EMILIA: A Phase III trial establishing the efficacy and safety
`of KADCYLA for the treatment of HER2+ metastatic breast
`cancer in patients who have previously received trastuzumab
`and a taxane
`Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for
`HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.
`
`Indication
`KADCYLATM (ado-trastuzumab emtansine) injection, for intravenous use, as a single agent, is
`indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer
`(MBC) who previously received trastuzumab and a taxane, separately or in combination.
`Patients should have either:
`
`• Received prior therapy for metastatic disease, or
`• Developed disease recurrence during or within six months of completing adjuvant therapy
`
`Important Safety Information
`Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO- FETAL TOXICITY
`• Do Not Substitute KADCYLA for or with Trastuzumab
`• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure
`and death in patients treated with KADCYLA. Monitor serum transaminases and
`bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA
`dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased
`serum transaminases or total bilirubin
`• Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular
`ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to
`and during treatment with KADCYLA. Withhold treatment for clinically significant
`decrease in left ventricular function
`• Embryo- Fetal Toxicity: Exposure to KADCYLA can result in embryo- fetal death
`or birth defects. Advise patients of these risks and the need for effective
`contraception
`HER2+=human epidermal growth factor receptor 2 positive.
`
`Please see back cover for additional important safety information and accompanying full Prescribing
`Information, including Boxed WARNINGS.
`
`IMMUNOGEN 2127, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Trial design (cont'd)
`Selected eligibility criteria2
`
`Inclusion criteria
`
`• Received prior treatment with trastuzumab and a taxane, and progressed during or after the most
`recent treatment for locally advanced or metastatic disease or ≤6 months after treatment for
`early-stage disease
`• Centrally confirmed HER2+ status, assessed by means of IHC analysis (with 3+ indicating positive
`status), FISH (with an amplification ratio ≥2.0 indicating positive status), or both
`• Left ventricular ejection fraction (LVEF) ≥50% (determined by echocardiography or MUGA scanning)
`
`
`
`
`
`Exclusion criteria
`
`• Prior treatment with KADCYLA, lapatinib, or capecitabine
`
`• Peripheral neuropathy Grades ≥3
`
`• Symptomatic central nervous system metastases or treatment for these metastases ≤2 months
`before randomization
`• History of symptomatic congestive heart failure or serious cardiac arrhythmia requiring treatment
`• History of myocardial infarction or unstable angina ≤6 months before randomization
`
`
`
`
`Selected baseline patient characteristics1
`
`• Most (>88%) patients received one or more lines of systemic therapy in the metastatic setting
`
`• More than half of the study population (55%) had ER+ and/or PR+ disease
`
`Select Important Safety Information:
`Pulmonary Toxicity
`
`• Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute
`respiratory distress syndrome or fatal outcome have been reported in clinical trials with
`KADCYLA. Treatment with KADCYLA should be permanently discontinued in patients
`diagnosed with ILD or pneumonitis
`
`About KADCYLA
`KADCYLA is the first antibody-drug conjugate (ADC) approved for HER2+ MBC. It is a single agent
`comprised of trastuzumab, the cytotoxic agent DM1, and a stable linker. Based on preclinical models,
`KADCYLA maintains the activities of trastuzumab and also directs the cytotoxic DM1 to HER2-
`overexpressing cells, where it is internalized and released. Thus, KADCYLA has the mechanisms of
`action of both trastuzumab and DM1.1
`
`Trial design
`EMILIA: A global, Phase III, randomized, open label trial in patients (N=991)
`with HER2+ unresectable locally advanced or metastatic breast cancer1
`
`EMILIA TRIAL DESIGN1
`
`Disease
`progression
`OR
`unacceptable
`toxicity
`
`KADCYLA
`3.6 mg/kg IV q3w
`
`lapatinib
`1250 mg/day po qd (Days 1-21)
`
`+c
`
`apecitabine
`1000 mg/m2 po bid (Days 1-14)
`
`Randomization 1:1
`
`HER2+ patients with locally
`advanced or metastatic disease
`• Prior taxane and trastuzumab treatment
`• Progression occurred within ≤6 months
` of adjuvant therapy or during
` metastatic treatment
`(N=991)
`
`• Primary endpoints: Progression-free survival (PFS) by independent review committee (IRC),
`overall survival (OS), safety1,2
`
`• Key secondary endpoints: PFS by investigator review, objective response rate (ORR), duration of
`response (DoR), and time to symptom progression (TTP)1
`
`Select Important Safety Information:
`Thrombocytopenia
`
`• Thrombocytopenia was reported in clinical trials of KADCYLA. The incidence and severity was
`higher in Asian patients. Independent of race, the incidence and severity of severe hemorrhagic
`events was low. Monitor platelet counts prior to initiation of KADCYLA and prior to each dose.
`Institute dose modifications as appropriate
`
`Please see front and back covers for additional important safety information and accompanying full
`Prescribing Information, including Boxed WARNINGS.
`
`IHC=immunohistochemistry; FISH=fluorescence in situ hybridization; MUGA=multigated
`radionuclide angiography; ER+=estrogen receptor–positive; PR+=progesterone receptor–positive.
`
`3
`
`2
`
`IMMUNOGEN 2127, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Primary endpoints
`
`KADCYLA significantly increased median OS by 5.8 months vs
`lapatinib + capecitabine1
`
`Safety profile
`
`Adverse reactions1
`
`PRIMARY ENDPOINT: OVERALL SURVIVAL (OS)1
`
`MOST COMMON ADVERSE REACTIONS (ARs)1
`
` 30.9
`
`months
`
` 25.1
`
`months
`
`HR=0.682
`95% CI: 0.55, 0.85
`P=0.0006
`
`KADCYLA
`(n=495)
`No. of events: 149
`lapatinib + capecitabine
`(n=496)
`No. of events: 182
`
`AR (>25%, all grades)
`
`KADCYLA
`(n=490)
`
`lapatinib + capecitabine
`(n=488)
`
`KADCYLA
`(n=490)
`
`lapatinib + capecitabine
`(n=488)
`
`All Grades (%)
`
`Grades ≥3 (%)
`
`Nausea
`
`Fatigue
`
`Musculoskeletal pain
`
`Thrombocytopenia
`
`Increased transaminases
`
`39.8
`
`36.3
`
`36.1
`
`31.2
`
`28.8
`
`45.1
`
`28.3
`
`30.5
`
`3.3
`
`14.3
`
`0.8
`
`2.5
`
`1.8
`
`14.5
`
`8.0
`
`0.8
`
`2.5
`
`3.5
`
`1.4
`
`0.4
`
`2.5
`
`0.8
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Proportion surviving (%)
`
`0
`
`No. at risk:
`KADCYLA
`lapatinib +
`capecitabine
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`28
`
`30
`
`32
`
`34
`
`36
`
`Months
`
`495
`496
`
`485
`471
`
`474
`453
`
`457
`435
`
`439
`403
`
`418
`368
`
`349
`297
`
`293
`240
`
`242
`204
`
`197
`159
`
`164
`133
`
`136
`110
`
`111
`86
`
`86
`63
`
`62
`45
`
`38
`27
`
`28
`17
`
`13
`7
`
`5
`4
`
`KADCYLA significantly improved PFS (median PFS 9.6 months,
`vs 6.4 with lapatinib + capecitabine)1
`
`• PFS hazard ratio=0.65, 95% CI: 0.55, 0.77 (P<0.0001)
`
`Key secondary endpoints1
`
`• Objective response rate (CR + PR): 43.6% vs 30.8% with lapatinib + capecitabine (12.7%
`difference; 95% CI: 6.0, 19.4)
`
`
`
`• Median duration of response: 12.6 months (95% CI: 8.4, 20.8) vs 6.5 months (95% CI: 5.5, 7.2)
`with lapatinib + capecitabine
`
`Please see front and back covers for additional important safety information and accompanying full
`Prescribing Information, including Boxed WARNINGS.
`
`Headache
`
`Constipation
`
`28.2
`
`26.5
`
`14.5
`
`11.1
`
`0.4
`
`0.0
`
`
`
`• Incidence of Grades ≥3 ARs was 43.1% with KADCYLA vs 59.2% with
`lapatinib + capecitabine1
`
`Select Important Safety Information:
`Infusion Related/Hypersensitivity Reactions
`• Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently
`discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment
`with KADCYLA is not recommended for these patients. KADCYLA treatment should be interrupted
`in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR
`
`5
`
`4
`
`IMMUNOGEN 2127, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Treatment discontinuation rates (EMILIA)
`
`ADVERSE REACTION (AR) MANAGEMENT OUTCOMES
`
`Treatment discontinuation1
`
`KADCYLA
`
`6.5%
`
`lapatinib
`
`8.4%
`
`capecitabine
`
`10.5%
`
`
`
`• ARs that most commonly led to discontinuation of KADCYLA were thrombocytopenia and
`increased transaminases1
`
`Additional safety information1
`
`
`
`
`
`
`
`• The most common (frequency >25%) ARs seen with KADCYLA were nausea, fatigue, musculoskeletal
`pain, thrombocytopenia, increased transaminases, headache, and constipation
`
`• The most common NCI-CTCAE (version 3) ≥ Grade 3 adverse drug reactions (frequency >2%) were
`thrombocytopenia, increased transaminases, anemia, peripheral neuropathy, hypokalemia, and fatigue
`
`• Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction.
`In the randomized trial, left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA
`group and in 3.3% in the comparator group. Assess LVEF prior to initiation of KADCYLA and at
`regular intervals during treatment. Permanently discontinue KADCYLA if significant decreases in
`LVEF have not improved or decrease further
`
`Please see front and back covers for additional important safety information and accompanying full
`Prescribing Information, including Boxed WARNINGS.
`
`Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer
`
`Sunil Verma, MD; David Miles, MD; Luca Gianni, MD; Ian E Krop, MD, PhD; Manfred Welslau, MD;
`José Baselga, MD, PhD; Mark Pegram, MD; Do-Youn Oh, MD, PhD; Véronique Diéras, MD;
`Ellie Guardino, MD, PhD; Liang Fang, PhD; Michael W Lu, PharmD; Steven Olsen, MD, PhD;
`Kim Blackwell, MD; for the EMILIA Study Group
`
`The EMILIA trial demonstrated the therapeutic
`potential of KADCYLA for HER2+ MBC patients
`who have progressed during or after treatment
`with trastuzumab and a taxane.2
`
`References: 1. KADCYLA Prescribing Information. Genentech, Inc. February 2013. 2. Verma
`S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive
`advanced breast cancer. N Engl J Med. 2012;367:1783-1791.
`
`6
`
`7
`
`IMMUNOGEN 2127, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Additional Important Safety Information
`
`Pulmonary Toxicity
`• Cases of interstitial lung disease (ILD), including
`pneumonitis, some leading to acute respiratory distress
`syndrome or fatal outcome have been reported in clinical
`trials with KADCYLA. In EMILIA the overall frequency of
`pneumonitis was 1.2%
`• Treatment with KADCYLA should be permanently
`discontinued in patients diagnosed with ILD or pneumonitis
`Infusion-Related Reactions, Hypersensitivity Reactions
`• Treatment with KADCYLA has not been studied in patients
`who had trastuzumab permanently discontinued due to
`infusion-related reactions (IRR) and/or hypersensitivity
`reactions; treatment with KADCYLA is not recommended for
`these patients. In EMILIA, the overall frequency of IRRs in
`patients treated with KADCYLA was 1.4%
`• KADCYLA treatment should be interrupted in patients with
`severe IRR and permanently discontinued in the event of a
`life-threatening IRR
`Thrombocytopenia
`• In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia
`was 14.5% in the KADCYLA-treated group and 0.4% in the
`comparator group
`• Monitor platelet counts prior to initiation of KADCYLA and
`prior to each KADCYLA dose. Institute dose modifications as
`appropriate
`Neurotoxicity
`• In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy
`was 2.2% in the KADCYLA-treated group and 0.2% in the
`comparator group
`• Monitor for signs or symptoms of neurotoxicity. KADCYLA
`should be temporarily discontinued in patients experiencing
`Grade 3 or 4 peripheral neuropathy until resolution to
`≤ Grade 2
`
`HER2 Testing
`• Detection of HER2 protein overexpression or gene
`amplification is necessary for selection of patients
`appropriate for KADCYLA. Perform using FDA approved
`tests by laboratories with demonstrated proficiency
`Extravasation
`• In KADCYLA clinical studies, reactions secondary to
`extravasation have been observed and were generally mild.
`The infusion site should be closely monitored for possible
`subcutaneous infiltration during drug administration
`Nursing Mothers
`• Discontinue nursing or discontinue KADCYLA taking into
`consideration the importance of the drug to the mother
`Pregnancy Registry
`• Encourage women who may be exposed to KADCYLA
`during pregnancy to enroll in the MotHER Pregnancy
`Registry by contacting 1-800-690-6720
`Adverse Reactions
`• The most common ADRs seen with KADCYLA in EMILIA
`(frequency > 25%) were nausea, fatigue, musculoskeletal
`pain, thrombocytopenia, increased transaminases,
`headache, and constipation. The most common
`NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%)
`were thrombocytopenia, increased transaminases,
`anemia, hypokalemia, peripheral neuropathy and fatigue
`You are encouraged to report side effects to Genentech
`and the FDA. You may contact Genentech by calling
`1-888-835-2555. You may contact the FDA by visiting
`www.fda.gov/medwatch or calling 1-800-FDA-1088.
`
`Please see front cover for additional important safety
`information and accompanying full Prescribing
`Information, including Boxed WARNINGS.
`
`© 2013 Genentech USA, Inc. All rights reserved. TDM0001493600 Printed in USA. (02/13)
`
`IMMUNOGEN 2127, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`This reprint contains data from a Genentech-sponsored Phase III clinical trial that led to the approval of Genentech’s product KADCYLA
`(ado-trastuzumab emtansine). The FDA has approved KADCYLA™ (ado-trastuzumab emtansine) injection, for intravenous use, as a single agent,
`for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane,
`separately or in combination. Patients should have either:
`• Received prior therapy for metastatic disease, or
`• Developed disease recurrence during or within six months of completing adjuvant therapy
`This reprint contains information that is not contained in the approved product labeling, including time to symptom progression (FACT-B analysis)
`and 1-year and 2-year overall survival analyses. Please see accompanying full Prescribing Information for KADCYLA.
`The following author(s) of the attached publication are present or former employees of Genentech: Ellie Guardino, MD, PhD; Liang Fang, PhD;
`Michael W Lu, Pharm D; and Steven Olsen, MD, PhD.
`The following authors of the attached publication are or have acted as paid consultants or advisors to Genentech:
`Sunil Verma, MD; David Miles, MD; Luca Gianni, MD; Manfred Welslau, MD; José Baselga, MD, PhD; Mark Pegram, MD, and Véronique Diéras, MD.
`
`Important Safety Information
`Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO- FETAL TOXICITY
`• Do Not Substitute KADCYLA for or with Trastuzumab
`• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA.
`Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose
`or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin
`• Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular
`
`ventricular function
`• Embryo- Fetal Toxicity: Exposure to KADCYLA can result in embryo- fetal death or birth defects. Advise patients of these risks and the
`need for effective contraception
`
`Additional Important Safety Information
`Pulmonary Toxicity
`• Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in
`clinical trials with KADCYLA. In EMILIA the overall frequency of pneumonitis was 1.2%
`• Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis
`Infusion-Related Reactions, Hypersensitivity Reactions
`• Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/
`or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated
`with KADCYLA was 1.4%
`• KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR
`Thrombocytopenia
`• In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group
`•
`Neurotoxicity
`• In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group
`• Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy
`until resolution to ≤ Grade 2
`HER2 Testing
`•
`
`Extravasation
`• In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely
`
`Nursing Mothers
`• Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother
`Pregnancy Registry
`• Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720
`Adverse Reactions
`• The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased
`transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia,
`increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue
`You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by
`visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
`
`Please see accompanying full Prescribing Information for additional important safety information, including Boxed WARNINGS
`for important safety information.
`
`Please see accompanying full Prescribing Information for additional important safety information, including Boxed WARNINGS.
`
`IMMUNOGEN 2127, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`This reprint contains data from a Genentech-sponsored Phase III clinical trial that led to the approval of Genentech’s product KADCYLA
`(ado-trastuzumab emtansine). The FDA has approved KADCYLA™ (ado-trastuzumab emtansine) injection, for intravenous use, as a single agent,
`
`This reprint contains information that is not contained in the approved product labeling, including time to symptom progression (FACT-B analysis)
`
`The following author(s) of the attached publication are present or former employees of Genentech: Ellie Guardino, MD, PhD; Liang Fang, PhD;
`
`Sunil Verma, MD; David Miles, MD; Luca Gianni, MD; Manfred Welslau, MD; José Baselga, MD, PhD; Mark Pegram, MD, and Véronique Diéras, MD.
`
`• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA.
`Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose
`
`• Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular
`
`• Embryo- Fetal Toxicity: Exposure to KADCYLA can result in embryo- fetal death or birth defects. Advise patients of these risks and the
`
`Additional Important Safety Information
`Pulmonary Toxicity
`• Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in
`clinical trials with KADCYLA. In EMILIA the overall frequency of pneumonitis was 1.2%
`• Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis
`Infusion-Related Reactions, Hypersensitivity Reactions
`• Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/
`or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated
`with KADCYLA was 1.4%
`• KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR
`Thrombocytopenia
`• In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group
`•
`Neurotoxicity
`• In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group
`• Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy
`until resolution to ≤ Grade 2
`HER2 Testing
`•
`
`
`
`Extravasation
`• In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely
`
`Nursing Mothers
`• Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother
`Pregnancy Registry
`• Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720
`Adverse Reactions
`• The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased
`transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia,
`increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue
`You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by
`visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
`
`Please see accompanying full Prescribing Information for additional important safety information, including Boxed WARNINGS
`
`Please see accompanying full Prescribing Information for additional important safety information, including Boxed WARNINGS.
`
`IMMUNOGEN 2127, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`