7/10/2017
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`Quick Minutes
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`US. Food and Drug Administration
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`Notice: Archived Document
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`The content in this document is provided on the FDA’s website for reference purposes
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`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 It was current when produced, but is no longer maintained and may be outdated.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
`Information office.
`
`These summary minutes for the December 16, 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
`what transpired.
`
`_/s/
`Nicole Vesely, PharmD.
`Designated Federal Official, ODAC
`
`/s/
`Wyndham Wilson, MD.
`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 and the sponsor. The meeting was called to order by
`Wyndham Wilson, MD. (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 persons in
`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
`proposed indication (use) for this product is first-line maintenance, monotherapy (first-choice, single drug)
`treatment in patients with a form of lung cancer called non-small cell lung cancer (NSCLC) that is either
`locally advanced (has spread regionally within the lung and/or within chest lymph nodes) or metastatic (has
`spread beyond the lung), and who have not progressed (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 Members Present (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, MD. (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 Members Not Present:
`S. Gail Eckhardt, M.D.
`Jean Grem, M.D., F.A.C.P
`Patrick Loehrer, Sn, M.D.
`
`FDA Participants (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
`
`Page 4
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`The agenda was asfollows:
`
`Call to Order
`Introduction of Committee
`
`Conflict of Interest Statement
`
`Sponsor Presentation
`Introduction and Regulatory History
`
`Wyndham Wilson, MD.
`Acting Chair, ODAC
`
`Nicole Vesely, Pharm.D.
`Designated Federal Official, ODAC
`
`OSI Pharmaceuticals, Inc.
`Karsten Witt, MD
`Senior Vice President
`
`Oncology Development
`OSI Pharmaceuticals, Inc.
`
`Rationale for NSCLC Maintenance
`
`Federico Cappuzzo, MD
`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
`
`Lung Cancer: Maintenance Therapy
`
`Clinical Development
`OSI Pharmaceuticals, Inc.
`
`Paul Bunn, Jr., MD
`
`Dudley Professor
`
`University of Colorado gwfiggen 047_004
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`Concluding Remarks
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`FDA Presentation
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`Aurora, Colorado USA
`
`Karsten Witt, MD
`Senior Vice President
`
`Oncology Development
`081 Pharmaceuticals, Inc.
`
`(sNDA) 021-743/S-016
`Martin Cohen, MD.
`Medical Officer, Division of Drug Oncology
`Products
`
`(DDOP), OODP, OND, CDER, FDA
`
`Questions to the Presenters
`
`Open Public Hearing
`
`Questions to the ODAC and ODAC Discussion
`
`Page 5
`
`Question to the Committee:
`
`The full 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 chemotherapy is better than therapy with erlotinib at disease progression
`
`0 Results of the study demonstrated a modest improvement in OS.
`
`VOTE: Based on these results, should Erlotinib be approved for the proposed indication?
`
`PROPOSED INDICATION
`
`“Tarceva monotherapy is indicated as first-line maintenance treatment in patients with locally advanced or
`metastatic NSCLC who have not progressed (including stable disease) on first-line treatment with platinum-
`based chemotherapy.”
`
`Vote :
`
`Yes=1
`
`N0 = 12
`
`Abstain = 0
`
`~ Members had issues that there was only one trial with a marginalfavorable survival
`
`improvement andfelt that this study had design flaws and limitations because patients in the
`control arm were not oflered Tarceva at disease progression.
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`~ Members had difliculty 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 whether this
`
`simply reflected access to Tarceva in the treatment arm. It was mentioned that with other
`products currently on the market that the barforfuture productsfor review is higher.
`
`~ It was noted that the study had a modest overall survival.
`
`~ It was felt that the subgroups that would benefitfrom maintenance therapy needed to be studied
`
`further and defined. Some members questioned the use of Tarceva in patients who were EGFR
`(IHC) negative and those patients with squamous cell carcinoma.
`
`Please see the transcriptfor detailed discussion.
`
`The meeting adjourned @ approximately 2:30 pm.
`
`Page 6
`
`Question for the
`Oncologic Drugs Advisory Committee Meeting
`December 16, 2009
`
`NBA 21743/8016
`
`Tarceva® (erlotinib) tablets oral
`Applicant: OSI Pharmaceuticals, Inc.
`
`PROPOSED INDICATION
`
`“Tarceva monotherapy is indicated as first-line maintenance treatment in patients with locally advanced or
`metastatic NSCLC who have not progressed (including stable disease) on first-line treatment with platinum-
`based chemotherapy.”
`
`BACKGROUND
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`One randomized trial is submitted, comparing Erlotinib with Placebo (randomized 1:1) as maintenance
`treatment in 889 patients with locally advanced or metastatic NSCLC who have not progressed after 4
`cycles of first-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 EGFR protein expression by IHC (EGFR Positive versus EGFR Negative versus EGFR
`Undetermined); Stage of disease at start of chemotherapy (IIIb versus IV); ECOG PS (0 versus 1);
`Chemotherapy regimen (gemcitabine plus cisplatin versus carboplatin plus docetaxel versus other);
`Smoking status (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
`EGFR protein expression by IHC. Treatment was continued until progression, death or unacceptable
`toxicity.
`
`The protocol specified 00- 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 conducted entirely 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 OS analysis was performed, censoring at the date of first open-label Erlotinib or second or
`further line Tyrosine Kinase Inhibitor (TKI) treatment. The HR in 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 OS results are shown in Table 1.
`
`Page 7
`
`Table 1 PFS and OS Results
`
`PLACEBO
`N
`
`ERLOTINIB
`N
`
`DIFFERENCE
`IN MEDIANS
`
`Median (Mo)
`
`Median (M0)
`
`(M0)
`
`Progression-Free Survival
`
`All Patients
`
`+
`EGFR (IHC )
`
`EGFR (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
`
`0.2
`
`.
`0 2
`
`04
`
`7 3
`'
`
`8
`
`HR ( 95% CI)
`LR P Value
`
`Unadjusted
`
`0.71 (062,082)
`p<0.0001
`0.69 (058,082)
`p<0.0001
`
`0.77 (0.51,1.14)
`p=0.1768
`
`0.10 (004,025)
`p<0.0001
`
`0.23 (0.12,0.45)
`p>0.0001
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`03
`
`1
`
`l
`
`.
`1 8
`
`—0.5
`
`0 2
`‘
`
`'
`
`1.1
`
`.
`2 3
`
`0 2
`'
`
`1.5
`
`3 2
`‘
`
`0.78 (0.63 0.96)
`p=0.01’82
`
`0.81 (070,095)
`p=0.0088
`
`0.85 (071,102)
`p=0.0839 *
`0.77 (0.64,0.93)
`p=0.0063
`0.91 (059,138
`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 (057,127)
`p=0.4219
`
`0.79 (0.64,0.96)
`P=0.0194
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`7/10/2017
`
`Quick Minutes
`
`EGFR Mutation —
`PFS Cut-0ft)
`Overall Survival
`
`,
`All Pane“
`
`All patients
`Stratified LR
`
`+
`EGFR (IHC )
`
`)
`
`EGFR IHC —
`(
`EGRF M t t,
`u 3 Ion
`
`+
`
`EGRF Mutation _
`
`Ad
`
`n a
`6 0°
`
`S uamous
`q
`
`OtherNSCLC
`
`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
`11.1
`
`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
`11.3
`
`67
`10.6
`
`N=272
`13.7
`
`6
`
`Page 8
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`Figure 1 PFS in 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 OS in All Patients
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`Applicant Figure
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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 concerns other available treatment options for patients in this randomized trial. Both single
`agent Erlotinib and Docetaxel are approved for treatment of NSCLC after failure of prior chemotherapy.
`Erlotinib and Docetaxel have a statistically significant improvement in median survival over Placebo of 2-3
`months in this setting, compared to a 1 month improvement in median survival in the Erlotinib versus
`Placebo maintenance trial (See Table 2). In both the Erlotinib and Docetaxel trials after failure of prior
`chemotherapy, the treated population is more difficult than in the Erlotinib maintenance trial. This is
`because the population includes both responders and non-responders to initial chemotherapy, while the
`Erlotinib maintenance trial includes only responders or stable disease. In addition, Pemetrexed was recently
`approved for maintenance therapy of non-squamous cell NSCLC in patients who did not progress on
`platinum-based initial chemotherapy based on a 5 month improvement in median survival (See Table 5).
`This raises the question whether treatment with single agent Erlotinib or Docetaxel after progression or
`Pemetrexed maintenance therapy are better options than treatment with Erlotinib as maintenance.
`
`Table 2 NSCLC After Failure of Prior Chemotherapy
`
`10
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`Median Survival
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`Diff in
`
`Hazard Ratio
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`Log Rank P Value
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`Erlotinib
`Placebo
`
`Docetaxel
`BSC
`
`(mo)
`
`6.7
`4.7
`
`7.5
`4.6
`
`Quick Minutes
`
`Medians
`(mo)
`2
`
`(95% CI)
`
`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 maintenance study, the findings in some subgroups may be
`issues for the wording of any approved indication or other sections in the package insert. The first issue is
`that the OS HR in the EGFR (IHC) Negative subgroup is 0.91. Notably in the Erlotinib advanced NSCLC
`trial after failure of at least one prior chemotherapy regimen, the OS HR of 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.
`
`11
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`Table 3 NSCLC EGFR (IHC) Negative Subgroup
`
`Median
`Survival
`(mo)
`
`Diff in
`Medians
`(m0)
`
`Hazard ratio
`(95%CI)
`
`Log Rank P
`Value
`Unadjusted
`
`10.6
`1 1 . 1
`
`5.35
`7.5
`
`-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 second issue is that in the squamous cell subgroup of the Erlotinib maintenance trial the Erlonitib
`effect on OS is very modest with median OS Erlotinib 11.3 months and Placebo 11.1 months, HR 0.86
`(O.68,1.10), p=0.2369. Pemetrexed is 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 maintenance only in the non-squamous cell subgroup
`(Approved 7/2/09). In the trial with all histological subgroups the median OS was Placebo 10.6 months and
`Pemetrexed 13.4 months, HR=0.79 (0.65, 0.95), LR p=0.012. In the squamous cell 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 squamous cell 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 Squamous Cell Subgroup Maintenance Rx
`
`Median
`Survival
`(mo)
`11.3
`1 1. 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 Maintenance trial in the non-squamous cell subgroup median OS was Placebo 10.5 months
`and Erlotinib 13.7 months, HR 0.79 (0.64-0.96). In the Pemetrexed Maintenance trial in the non-squamous
`cell subgroup OS was Placebo 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-squamous cell
`subgroup.
`
`Table 5 Non-Squamous Cell Subgroup Maintenance Rx
`
`12
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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
`
`The third 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 accounted for by the lack of mature survival data in the EGFR Mutation Positive subgroup (55%
`dead) because of the longer survival in this subgroup. However, it seems unlikely the results will change
`greatly with more events.
`
`The Applicant attributes 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% of patients in the
`Placebo group and 27% of patients in the Erlotinib group.
`
`The Applicant’s argument that in the EGFR Mutation + subgroup, OS in the Placebo group is prolonged to
`equal OS in the Erlotinib group by Tyrosine Kinase Inhibitor treatment at progression contradicts the
`Applicant’s claim that Erlotinib maintenance has clinical benefit.
`
`https://webcache.goog|eusercontent.com/search?q=cache:ViK53b79t60J :https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingM . ..
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`15/17
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`13
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`APOTEX EX. 1047-015
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`APOTEX EX. 1047-015
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`7/10/2017
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`Quick Minutes
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`Page 15
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`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)
`7.3
`
`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 issue is that in the Erlotinib trial in patients with advanced NSCLC after failure of at least one
`prior chemotherapy regimen, 47% of the patients with known EGFR (IHC) status were EGFR (IHC)
`Negative. However, in the Erlotinib maintenance trial only 16% of patients with known EGFR (IHC) status
`were EGFR (IHC) Negative. This apparent discrepancy is concerning. We can not have personalized
`therapy if the tests are not reliable.
`
`Bevacizumab is approved for treatment of locally advanced, metastatic or recurrent non-squamous NSCLC
`in combination with carboplatin and paclitaxel for 6 cycles and Bevacizumab continues alone after 6 cycles
`until progression or unacceptable toxicity (approved 10/11/06). There was no randomization at the start of
`the maintenance phase, so there are no data supporting Bevacizumab for maintenance therapy.
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`https://webcache.goog|eusercontent.com/search?q=cache:ViK53b79t60J :https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingM . ..
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`16/17
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`APOTEX EX. 1047-016
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`APOTEX EX. 1047-016
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`7/10/2017
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`Quick Minutes
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`14
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`17/17
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`APOTEX EX. 1047-017
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`APOTEX EX. 1047-017
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`