ANTIFOLATE ADVISORY PANEL
`Minutes of Meeting
`March 16, 1998
`Ixtapa, Mexico
`
`CONFIDENTIAL
`
`Panel Participants
`
`Carmel Allegra
`Robert Allen
`Joseph Bertino
`Hilary Calvert
`James Carmichael
`Karin Mattson
`Enrico Mini
`Jean Louis Misset
`Herbie Newell
`PeterO'Dwyer
`Louis Paz-Ares
`Hans Schmoll
`
`Panel Discussion Leader
`
`Jackie Walling (Lilly)
`
`Investigator Participants
`
`Stephen Clarke
`
`Lilly Attendees
`
`Marilyn Arnett, Johannes Blatter, Victor Chen, Stephen Clarke, Dawn Gardner, Steve
`Hamburger, Içim Hartsock, Constanza Ilardi, Robert Johnson, Louis Kayitalire, Diana
`Kelley, Sean McCarthy, Mark Miller, Katrina Nelson, Robin Nelson-Rice, Steve Nicol,
`Clet Niyikiza, Angela Panadero, Angela Ribecco, Michael Scott, Julia Stickland, Adrian
`Thomas, Jerry Thompson, Don Thornton, Donna Watts
`
`cc of minutes: Rick Schilsky, Dan Von Hoff, meeting participants, MTA Product Team
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`MINUTES OF MEETING:
`
`The primary objectives of this meeting were to obtain input from the Panel on the fastest
`route to MTA registration, and to consider the prioritization of the ongoing and planned
`clinical trials. These objectives were related to the mission/vision/strategic intent
`statements for the project These statements include speed to market as the initial
`registration olecfive with parallel development of several indications in different clinical
`settings as a means of accomplishing this objective, and maximizing the value of MTA in
`the treatment of cancer. Activity of MTA has been demonstrated in a number of areas,
`and there are insufficient resources to bring all of the possibilities forward to:registration
`atthistime.
`
`Discussion fobused on NSCLC, breast cancer, mesothelioma, cervical cancer, head and
`neck cancer, bladder cancer, renal cancer, and pancreatic cancer. Generally, discussion
`for each indication was initiated with a marketing overview, followed by clinical data,
`clinical plans and development/registration strategies.
`
`Non-Small cell lung cancer (NSCLC)
`
`Marketing
`Market research data from the u.sJ
`on the incidence and treatment of 1' and 2" line NSCLC
`Redacte d
`were provided by Lilly. These data were approximately one year old and involved a data
`base of 60 physicians (20 patients per physician) in each country.
`
`Redacted
`
`Redacted
`
`Redacted
`
`Other drugs that may be used at the time of an MTA
`launqh could becajecitabine and CPT-1 1. Taxotere is available in Europe and is being
`used in NSCLC aM ough not currently approved for this indication.
`
`NSCLC 7' line - Clinical Studies/Plans
`An approach that is being considered by Lilly to achieve rapid registration involves Phase
`2/3 studies in 2nd line NSCLC. If this option does not accomplish a speed-to-market
`objective, these studies may not be pursued at this time.
`
`A Phase 2 study (JMBR) in patients who have received one prior chemotherapy regime
`with or without platinum has been initiated (Europe), but it is too early to provide
`response data. Another proposed study (JMBQ, U.S.) in platinuin/taxane failures is
`planned. This latter study is designed as a pivotal U.S. registration study, with the
`objective of determining MTA activity in a 2" line setting, gaining speed to registration
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`through a single Phase 2/3 study, and asking if vitamin supplementation has an effect on
`the toxicity of MTA in this group of patients.
`
`Panel input to this study design was requested. The following summarizes
`recommendations from that discussion:
`The suggested Phase 2/3 study design compares MTA, MTA + vitamins
`(vitamins are 1mg folic acid, 25mg B6, and 2mg B12), and Navelbine. In
`the initial phase II portion of the study response rate will be used as the hurdle
`and flP will be the primary endpoint of the study. There was considerable
`debate about the designof the study, and Jim Carmichael felt that it might be
`premature, given our understanding of the toxicity of the compound. Peter 0'
`Dwyer felt that the interim hurdle should be based on flP also.
`The MTA dose of 600 mg(m2, decreasing if necessary, rather than.starting
`with the 500 mg/m2 was recommended. To date, there is no evidence of a
`clinical dose-response relationship between the 500 nig/m2 and 600 mg/m2
`dosage levels. However, it also is too early to conclude that there is no
`àlinical difference betweenthe two dosages.
`Pharmacokinetic studies (real time) were suggested to expand our knowledge
`of MTA's toxicity profile.
`If a minimum response rate is achieved in the MTA- and MTA/vitamin-
`treated patients (a 10% rdsponse rate in the 2 arms combined), a decision of
`'which of the two MTA a*fis to carry forward into a standard Phase 3 study
`will be determine 4 on ;thél asis of the relative toxicity profiles between the
`two arms. The decisiOfi théldng criteria need to be defined up front in the
`protocol.
`There will be balancing oKpatients in this study for prognostic factors (e.g.
`performance status, homoçysteine levels, investigator sites) so that the
`treatment effect can beevaluated. Approximately 540 patients will be
`nrolled in the Phase 2(3 study.
`Navelbine was the recdniended comparator, although there was considerable
`cOncern about obtaining signed informed consents/fiB approvals in a study
`involving Navelbinó sincel this dmg is not approved for 2nd line NSCLC and
`has been shown to be infive in 2 line in terms of response rates. It'was
`pointed out, however, that no chemotherapeutic agent cunently is approved in
`21(1 line, and that Navelbine is used routinely at some stage of atpatient's
`disease (U.S. mentioned specifically), with a substantial number of patients
`deriving benefit (e.g. improvement of symptoms). It will be important to
`utilize a comparator that offers effective treatment, even if is this comparator
`is not approved. The choice of the comparator as well as other ,rotocol
`parameters will be discussed with the FDA when the Phase 2/3development
`plans are reviewed.
`The endpoints agreed to by the Panel were time to progression as the primary
`endpoint, with an index of palliation (e.g. clinical benefit, quality of life) and
`median duration of survival as secondary endpoints. Response rates were not
`considered critical, nor a good surrogate for palliation.
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`The estimate of enrolling 540 patients in 1 year for the above study was considered
`reasonable in view of the Panel's and Lilly's experiences. The. first patient visit was
`estimated as June, 1998 with a U.S. submission/approval in Q4001Q30i (assuming that
`necessary safety data for selection of an MTA arm and efficacy data are available and that
`enrollment into the Phase 3 portion of the study will not be delayed.)
`
`The Panel felt that there currently was insufficient information to know the activity of
`MTA in 2'
`line NSCLC, and agreed that additional studies in this patient population
`were warranted.
`
`NSCLC 1st line - Clinical Studies/Plans
`Lilly's two Phase 2 studies (chemonaive, Stage 3 and 4) have indicated response rates of
`23%, median survival 9.2 months (JMAO, n=30) and 17%, median survival 7.5 months4
`(JMAL,: n35) (these data are heavily, censored, with several patients remaining on
`study). Another Phase 2 study in NSCLC (JMAY) involves combination cisplatin (75
`mg/m2)ind MTA (500 mg/m2) every 21 days. Responses have been reported in this
`study, but it is too early to detenuine response rates.
`
`The Panel agreed that MTA had shown activity in 1' line NSCLC, but that additional
`efficacy and safety data were needed before strategic discussions could be made, given
`thecompetition in this indication.
`
`Because the MTA combination Phase 1 studies with cisplatin will be completed prior to
`combination studies with other possible combination agents, the combination of MTA
`and cisjilatin may offer a means of securing the most rapid route to registration in l' line
`NSCLC. The advisors, however, generally did not favor proceeding with this
`combination. Carboplatin was the favored combination agent, although a number of
`combinMions including carboplatinTaxol, cisplatin Taxol, gemeitahine cisplatin and
`cisplàtii Taxotere are currently being compared in the big ECOG study. Despite the lack
`ofjilaS III data, carboplatin/Taxol is a broadly Aclepted regimen.(described.by some as
`eeácius and easy to administer). These combinations have response rates of the order
`of 40 to 60% and hence have established a iirly high hurdle rate for an MTA
`combination. The advisors felt that the MTA/cisplatin combination would have to have
`significant safety and/or efficacy advantages to be adopted in the marketplace in
`prdt'erence to these regimes. In Phase 2 studies, it would be critical to demonstrate a
`réathnable and acceptable safety profile, a comparable response rate to these regimes and
`a median survival of greater than one year before proceeding to Phase 3. Days of
`hbpitalization due to complications of chemotherapy was suggested as an endpoint
`(jàssibly a tertiary endpoint). There was concern expressed regarding possible
`nephrotoxieity of an MTAlcisplatin combination when administered the same day. The
`possible renal toxicity of MTA is being investigated further in several studies.
`
`line NSCLC studies will depend on theoutcome of ODAC's
`The comparator for l
`review of Taxol on March20 (Taxol + cisplatin, NSCLC) and results of the ongoing
`ECOG study. (t'4ote: Taxol was approved in combination with cisplatin for front line
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`NSCLC.) MTA + GBMZAR was suggested as a combination for future evaluation,
`although Jim Carmichael expressed concerns about the dose intensity of the gemcitabine
`in the MTA plus Gem phase I study. This combination will pmbably need further
`evaluation in a phase I setting before taking it into phase II.
`
`Biómarker studies were suggested as a means of stratifying the population and.
`discriminating between patient groups. Particular subgroups could then be selected for
`MTA treatment to determine if there was a distinct advantage for MTA. Such studies
`could be conducted in parallel with other evaluations.
`
`From a strategic standpoint, the Panel agreed that l line NSCLC studies were not a high
`priority. There was more enthusiasm for pursuing
`line NSCLC as an immediate
`registration strategy, and for generating additional data in
`line that would be analyzed
`for subsequent decision-making.
`
`If one were to proceed in a front-line setting with MTA plus Gem, the accrual
`assumptions of 1 year to enroll 600 patients were considered reasonable assuming
`encouraging Phase 1 dat,i Assuming combination MTA + cisplatin, studies would not
`begin enrollment until QI 99, with submission/approval Q401/Q302. This assumes
`initial submission with interim data (TTP data on one-half of the patients), with
`remaining TTP and survival data made available to reviewers as it is available.
`
`Breast Cancer
`
`Mark' tiiw
`
`Redacted
`
`2n4 line
`Breast Cancer
`The response rate in a single Phase 2 study QMAG) that involved a heterogeneous
`population (i.e. including patients treated in the metastatic setting previously) was 33% (1
`CR, 9 PR). Some of the patients in this study had failed an anthracycline or taxane. A
`second Phase 2 study (HASP) in anthracycline failures is ongoing. Responses have been
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`reported, but it is too early to determine response rates. Mother Phase 2 study (JMBT)
`involving patients previously treated with an ahthracycline/taxane regimen will be
`initiated in Q3 98.
`
`The advisors agreed that data indicate sufficient activity of MA in breast cancer to
`proceed with additional studies. The proposed clinical strategy presented to the advisors
`for discussion was a Phase 2 study followed by a Phase 3 randomized study in patients
`previously treated with an anthracycline/taxane regimen. The Phase 3 study would
`compare MTA vs. vinorelbine/capecitabine/or other agent and would involve 500
`patients. Proposed endpoints were flP and 6 month survival. A separatestudy in
`Europe, MTA vs. Taxotere, in anthracycine failures also is being considered.
`
`The advisors agreed with the need for and the importance of a comparative study, and
`that ai tbracycline/taxane thilures were an appropriate population. They felt, however,
`that 2W3M line studies should not be restricted to this patient population, and suggested
`additi4nal studies in patients who had failed other chemotherapeutic regimes (e.g. FEC).
`A suggested study was a 3-arm study comparing IsIFA, MTA + Taxotere, and Taxotere in
`FEC thihires. The advisors indicated that it would be difficult to beat Taxotere in this
`patient population.
`
`The Pnel felt that 2 line breast cancer was not a priority for registration at this time,
`assuz$ng that MTA has approximately the same efficacy as other agents currently on the
`matkq. The clinical studies axe long, and there are currently many therapeutic options.
`Phas&2 trials are critical to a decision on further evaluations. If favorable response rates
`ar&ol*ained in the planned Phase 2 study in anthracycline/taxane failures (i.e >30%-
`50%) this position could change. The toxicity profile will he an important consideration.
`The 600mg dose of MTA is recommended for these studies.
`Reacted
`
`Proposed endpoints are TIP and lime without symptoms. Survival differences are
`difficult to measure since so many 3 and 4th line treatments are available. Quality of life
`measwements become complicated because we would be comparing IV (MTA) vs. oral
`(assuthing capecitabine) dmgs. The estimate of enrolling 600 patients in 2 V2 to 3 years is
`corisiklered reasonable. Initiation of Phase 3 studies currently is planned Ql 99, with first
`subntsionlapproval Q303/Q204
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`Mesothelioma
`
`No market research information was provided. The value of pursuing registration in this
`disease at this time would be speed to market.
`
`As background, Dr. Karin Mattson provided information confirming that this type of drug
`seems to be active in mesothelioma. First, a study conducted in Norway in 1992 (British
`Journal of Cancer) involving high-dose methotrexate (3 gm every 2 weeks for 3 doses)
`demonstrated a 37% response rate, 32% stable disease, and median survival of 11
`months. Dr. Mattson also has conducted a study involving high-dose methotrexate with
`the addition of alpha and gamma interferons (n=26 patients). The regime was well
`tolerated, and achieved a 26% response rate and 14 month median survival. Routine CT
`scans and MBIs were conducted on all patients to evaluate tumor responses.
`
`In the Lilly Phase I study (MTA + cisplatin), there were 4 of 7 mesotheliomapatients
`who, responded, with two respondersat 600 mg/m2 MTA and 75 mglm2 cisplatin and
`two responders at 600 mg/m2 MIA and 100 mg/m2 cisplatin dosage regimes. These
`responses have been independently xpviewed and confirmed. One patient hadprior
`therapy with an investigational agent The duration's of responses were reported at 8+, 5,
`and 3 (2) months, and are continuing. Two proposed additional studies were discussed:
`one phase 2 study (n=70) to conthnithe initial data and one randomized trial (nc120
`patients) to achieve registration.
`
`Based on the data presented, the Panel strongly supported proceeding with a npid
`registration strategy in mesothelioi$. The Panel agreed that a randomized Phase 2 study
`would be required to secure registration, assuming positive results in the confirmatory
`single-arm.Phase 2 study. There wa considerable discussion regarding the arms for this
`randomized study, with the recommendation being a 3-arm trial comparing MTA +
`cisplatin, MTA, and cisplatin. While a 2-arm proposal (excluding the cisplatin ann) was
`conàidered toaccomplish speed, thejFDA' s requirement for approximately 200 patients
`(100 efficacy, 200 safety) would be kate-limiting and reduction to two arms would offer
`no speed advantage. The recomiriended dose of cisplatin when combined with IVITA is
`75mg/m2.
`
`The advisors expressed concern regarding the ability to enroll patients in the cisplatin arm
`of the randomized study, and the option was proposed to either allow cross-over of
`patients from the two single agent arms to the MTAlcisplatin combination, or have a
`separate protocol that would allow these patients to receive the combination following
`assessment of response. The investigators also encouraged that the randomized study be
`designed with the fewest number of patients possible, and that registration not be pursued
`with a response rate of 30% or less.
`
`The recommended primary endpoint is response rate with secondary endpoints of quality
`of life, lung function (e.g. total respiratory reserve, vital capacity) and toxicity. Based on
`information provided by the investigators, patient enrollment is estimated as at least 10
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`patients per month. The current target date for initiation of the Phase 2 trials is
`September, with estimated submissionlregistration Q4001Q301.
`
`Cervical Cancer
`
`Marketing
`
`For U.S chemotherapy protocols in Stage I/Il cervical cancer, the primary regimens are
`eisplatinl5-FU +1- LV and cisplatin alone. For Stage Ill/TV, there are a number of
`protocols, including cisplatin/5-FU +1- LV, cisplatin alone, carbo/Taxol, and
`cisplatin/ifosfamide.
`
`Clinical Studies/Plans
`
`Phase 2 data (JMAI4, South Africa) indicate an approximate 25% response rate. While
`symptom:atic improvement was reported, many patients were discontinued because of
`toxicity, primarily myelosuppression. There was some indication that thispatient
`population tony be at increased risk of renal dysfunction. Because of these toxicities and
`uncertainties concerning the data, it is planiied to repeat this study with vitamin
`supplem4ittation (folic acid, B6..and B. 12) and in a patient population that is more
`representSve of Stage LIIB/IV disease (JMJ4). The initial study did not include patients
`who had received prior pelvic radiotherapy, and who might therefore be. at greater risk of
`increaàed myclo suppression. The repeat study will involve ehcmonaive patients who
`have 'received pnor radiotherapy A chmeal benefit/quality of life tool will be piloted m
`this study Clinical benefit is being considered as an endpomt, although the panel felt that
`it would be difficult to use this as a primary endpoint.
`
`The investigators encouraged a repeat study, and urged further analysis of renal function
`data frOm the initial Phase 2 study. Discrepancies between the reported improvements
`and toxicities (e.g. renal impairment and hydronephrosis) were a concern.
`
`As with mesothelioma, proceeding with cervical cancer as a registration strategy at this
`time would be pursued only if such a strategy provided speed to market. The current
`timeline does not offer a speed strategy (submission/approval, Q301/Q202) relative to
`some other indications.
`
`Head and Neck Cancer
`
`Redacted
`the U.S., 5-PU and cisplatin are the two major chemotherapeutic
`agents emg use. in head and neck cancer. Other agents are carboplatin, Taxol (largely
`Redacted
`U.S. only) and methotrexate.
`Ithe U.S., Cisplatin/5-FU is the most
`frequently used protocol.
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`Clinical Studies/Plans
`In the Phase 2 MTA study (JMAJ, France), early data indicates a 50% response rate (5/10
`patients) with symptomatic improvenent. Because of safety concerns in this patient
`population (i.e. poor nutritional status), the protocol is being modified to include vitamin
`supplementation (folic acid, B6, and B12) in a randomized setting. This modification
`will allow examination of the effect of vitamins on both safety and efficacy in a
`ehemo sensitive disease. While Lilly felt that such a study will provide valuable
`information on vitamin supplementation, Lilly's recommended approach was not to
`develop a registration study at this time given the number of achemotherapeutic agents
`currently available and the fact that none of these agents have been found to have a
`impact on thebiology of the disease, i.e. extend survival.
`
`The Panel felt that initial Phace 2 results were very encouraging, and indicated a high
`level of interest in MTA therapy in this disease if the planned Phase 2 study in patients
`with prior radiation confirmed the early clinical results (i.e. 50% response rate). The
`Panel recommended conducting single agent studies in a 2 line setting (5-FtJ/cisplatin
`ilures) as a rapid route to registration, possibly comparing MTA (+ or - vitamins,
`depending on results of the planqed ithase 2 study) with the preferred drug regimen
`emerging from the ongoing EORTC study (methotrexate or Taxol). It was pointed out
`that a comparator may not be necessary if striking results were obtained in the MTA
`Phase 2 study. Survival would b the primary endpoint, with quality of life second, and
`toxicity third.
`
`Bladder Cancer
`
`While there is a niche in 2 line bladder cancer chemotherapy for an active agent,
`currently, there is a high level of competition in this area. It is anticipated that a number of
`new regimen will be entering the marketplace in the near-term for front-line therapy(e.g.
`MVAC components, Taxol, carboplatin/Taxotere, gemcitabine cisplatin); The renal
`ftnctiôn of patients is generally impaired once they have received front-line therapy
`(especially after MVAC) and this may mean that they are not suitable candidates for
`treatment with MTA secondline.
`
`While the Panel was enthusiastic about the clinical data currently available on MTA, it
`was felt that pursuit of this indication did not offer a rapid route to registration. The
`Panel indicated that Lilly may want to conduct studies at a later dRte and, if so,
`combination with gemeitabine or Taxol should be considered. The high degree of
`myelosuppression caused by MTA in the phase II study was mentioned as a potential
`issue. This needs to be addressed.
`
`Renal Cancer
`
`There was no interest in furiher evaluations at this time.
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`Pancreatic Cancer
`
`In view of the other developmental options for MTA and the higher priority of other
`diseases, the Panel recommended that registratIon of this indication not be pursued at this
`time.
`
`Vitamin Sunpiementafion
`
`The Panel was asked for their recommendation concerning possible routine vitamin
`supplementation for all MTA clinical studies. This vitamin supplementation likely would
`include flit iecommended levels of folio acid (1 mg), B6 (25 rag) and BI 2 (2. mg)
`administered in a single inultivitamin tablet or capsule.
`
`The Panel agreed that there currently is insufficient data available to recommend routine
`vitamin supplementation. Studies are either ongoing or planned to ftirther evaluate the
`effect of vitamin supplementation on safety/efficacy of MTA (e.g. head and neck,
`NSCLC, Phase 1 study with folic acid studies). Data from JMAS (the Phase 2 study with
`folic acid and escalating doses of MTA) is considered critical to a decisionconcerning
`rauthe vitamin supplementation. Jt was suggested that a pharmacokinetic study be.
`condubtedi in which the me patients receive MTA with or without folic acid. It also was
`suggcted that the decision to supplement with vitamins may depend on the specific
`disec bcbg treated, unless there are sufficient data to indicate a standard biochemical
`mechâni4 exists across nil tumors. If it is determined by the clinical studiesthat routine
`vitamin supplementatioawith MTA chemotherapy offers a satèty advantage, without
`cothpromWug activity, then the inclusion of vitamins in the patients' therapeutic regimen
`is nOt conidered art issue by the advisors.
`
`It was pointed out that the FDA has nojuristhction over vihm,ins, and consequently no
`standards exist for dissolution etc. A company in Oregon is making a vitamin for an NIH
`stroke study that contains close to the our recommended content of folic acid B6, and
`Bfl. Prot a regulatory perspective, use of vitamins with MTA may not be considered as
`vitamin supplementation. The vitiimins may be considered as aents to mitigate toxicity
`Redacted
`associated with the drug, and hence may be considered as drugs.I
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`t
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`Conclusion
`
`Based on the infbrmation presented at the investigators' and the Folate Advisory Pane!
`Meetings, the advisors were requested to vote on their level of interest in each of the
`various tumor types that were discussed, not separating speed from market size. Each
`advisor was given ten votes to divide between 8 indications, with a maximum of 4 for any
`single indication.
`
`The results of that.voting are as follows, in order of votes received:
`
`Mesothelioma (29)
`Head and Neck (25.5)
`NSCLC (2ThI line) (18.5)
`Breast (21d line) (15)
`Cervix (6)
`Bladder (4)
`NSCLC (1Jine) (2)
`Pancreas (0)
`
`The Panel members were thanked for their contributions to the discussion. Sites for the
`next meeting were briefly discussed, with Greece mentioned as a possible location
`(associated with the ESMO meeting).
`
`Marilyn Amett
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