change
`greatly with more events.
`
`The Applicantattributes the lack of an Erlotinib OS effect to subsequent systemic therapy at progression.
`After progression any subsequent systemic therapy was given to 89% of patients in the Placebo group and
`73% of patients in the Erlotinib group. After progression TKI therapy was given to 70% ofpatients in the
`Placebo group and 27% ofpatients in the Erlotinib group.
`
`The Applicant’s argument that in the EGFR Mutation + subgroup, OSin the Placebo groupis prolongedto
`equal OS in the Erlotinib group by Tyrosine Kinase Inhibitor treatment at progression contradicts the
`Applicant’s claim that Erlotinib maintenancehasclinical benefit.
`
`https://webcache.googleusercontent.com/search?q=cache:ViK53b79t6cJ:https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingM...
`
`15/17
`
`13
`
`APOTEX EX. 1035-015
`
`APOTEX EX. 1035-015
`
`

`

`7/10/2017
`
`Quick Minutes
`
`Page 15
`
`Table 6 EGFR Mutation Positive Subgroup
`
`PFS
`
`Median (mo)
`
`Erlotinib
`Placebo
`
`os
`
`Erlotinib
`Placebo
`
`10.3
`3.0
`
`23.6
`23.8
`
`Diff in
`Medians
`
`(mo)
`73
`
`Hazard Ratio
`
`0.10 (0.04-0.25)
`
`Log Rank P
`Value
`
`Unadjusted
`<0.0001
`
`-0.2
`
`1.01 (0.47-2.16)
`
`0.99
`
`The EGFR Mutation Positive subgroup is a small minority of NSCLC patients in this study. Only 11% of
`patients with known EGFR Mutation status were EGFR Mutation Positive. Additional follow-up is needed
`in this subgroup.
`
`The fourth issueis that in the Erlotinib trial in patients with advanced NSCLCafter failure of at least one
`prior chemotherapy regimen, 47% ofthe patients with known EGFR (IHC) status were EGFR (IHC)
`Negative. However, in the Erlotinib maintenancetrial only 16% of patients with known EGFR (IHC)status
`were EGFR (IHC) Negative. This apparent discrepancy is concerning. We can not have personalized
`therapyif the tests are notreliable.
`
`Bevacizumabis approvedfor treatment of locally advanced, metastatic or recurrent non-squamous NSCLC
`in combination with carboplatin and paclitaxel for 6 cycles and Bevacizumabcontinuesalone after 6 cycles
`until progression or unacceptable toxicity (approved 10/11/06). There was no randomizationatthestart of
`the maintenance phase,so there are no data supporting Bevacizumab for maintenance therapy.
`
`https://webcache.googleusercontent.com/search?q=cache:ViK53b79t6cJ:https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingM...
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`16/17
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`APOTEX EX. 1035-016
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`APOTEX EX. 1035-016
`
`

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`7/10/2017
`
`Quick Minutes
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`14
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`https://webcache.googleusercontent.com/search?q=cache:ViK53b79t6cJ:https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingM...
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`17/17
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`APOTEX EX. 1035-017
`
`APOTEX EX. 1035-017
`
`