`
`-
`
`February 1, 2011
`
`.
`
`_
`
`Comorbidity and Mortality Results From a Randomized Prostate Cancer
`Screening Trial. E. D. Crawford et al. Editorial. P.R. Carroll et al
`Identification of Patients With AML Who Benefit From the Addition of
`Gemtuzumab Ozogamicin: Results of the MRC AML15 Trial. A. K. Burnett et al.
`Editorial: F. Ravandi
`'
`.
`Improved Prognosis for Older Adolescents With Acute LymphOblastic
`‘Leukemia. CHH.Pui et al
`. Phase II Study of the Antibody Drug Conjugate Trastuzumab—DM1 for the
`Treatment Of _HER2—Positive Breast Cancer After Prior HER2- DirectedTherapy
`H.A. Burris III et al. Editorial 5.I. Isakoff et aI
`Intravenous Calcium and Magnesium Prevents Oxaliplatin-Induced Sensory
`Neurotoxicity'In Adjuvant Colon Cancer: NCCT‘G N04C7. A. Grothey et al
`Risk of MDS in People Exposed to, IOnizing RadiaItIOn: A Retrospective Cohort
`Study of Nagasaki Atomic Bomb Survivors. M. Iwanaga et aI
`.
`Review Article: How Long Have I Got? Estimating Typical, BestCase, and
`Worst—Case Scenarios for Patients Starting First-Line Chemotherapy for
`Metastatic Breast Cancer. B. E. Kiely et ai. Editorial: L Schapira
`StatisticsIn Oncology: What Is the True Number Needed to Screen and Treat
`to Save a Life With Prostate—Specific Antigen Testing? 5. Loeb et al.
`Editorial: P.R. Carroll et aI
`
`wWw.jco.org
`
`@Official 10urna| of the American Society of Clinical Oncology
`
`,
`
`INEN 2125. " '
`Phigenix v. Immunogen
`|PR2014-00676
`
`'
`
`'
`
`IMMUNOGEN 2125, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`:3;5
`,5,
`fix?
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Editorials
`
`Serum Prostate-Specific Antigen for the Early Detection of Prostate Cancer: Always, Never, or
`Only Sometimes?
`Peter R. Carroll, Jared M. Whitson, and Matthew R. Cooperberg (see articles on pages 355 and 464) ...............................................
`
`Simple Rules Can Improve Prognostic Accuracy
`Lidia Schapira (see article on page 456)
`...................
`. ..
`
`.
`
`..
`
`Gemtuzumab Ozogamicin: One Size Does Not Fit All—The Case for Personalized Therapy
`Farhad Ravandi (see article on page 389)
`...........................................................................................
`...........................
`
`Trastuzumab-DMl: Building a Chemotherapy-Free Road in the Treatment of Human Epidermal
`Growth Factor Receptor 2—Positive Breast Cancer
`.
`Steven J. lsakoff and Jose Baselga {see article on page 398)
`........
`
`....................................................................
`
`345
`
`347
`
`349
`
`Original Reports
`
`UROLOGIC ONCOLOGY
`
`Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial
`E. David Crawford, Robert Grubb Ill, Amanda Black, et al (see editorial on page 345 and article on page 454)
`
`............................
`
`355
`
`Comparison of Health-Related Quality of Life 5 Years After SPIRIT: Surgical Prostatectomy Versus
`Interstitial Radiation Intervention Trial
`_
`Juanita Mary Crook, Alfonso Gomez-lturriaga, Kris Wallace, at al
`
`HEMATOLOGIC MALIGNANCIES
`
`CD Identification of Patients With Acute Myeloblastic Leukemia Who Benefit From the Addition of
`Gemtuzumab Ozogamicin: Results of the MRC AML15 Trial
`Alan K. Burnett, Robert K. Hills, Donald Milligan, et al (see editorial on page 349)
`
`..
`
`Racial Differences in Chronic Immune Stimulatory Conditions and Risk of Non-Hodgkin's
`Lymphoma in Veterans From the United States
`Jill Koshiol, Tram Kim Lam, Gloria Gridley, et al
`........
`
`Improved Prognosis for Older Adolescents With Acute Lymphoblastic Leukemia
`Ching-Hon Pui, Deqing Pei, Dario Campana, et al
`
`DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis
`That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status
`Naseema Gangat, Domenica Caramazza, Rakhee Vaidya, et al
`.................................................
`
`(continued on following page)
`
`
`
`
`Phigenix v. Immunogen
`|PR2014-00676
`
`IMMUNOGEN 2125, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`Y
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`201
`
`
`
`ORIGINAL REPORT»
`
`Phase 11 Study of the Antibody Drug Conjugate
`Trastuzumab-DMI for the Treatment of Human Epidermal
`Growth Factor Receptor 2 (HERZ) —Positive Breast Cancer
`After Prior HERZ—Directed Therapy
`Howard A. Burris III, Hope S. Raga, Svetislava I. Vukelja, Charles L. Vogel, Rachel A. Borson,
`Steven Limentani, Elizabeth Ton—Chin, Ian E. Krop, Richard A. Michaelson, Sandhyo Girish, Lukas Amler,
`Maoxic Zheng, Yu—Waye Chu, Barbara Klericke, and Joyce A. O’Shaughnessy
`See accompanying editorial on page 351
`
`
`Purpose
`(T—DMi) combines the biologic activity of trastu—
`The antibody—drug conjugate trastuzumab—DMi
`zumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth
`factor receptor 2 (HERZ) —overexpressing cancer cells. Based on results from a phase I study that
`showed T—DM1 was well tolerated at the maximum—tolerated dose of 3.6 mg/kg every 3 weeks,
`wi h evidence of efficacy,
`in patients with HERZ—positive metastatic breast cancer (MBC) who
`were previously treated with trastuzumab, we conducted a phase II study to further define the
`sa ety and efficacy of T—DM1 in this patient population.
`Patients and Methods
`Th's report describes a single~arm phase II study (TDM4258g) that assessed efficacy and
`safety of intravenous T—DM1 (3.6 mg/kg every 3 weeks) in patients with HERZ—positive MBC
`wro had tumor progression after prior treatment with HERZ—directed therapy and who had
`received prior chemotherapy.
`Results
`
`Wi h a follow—up of 2 12 months among 112 treated patients, the objective response rate by independent
`assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a
`result of insufficient events (lower limit of 95% Cl, 6.2 months), and median progression—free survival
`tirre was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients
`with confirmed HEBZ—positive tumors (immunohistochemistry 3-1- or fluorescent in situ hybridization
`positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients
`wrose tumors expressed 2 median HER2 levels by quantitative reverse transcriptase polymerase chain
`reaction for HERZ expression, compared with patients who had less than median HERZ levels. T—DM1 was
`well tolerated with no dose—limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the
`most frequent grade 2 3 AEs were hypokelemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%).
`Conclusion
`T—DM1 has robust single—agent activity in patients with heavily pretreated, HERZ—positive MBC and
`is well tolerated at the recommended phase II dose.
`
`
`
`J C/ll’i Onco/ 29:398—405. © 2010 by American Society of Clinical Oncology
`
`
`
`Overexpression of human epidermal growth factor
`receptor 2 (HERZ) occurs in 15% to 25% ofall breast
`cancers and is associated with poor prognosis.1’2 The
`humanized anti—HERZ antibody trastuzumab (Her—
`ceptin; Genentech, South San Francisco, CA), in .
`combination with chemotherapy, prolongs survival
`of patients with HERZ—positive breast cancer in
`metastatic and adjuvant settings?6 However,
`
`most patients with HERZ—positive metastatic
`breast cancer (MBC) eventually develop progres—
`sive disease on available therapies, including the
`HERZ—targeted therapies trastuzumab and lapa—
`tinib.7 Consequently, the development of addi—
`tional
`therapeutic options
`for
`this patient
`population is strongly warranted.
`Trastuzumab—DMI (T—DMl) is a novel anti—
`HERZ antibody—drug conjugate (ADC) in develop-
`ment for treatment of patients with HERZ—positive
`
`From the Sarah Cannon Research Insti—
`tute, Nashville, TN; University of Califor-
`nia, San Francisco Helen Diller Family
`Comprehensive Cancer Center, San Fran-
`cisco; Genentech, South San Francisco,
`CA; Tyler Cancer Center, Texas Oncology,
`US Oncology, Tyler; BaylorvSammons
`Cancer Center, Texas Oncology, US
`Oncology, Dallas, TX; Lynn Cancer Insti»
`tute, Boca Fiaton; Florida Cancer Care,
`Davie, FL; St Louis Cancer and Breast
`Institute, St Louis, MD; University of
`North Carolina, Blumenthal Cancer
`Center, Charlotte, NC; Dana~Farber
`Cancer institute, Boston, MA; and St
`Barnabas Medical Center, Livingston, NJ.
`Submitted March 30, 2010; accepted
`September 30, 2010; published online
`ahead of print at www.jco.org on
`December 20, 2010.
`Presented in part at the 45th Annual
`Meeting of the American Society of
`I
`Clinical Oncology. May 29-June 2,
`2009, Orlando, FL; and the 34th‘fiinnual
`Meeting of the European Society for
`Medical Oncology, September 20-24,
`2009, Berlin, Germany.
`
`Authors' disclosures of potential con-
`flicts of interest and author contribu»
`tions are found at the end of this
`article.
`
`Clinical Trials repository .ink available on
`JCO.org.
`Corresponding author: Howard A. Burris
`III, MD, Sarah Cannon Research Insti»
`tute, 250 25m Ave North, Ste 110,
`Nashville, TN 37203-1632; e-mail:
`howard.burrisIscresearchnet.
`
`© 2010 by American Society of Clinical
`Oncology
`0732-183X/11/2904‘398/$Z0.00
`DOI: 10.1200/JCO.2010.29.5865
`
`398
`
`© 2010 by American Society of Clinical Oncology
`
`IMMUNOGEN 2125. P9. 3
`Phigenix v. lmmunogen
`lPR2014-00676
`
`IMMUNOGEN 2125, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`Phase II Study of T-DM1 for MBC After Prior Therapy
`
`breast cancer.8 T~DM1 combines the HER2~targeting properties of
`trastuzumab with intracellular delivery ofDM1, a highly potent deriv—
`ative of the antimicrotubule agent maytansine?"ll DMI binds to
`tubulin and inhibits microtubule assembly with greater potency than
`vincristine or vinblastine.11 In T-DMl, trastuzumab and DM1 are
`covalently linked via the thioether linker (N—maleimidomethyl)
`cyclohexane— l—carboxylate (MCC). The stability of MCC, compared
`with disulfide linkers, was shown to strongly contribute to the favor—
`able activity and toxicity profiles ofT-DMI in preclinical testing (data
`on file, Genentech, South San Francisco, CA)”; exposure of HER2—
`positive tumors to DMl is maximized, whereas exposure of normal
`tissue is minimized. Additionally, T—DM1 seems to retain the antitu—
`mor properties of trastuzumab, including flagging HER2—positive tu—
`mor cells for destruction by antibody—dependent cellular cytotoxicity
`and inhibiting HER2 signaling (data on file, Genentech, South San
`Francisco, CA). ”’13
`A phase I dose—escalation study evaluated dosing schedules of
`T—DM1 in patients with HER2—positive MBC who had experienced
`progression on trastuzumab—based therapy.8 Most adverse events
`(AE5) attributed to T—DMl were S grade 2. The maximum—tolerated
`dose of T—DMI was 3.6 mg/kg every 3 weeks, based on the dose—
`]jmiting toxicity ofgrade 4 thrombocytopenia at 4.8 mg/kg. For the 15
`patients treated at the maidmum—tolerated dose, median progression—
`free survival (PFS) was 10.4 months, and four (44%) of nine patients
`with measurable disease had an objective response. The pharmacoki-
`netics of T—DM1 were characterized by relatively slow clearance, a
`small volume of distribution (limited to plasma volume), and a half—
`life of approximately 4 days. Systemic DM1 exposure was low (average
`of approximately 5 ng/mL maximum plasma levels). On the basis of
`these results, a phase II study (TDM4258g) was initiated to evaluate
`T—DMl treatment in patients with HER2—positive MBC who experi—
`enced progression on HER2—directed therapy.
`
`
`
`Patients
`Eligibility criteria included HER2-positive disease by fluorescence in
`situ hybridization (FISH) or immunohistochemistry (IHC; 3+) assess—
`ment at a local laboratory. All patients received 2 one prior HER2—targeted
`therapy and had measurable disease per Response Evaluation Criteria in
`Solid Tumors (RECIST; version 1.0).14 All patients also had prior tumor
`progression while receiving HER2—directed therapy or S 60 days after the
`last dose of trastuzumab.
`Additional eligibility criteria included the following: prior treatment
`with 2 one chemotherapy agent for MBC; no history of significant cardiac
`disease; left ventricular ejection fraction (LVEF) 2 50% by echocardiogram or
`inultigated acquisition scans; no history of 2 grade 3 hypersensitivity to
`trastuzumab or toxicity requiring discontinuation; no 2 grade 3 peripheral
`neuropathy; no untreated or symptomatic brain metastases; and no treatment
`for brain metastases 5 3 months before first T-DMI dose.
`
`Study Design and Objectives
`In this single-arm study, T—DMI was administered intravenously at 3.6
`mg/kg every 3 weeks for up to 1 year, with the option ofcontinued treatment in
`an extension study. The primary end points were objective response rate
`(ORR) by independent radiologic facility (IRF) review, safety, and tolerability.
`Secondary objectives included ORR by investigator review, duration of objec—
`tive response (DOR), PFS by IRF and investigator, and characterization of
`pharmacokinetics. Correlation of efficacy with HER2 status as a biomarker
`was an exploratory objective.
`
`wcha.org
`
`All patients provided written informed consent. The study was reviewed
`and approved by the institutional review board at each site, according to local
`clinical guidelines. The study is in accordance with assurances filed with and
`approved by the Department of Health and Human Services.
`Assessments and Data Collection
`Tumor assessments per RECIST were conducted every other cycle by
`investigator and retrospectively by single-reader IRF. Echocardiograms or
`multigated acquisition scans were obtained after cycles 1 and 2 and then every
`two cycles thereafter until study termination. Serum cardiac troponin I levels
`were assessed on day 8 of every other cycle.
`Serum and plasma samples were obtained from all patients before dosing
`and 30 minutes after treatment infusion to determine T-DMl and total tras—
`tuzumab and DM1 levels. Additional samples were obtained on days 8 and 15
`ofcycles 1 and 4. T—DM1 and total trastuzumab levels (conjugated and uncon—
`jugated T—DMl)in serum were quantitated using a validated enzyme——linked
`immunosorbent assay.8DM1 concentrations in plasma were determined by
`Xendo Drug Development B.V. (Groningen, the Netherlands) using a vali—
`dated liquid chromatography—tandem mass spectrometry method. Pre~ and
`postdose serum samples (day 1 of cycles 1 and 4) were assessed for anti—T~
`DMl antibodies using a bridging—antibody electrochemiluminescent assay.8
`HERZ Testing
`Archival tumor tissue blocks from tumors obtained at initial diagnosis
`were retrospectively assessed for HER2 overexpression by central laboratory
`using IHC (HercepTest kit; DAKO, Glostrup, Denmark) and/or FISH (Vysis
`Patthsion HER2 FISH kit; Abbott Molecular, Abbott Park, IL). By central
`retesting, patients were defined as HER2—pdsitive based on a score of 3+ by
`IHC (strong, complete membrane staining in > 10% of the tumor cells)
`and/or an HER2/CEP17 ratio of 2 2.0 by FISH.
`HER2 and glucose—o—phosphute dehydrogenase expression were measured
`by real-time, reverse transcriptase polymerase chain reaction (RT—PCR);
`methods and primer and probe sequences have been previously described.15’16
`RNA was extracted from tumor material using commercially available re—
`agents (Roche Diagnostics, Mannheim, Germany). HER2 expression was ex—
`pressed as normalized ratio to glucose—6—phosphate dehydrogenase mRNA
`expression. The kit to conduct these assays is not approved by the US Food and
`Drug Administration but is technicallyvalidated; the laboratory setting was in
`compliance with Clinical Laboratory Improvement Amendments standards.
`Statistics
`Statistical analyses were conducted after all patients had completed 1 year of
`treatment and/or discontinued from study (approximately 12 months of mini—
`mum follow—up). Primary and secondary efl'lcacy and safety end points were
`analyzed on the treated population, which was defined as patients who received 2
`one dose of T—DMI. Objective response was defined as complete or partial re—
`sponse on two consecutive tumor assessments 2 4 weeks apart; the 95% CI for
`OR was calculated using Blythe—Still—Casella methodology. The Kaplan-Meier
`method was used to calculate median FPS and DOR with 95% C315 by Green—
`wood’s formula. For patients who experienced no disease progression and did not
`die while on study, data were censored at the date oflast tumor assessment
`Exploratory diagnostic analyses based on central HER2 testing and RT-PCR
`expression levels were also conducted. Exploratory analyses ofefficacy in relation
`to HER2 testing were conducted on the efficacy-evaluable population, which was
`defined as patients who received 2 one dose ofT—DMI and had 2 one postbase-
`line tumor assessment or died 5 50 days after last study treatment. For patients
`with evaluable pharmacokinetics data, standard noncompartmental modeling
`was used to calculate parameters at cycles 1 and 4, using WinNonLin 5.2.1 in the
`Pharsight Knowledgebase Server (Pharsight, Mountain View, CA).
`
`
`
`Patient Demographics and Characteristics
`One hundred twelve patients were enrolled onto the study and
`received at least one dose of T-DMI (Table 1). Patients received a
`
`© 2010 by American Society of Clinical Oncology
`
`399
`
` "
`
`IMMUNOGEN 2125, P9. 4
`Phigenix v. Immunogen
`|PR2014-00676
`
`IMMUNOGEN 2125, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Burris III et al
`
`Table 1. Baseline Patient Demographics and Clinical Characteristics
`No. of Patients
`Characteristic
`(N = 112)
`
`%
`
` Race
`
`White
`'
`Black
`Asian or Pacific Islander
`Hispanic
`
`ER positive or PR positive
`ER negative and PR negative
`Unknown
`
`101
`9
`2
`0
`
`53
`56
`3
`
`90.2
`8.0
`1.8
`O
`
`47.3
`50.0
`
`
`
`
` No. of distinct metastatic Sites
`< 3
`28
`25
`a 3
`84
`75
`
`70.5
`
`
`
`25.9% (Table 2). By investigator assessment, there were 42 objective re—
`sponses (37.5%), including four complete responses (3.6%). There was
`82% agreement between IRF and investigator assessments. The primary
`reasons for differences between the IRF- and investigator—determined
`ORR were the independent selection of different lesions by the reviewers
`and alternative interpretations ofnontarget lesions. Among the 75 treated
`patients who reported discontinuation ofa prior trastuzumab—containmg
`regimen as a result of progressive disease, 21 patients had objective re-
`sponses, for an ORR of 28.0% (95% CI, 18.2% to 38.9%).
`The median DOR was not reached (95% CI, 6.2 months to not
`estimable [NED by IRF assessment and was 9.4 months (95% CI, 7.0
`months to NE) by investigator assessment (Fig 1A). Median PFS for
`efficacy—evaluable patients was 4.6 months by both IRF (Figure 1B)
`and investigator (Figure 1C) assessment (95% CI, 3.9 to 8.6 months
`' and 4.1 to 6.0 months, respectively).
`Among efficacy—evaluable patients with prior lapatinib treatment
`(n = 66), the ORR was 24.2% (95% CI, 14.5% to 36.0%) by IRF and
`34.8% (95% CI, 23.5% to 46.8%) by investigator. Median PFS times
`were 5.3 months (95% CI, 3.6 to 8.9 months) and4.2 months (95% CI,
`2.8 to 6.8 months) per IRF and investigator, respectively.
`
`Exploratory HERZ Testing Analyses
`Ninety-five efficacy—evaluable patients had HER2 status reas-
`sessed on archival primary tumor by a central laboratory using IHC or
`FISH. Seventy—four of 95 patients were confirmed as having HERZ—
`positive tumors, and 21 patients had HER2-normal tumors. By IRF
`assessment, ORR was 33.8% (95% CI, 23.2% to 44.9%) in patients
`with confirmed HERZ—positive tumors and 4.8% (95% CI, < 1.0% to
`21.8%) in patients with HERZ—normal tumors by central retesting
`(Table 2). Median PFS was 8.2 months (95% CI, 4.4 months to NE)
`among patients with confirmed HERZ—positive tumors and 2.6
`months (95% CI, 1.4 to 3.9 months) among patients with confirmed
`HERZ—normal tumors (Fig 2A).
`Patients with retrospectively confirmed HEM—positive disease
`were grouped according to HERZ expression levels (2 or < median)
`determined by quantitative RTePCR. Distributions and ranges of
`HERZ levels assessed by quantitative RT—PCR are shown in Figure 2B.
`With available data from 50 patients, ORR per IRF in patients with 2
`median HER2 expression (11 = 25) was 36% (95% CI, 18.5% to 56.9%;
`Table 2); median PFS was not reached (95% CI, 4.6 months to NE; Fig
`2C). OR in patients who had tumors with less than median HERZ
`expression (n = 25) was 28.0% (95% CI, 12.1% to 47.5%), and
`median PFS was 4.2 months (95% CI, 2.7 to 6.8 months). Similar
`trends were observed by investigator assessment (data not shown).
`
`Safety
`The 112 treated patients received a median of seven doses (range,
`one to 17 doses) ofT—DMl on study, with a median duration of exposure
`of4.2 months. Twenty—one patients completed 1 year ofstudy treatment,
`ofwhom 19 continued therapy in an extension study.
`The most common AEs (any grade) were fatigue, nausea, and head—
`ache (Table 3). The most frequently observed grade 3 or 4 ABS were
`hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). Hy—
`pokalemia was not associated with vomiting, diarrhea, or diuretic use. No
`single serious AE occurred in more than three patients.
`Three patients died within 30 days of receiving T—DM1. Disease
`progression was documented before death in two patients; the third
`patient was discontinued because ofclinical deterioration as a result of
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`IMMUNOGEN 2125. P9. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`
`
`Prior therapies
`No. of systemic agents in all settings
`Median
`Range
`No. of systemic agents in metastatic setting
`Median
`Flange
`'
`Prior taxane
`Prior anthracycline
`Prior capecitabine
`Prior carboplatin
`
`,
`
`'
`
`
`
`‘
`
`8
`249
`
`5
`1—17
`
`94
`79
`74
`47
`
`83.9
`
`66.1
`42
`
`
`
`.093
`Received prior lapatinib therapy
`18.
`
`-
`
`67
`
`59.8
`
`
`
`
`
`Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance
`status; ER, estrogen receptor; PR, progesterone receptor.
`
`
`median of eight prior anticancer agents in all disease settings, includ—
`ing taxanes (84%), anthracycline (71%), capecitabine (66%), and
`carboplatin (42%). All patients received prior trastuzumab (median
`exposure, 17.6 months). In a post hoc exploratory analysis, 75 patients
`reported discontinuation of a trastuzumab—containing chemotherapy
`regimen as a result of progressive disease. Sixty—seven patients (60%)
`also received prior lapatinib (median exposure, 6.0 months).
`
`Efficacy
`Among treatedpatients, 29 patients had an objective tumor response
`(all partial responses) by IRF assessment, corresponding to an OR of
`
`400
`
`© 2010 by American Society of Clinical Oncology
`
`IMMUNOGEN 2125, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`No: ottr'éated'lpatiengt
`
`Objective response
`95% CI, °/o
`18.4 to 34.4
`28.6to 46.6
`comaiétéréspanse‘g
`,
`n
`z
`
`' Partial response
`29
`25.9
`38
`33.9
`
`_,
`”[4911
`.
`.
`stabiefcif
`
`
`19.6
`22
`l9.6
`
`
`Mls‘Sll’ig
`' Eval
`
`’1
`
`_
`
`,
`
`,
`
`,
`
`Phase II Study of T-DM1 for MBC After Prior Therapy
`
`
`
`Table 2. Objective Responses
`|RF*
`INVT
`
`
`Response
`No. of Patients
`%
`No. of Patients
`%
`.
`1.132 g
`1
`
`42
`37.5
`
`
`
` Abbreviations:
`
`
`lHC,
`
`immunohistochemistry; FISH,
`
`investigator; HER2, human epidermal growth factor receptor 2:
`INV,
`independent review facility;
`IRF,
`fluorescence in situ hybridization; RT—PCR, reverse transcriptase polymerase chain reaction.
`“Among patients with measurable disease at baseline per IRF.
`tAmong patients with measurable disease at baseline per investigator.
`
`underlying MBC. Four patients (3.6%) discontinued T—DMI for the
`following reasons: concurrent thrombocytopenia and hepatotoxicity
`(n = l); thrombocytopenia (n = 1); concurrent asthenia and failure to
`thrive (n = 1); and secondary malignancy with onset retrospectively
`determined to occur before T-DMl dosing (n = 1). Six patients had
`T—DM1 dose reductions as a result of thrombocytopenia (n = 2),
`peripheral neuropathy, concurrent thrombocytopenia and neutrope-
`nia, back pain, epistaxis, and unknown reason. Five patients had
`T—DMl doses reduced to 3.0 mg/kg; one patient had a further dose
`reduction to 2.4 mg/kg.
`Thrombocytopenia, which was defined as the dose—limiting tox—
`icity in phase I,8 was not associated with serious hemorrhage. The
`most commonly reported hemorrhagic AE was grade 1 or 2 epistaxis,
`which occurred in 34% of treated patients. There were six reported
`grade 3 hemorrhagic AEs, including epistaxis (n = 2), hematochezia
`(n = 1), hemorrhoidal hemorrhage (n = 1), subdural hemorrhage
`(n = 1), and upper GI hemorrhage (n = 1). No patients discontinued
`treatment as a result of hemorrhage. Concurrent grade 3 thrombocy—
`topenia was reported in one patient with grade 3 epistaxis. Episodic
`platelet transfusions were administered to four patients for thrombo—
`cytopenia; no patient required chronic platelet transfusions.
`AEs associated with eye disorders were reported in 35 patients
`(31.3%), mostly grades 1 and 2 (commonly dry eye7 increased lacti—
`mation, vision blurred/Visual impairment, and conjunctivitis). One
`patient with a history ofglaucoma had grade 3 glaucoma and transient
`
`wwcho. org
`
`grade 4 reduced visual acuity, reported as unrelated to T—DM1; the
`patient remained on therapy without recurrence.
`Characterization of the cardiotoxicity profile of T—DMl was of
`interest, given the well—documented association of cardiotoxicity with
`trastuzumab treatment.17 No cases ofgrade 3 LVEF decline or symptom—
`atic congestive heart failure were observed; no patients discontinued treat—
`ment as a result of cardiac toxicity. Two patients had LVEF declines to
`40% to 45%. No elevations in serum troponin 1 levels were observed.
`
`Pharmacokinetics
`
`Pharmacokinetic parameter values for T-DMl from all patients
`evaluable for pharmawkinetics are shown in Table A1. T—DMl maxi—
`mum serum concentration and area under the curve in cycles 1 and 4 were
`comparable, indicating no accumulation ofT-DMI with a dosing sched—
`ule ofevery 3 weeks (Table A1). As observed in phase 1,3 total trastuzumab
`had a higher maximum serum concentration, area under the curve, and
`longer terminal half—er than T—DM1 (Figure 3). Systemic exposure to
`DM1 was consistentlylow (Fig 3); maximum DM1 levels averaged 5.35 i
`2.03 ng/mL in cycle 1. The highest reportable concentration ofDM1 was
`less than 17 ng/mL. No formal phannacokinetic analysis was possible
`because DM1 was only measurable immediately after T—DMl adminis—
`tration. Repeated T—DMI administration did not result in DM1 accumu-
`lation. Forty—four percent of patients had measurable total serum
`trastuzumab (0.044 to 66.9 ug/mL) before receiving T—DMl; thiswas not
`unexpected because patients had received prior trastuzumab treatment;
`
`© 2010 by American Society of Clinical Oncology
`
`401
`
`' lMMUNOGEN 2125, pg. 6
`Phigenix v. Immunogen
`|PR2014-00676
`
`IMMUNOGEN 2125, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`Burris III et al
`
`>
`
`
`
`Progressron-FreeResponders(proportion)
`
`O_\
`
`onO
`
`.0 c: .04s
`
`.0
`
`-- T-DM1 (n : 29)
`
`Median. not estimable
`
`95% CI, 6.2 to not estimable
`+ = censored values
`
`
`2
`4
`6
`8
`10
`12
`
`0
`
`>
`
`
`
`ProgreSSIon-FreeSurvival(proportion)
`
`1-0 M31
`13*
`P00
`g M...‘5,
`
`.C’ o:
`
`$34:.
`
`sews-um:
`has;
`ti»
`"is
`
`..., HERZnnrmal(n=2l);
`median, 2.5; 95% El, 1.4tu 3.9
`m HEHZ positive in = 74);
`median, 8.2; 35% CI, 4.4 to not estimable
`
`"mm-"w":
`"Huh“:-
`m...
`‘1..m.m..um...um
`
`C]Li o
`
`6
`
`a
`
`10
`
`12
`
`14
`
`2
`
`4
`
`No. at risk
`T-DM1
`
`29
`
`Time on Study (months)
`2O
`15
`11
`
`27
`
`5
`
`0
`
`No. at risk
`21
`HER2 normal
`HER2 positive 74
`
`Time on Study (months)
`4
`1
`U
`0
`41
`31
`26
`153
`
`11
`57
`
`D
`6
`
`0
`0
`
`B
`
`1.0
`
`a; ._
`C” E 0.8
`*— ‘l:
`
`“E e
`m o.m ._.
`.9 E 0.6
`E E 0-4
`131.2
`O 2
`L :.>_
`“- 3 '
`
`
`
`B
`
`_
`G)
`
`>a:—J
`
`100
`
`1
`
`a
`
`.——. Maximum,5.19
`
`
`E i Maximum,59.09
`
`|—# Minimum, 2.63
`
`E
`.
`g
`o
`
`-
`Maxrmum,5.19
`Median, 2.14
`
`
`
`
`
`
`
`-—T-DM1(n=108)
`W
`
`
`Median,4.6
`
`+ : censored values
`95% Cl,3.910 8.5
`
`
`
`6
`8
`10
`12
`14
`2
`4
`
`0 ,
`
`No. at risk
`T—DM1
`
`108
`
`Time on Study (months)
`52
`38
`29
`20
`
`79
`
`6
`
`o
`
`1.0
`
`m .—
`5" E 0.8
`5- 1:
`”,- oc.
`m a.m v
`E e 0'5
`
`....
`E E 0 2
`3
`'
`a:
`
`0
`
`-T—DM1(n=108)
`
`
`Median, 4.6
`95% CI, 4.1 to 6.0
`+ = censored values
`
`
`
`2
`4
`6
`8
`10
`12
`14
`
`Time on Study (months)
`No. at risk
`T—DM1
`108
`84
`60
`40
`33
`24
`8
`D
`
`
`
`
`Fig 1. Progressiom‘ree response (FPS) and duration oi objective response. (A)
`aplan-Meier plot of duration of objective response by IRF assessment,
`(B)
`aplan-lvleier plot of PFS by IRF assessment. (C) Kaplan~Meier plot of PFS by INV
`assessment. T—DM 1, trastuzumab-Dlvli.
`
`these baseline values had no impact on T—DMI exposure. Seven of 108
`evaluable patients developed anti—T—DMl antibodies, with no obvious
`impact on pharmacokineiics (Table A2).
`
`
`
`The treatment of HER2 —positive MBC after initial HER2—directed
`therapy continues to be a significant medical need. ADCs represent a
`
`402
`
`© 2010 by American Society of Clinical Oncology
`
`Cl:
`0 10
`e
`E
`U“
`E
`Lu
`I
`
`O
`
`_\ 0
`
`0 8
`
`0. 6
`
`P.b
`
`E
`5
`n
`°
`0
`Minimum, 0.51
`
`HER2 Positive
`HER2 Normal
`(n = 50)
`(n = 14)
`W, HER2 positive, 2 median (n = 25); median, not estimable;
`85% CI, 4.6 to not estimable
`~= HER2 positive, < median (n = 25); median, 4.2; 95% CI, 2.7 to 6.8
`mad"
`H“ HER2 normal (n = 21); median, 2.6; 95% CI, 1.4 to 3.8
`"
`5*“ mm...
`“is
`:
`«I
`g
`:
`Wtwparuaamww%
`I.
`5mm,
`u....- In...
`L I
`5
`grammes-mum»
`
`Progressron-FreeSurvival(proportion) o
`
`
`
`2
`
`4
`
`6
`
`s
`
`10
`
`12
`
`14
`
`
`
`Time on Study (months)
`
`25
`
`20
`
`i0
`
`5
`
`2
`
`2
`
`0
`
`El
`
`No. at risk
`HER2 positive.
`< median
`HER2 positive,
`0
`3
`10
`13
`14
`17
`18
`25
`2 median
`0
`0
`0
`0
`1
`4
`ll
`21
`HER2 Normal
`
`
`Fig 2. Efficacy based on centrally assessed human epidermal growth factor
`receptor 2 (HER2) status and quantitative reverse transcriptase polymerase chain
`reaction (qRT-PCR) expression levels of HEFr‘2.
`(A) Kaplan»l\/leier plot 0'
`progression-free survival (PFS) per independent radiologic facility (IRF) assess-
`ment, by centrally assessed HER2 status (HER2 positive or HER2 normal).
`(B)
`HER2 qRT-PCR levels by retrospectively confirmed HER2 status are shown in
`box plots as the levels of HER2 mRNA normalized to glucose-6—phosphate
`dehydrogenase mRNA expression, for centrally assessed tumor samples that
`were found to be HER2 positive (leit) and HER2 normal (right). The upper and
`lower limits within the box represent the 75th and 25th percentiles, respectively.
`Open circles represent HEFiZ expression levels from individual tumor samples.
`(C) Kaplan—lvleier plot of PFS per
`lRF assessment for centrally confirmed
`HER2—normal patients and HER2—positive patients based on expression of HER2
`measured by quT—PCR (2 and < median). PFS results presented are based on
`lRF assessment. lNV, investigator.
`
`JOURML OF CLINICAL ONCOLOGY
`
`IMMUNOGEN 2125. P9. 7
`Phigenix v. Immunogen
`|PR2014-00676
`
`IMMUNOGEN 2125, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`
`Phase II Study of T-DM1 for MBC After Prior Therapy
`
`Table 3. Adverse Events Occurring in 2 20% of Patients
`
`Grade 1 or 2 All Grades Grade 4
`Grade 3
`
`Adverse Event
`No. of Patients
`No. of Patients
`%
`No. of Patients
`%
`%
`No. of Patients %
`
`
`Adverse Events grade. Events are presented by Medical Dictionary for Regulatory Activities preferred terms.
`
`
`
`
`
`
`Diarrhea
`
`”Pyrexia
`
`{ Essex
`Constipation
`34
`30.4
`0
`
`29
`25.9
`0
`o
`0
`0
`29
`25.9"
`
`0.9
`O
`0
`27
`24.1
`Vomiting
`26
`23.2
`1
`
`in, in'féxtreim
`
`Arthralgia
`
`
`'2
`20.5
`
`Dyspnea
`20‘
`17.9 H
`NOTE. Multiple occurrences of a specific adverse event for a patient were counted once at the highest National Cancer Institute Common Terminology Criteria for
`
`
`
`novel approach for tumor—targeted therapies. By combining the tar—
`geted Specificity and efl’ector functions of trastuzumab With DM1,
`T—DMl specifically delivers the cytotoxic agent into HER2—positive
`tumors at much higher concentrations than achievable using free
`drug. Clinical development of the DMl parent compound, may—
`tansine, was stopped because of its narrow therapeutic window as a
`free agentg’lo’ls'20 The stability ofT—DMl’s MCC linker, evidenced by
`the approximately 60—fold molar difference between levels of circulat—
`ing DM1 and T—DMl, minimizes systemic exposure to DMl, contrib—
`uting to the favorable toxicity profile of T-DMl.
`In this single—arm study for heavily pretreated patients with
`HER2—positive MBC, many of whom had previously received two
`HER2—directed therapies, T—DMl administration resulted in ob—
`jective responses by [RF and investigator assessment. In a post hoc
`exploratory analysis, ORR in patients who received both prior
`lapatinib and trastuzumab was not significantly different from
`
`
`
`
`
`overall ORR, suggesting that T—DMl is active after progression on
`prior HER2—directed inhibitors.
`_/‘
`The OR in this study compares favorably with ORRs associated
`with other therapies in development for treatment of HERZ—positive
`breast cancer. Treatment with neratinib (Hm-272), an oral, irreversible
`pan—ErbB receptor tyrosine kinase inhibitor, resulted in a 24% OR
`among patients previously treated with trastuzumab.21 However, grade 3
`or 4 diarrhea was observed in 30% of patients, and 29% of patients
`required dose reduction because of this AE. Pertuzumab is an HER2—
`directed monoclonal an