KADCYLA®: The first antibody-drug conjugate
`for HER2-positive metastatic breast cancer
`
`KADCYLA contains the active
`antibody trastuzumab, the cytotoxic
`agent DM1, and a stable linker
`
`Indication
`KADCYLA® (ado-trastuzumab emtansine), 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
`
`Please see full Prescribing Information at this booth for additional important safety information, including Boxed WARNINGS.
`
`© 2013 Genentech USA, Inc. All rights reserved. TDM0002134300 (10/13)
`
`IMMUNOGEN 2229, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`The first HER2-targeted ADC
`
`KADCYLA structure
`
`A SINGLE AGENT WITH 3 COMPONENTS1-3
`
`In preclinical studies:
`
`Trastuzumab (monoclonal antibody)
`Binds to HER2 at subdomain IV to suppress
`downstream signaling
`
`MCC* (stable linker)
`Stabilizes KADCYLA in circulation to release
`DM1 after entering the target cell
`
`DM1* (cytotoxic maytansinoid)
`Inhibits tubulin polymerization to induce
`cell-cycle arrest and cell death
`
`*Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.1
`
`Proposed mechanism of action for KADCYLA, based on
`preclinical models1,4
`
`Trastuzumab antibody activities
`
`DM1† cytotoxic activity
`
`HER2 BINDING
`Selectively binds to
`HER2 receptor at
`subdomain IV
`
`TRASTuzuMAB ANTITuMOR
`ACTIVITIES
`• Suppresses ligand-independent
`HER2 downstream signaling
`(antiproliferative and
`apoptotic effects)
`• Triggers the ADCC immune
`response
`• Inhibits HER2 shedding
`
`INTERNALIzATION
`Once bound, the KADCYLA/
`HER2 receptor complex is
`internalized via endocytosis
`
`DOWNSTREAM
` SIGNALING
` PATHWAYS
`
`DM1 RELEASE
`KADCYLA is degraded inside
`the tumor to release DM1
`
`DM1 CYTOTOXICITY
`DM1 binds to microtubules and inhibits
`their polymerization, causing cell-cycle
`arrest and cell death
`
`ADCC=antibody-dependent cell-mediated cytotoxicity.
`†Cytotoxic DM1-containing catabolites (primarily lysine-bound emtansine).1
`
`References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the
`mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356. 3. Verma S, Miles D, Gianni L,
`et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;
`367:1783-1791 and Supplementary Appendix. 4. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hassmann M. Strongly enhanced antitumor activity of trastuzumab and
`pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330-9336.
`Please see full Prescribing Information at this booth for additional important safety information, including Boxed WARNINGS.
`
`© 2013 Genentech USA, Inc. All rights reserved. TDM0002134300 (10/13)
`
`IMMUNOGEN 2229, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Trial design
`
`The EMILIA trial was a large (N=991), Phase III, multi-institutional,
`open-label, randomized trial in patients with HER2+ unresectable
`locally advanced or MBC1
`
`EMILIA TRIAL DESIGN1
`
`Disease
`progression
`OR
`unacceptable
`toxicity
`
`21-day cycles
`
`KADCYLA
`3.6 mg/kg IV (Day 1)
`
`lapatinib
`1250 mg/day oral, once-daily
`
`+c
`
`apecitabine
`1000 mg/m2 oral, twice-daily
`(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)
`
`Trial endpoints
` • Primary endpoints: Progression-free survival (PFS) by independent review
`committee (IRC), overall survival (OS), safety2
` • Key secondary endpoints: PFS by investigator review, objective response rate
`(ORR), duration of response (DoR), and time to symptom progression (TTP)1
`
`Selected baseline patient characteristics
` • Most patients (>88%) had received one or more lines of systemic therapy in the
`metastatic setting1
` • More than half of the trial population (55%) had ER+ and/or PR+ disease3
` • 12% of patients received only neoadjuvant or adjuvant therapy and had
`disease relapse during or within 6 months of completing treatment1
`
`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
`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
`
`ER=estrogen receptor; PR=progesterone receptor.
`References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive
`advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;367:1783-1791 and Supplementary Appendix. 3. Data on file. Genentech, Inc.
`Please see full Prescribing Information at this booth for additional important safety information, including Boxed WARNINGS.
`
`© 2013 Genentech USA, Inc. All rights reserved. TDM0002134300 (10/13)
`
`IMMUNOGEN 2229, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Efficacy summary
`
`KADCYLA significantly increased median OS by nearly 6 months
`vs lapatinib + capecitabine; P=0.00061
`
`PRIMARY ENDPOINT: OVERALL SuRVIVAL (OS)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
`
`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
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Proportion surviving (%)
`
`No. at risk:
`KADCYLA
`lapatinib +
`capecitabine
`
`KADCYLA significantly improved progression-free survival (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)
` • Duration of response: median 12.6 months (95% CI: 8.4, 20.8) vs 6.5 months
`(95% CI: 5.5, 7.2) with lapatinib + capecitabine
`
`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
`
`CI=confidence interval; CR=complete response; PR=partial response.
`Reference: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013.
`Please see full Prescribing Information at this booth for additional important safety information, including Boxed WARNINGS.
`
`© 2013 Genentech USA, Inc. All rights reserved. TDM0002134300 (10/13)
`
`IMMUNOGEN 2229, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Safety profile
`
`MOST COMMON ADVERSE REACTIONS (ARs)1,2
`
`All Grades (%)
`
`Grades ≥3 (%)
`
`KADCYLA
`(n=490)
`
`lapatinib +
`capecitabine
`(n=488)
`
`KADCYLA
`(n=490)
`
`lapatinib +
`capecitabine
`(n=488)
`
`39.8
`
`36.3
`
`36.1
`
`31.2
`
`28.8
`
`28.2
`
`26.5
`
`24.1
`
`21.2
`
`19.2
`
`14.3
`
`14.1
`
`11.6
`
`10.2
`
`6.7
`
`1.4
`
`45.1
`
`28.3
`
`30.5
`
`3.3
`
`14.3
`
`14.5
`
`11.1
`
`79.7
`
`13.5
`
`29.9
`
`10.5
`
`32.6
`
`27.5
`
`9.4
`
`9.0
`
`59.0
`
`0.8
`
`2.5
`
`1.8
`
`14.5
`
`8.0
`
`0.8
`
`0.4
`
`1.6
`
`2.2
`
`0.8
`
`4.1
`
`0.2
`
`0.0
`
`2.7
`
`2.0
`
`0.0
`
`2.5
`
`3.5
`
`1.4
`
`0.4
`
`2.5
`
`0.8
`
`0.0
`
`20.7
`
`0.2
`
`4.5
`
`2.5
`
`2.5
`
`1.8
`
`4.7
`
`4.3
`
`17.6
`
`AR*
`
`Nausea
`
`Fatigue
`
`Musculoskeletal
`pain
`
`Thrombocytopenia
`
`Increased
`transaminases
`
`Headache
`
`Constipation
`
`Diarrhea
`
`Peripheral
`neuropathy
`
`Vomiting
`
`Anemia
`
`Stomatitis
`
`Rash
`
`Hypokalemia
`
`Neutropenia
`
`PPES
`
` • The most common NCI-CTCAE (version 3) ARs Grades ≥3 (frequency >2%)
`were thrombocytopenia, increased transaminases, anemia, hypokalemia,
`peripheral neuropathy, and fatigue1
`
`PPES=palmar-plantar erythrodysesthesia syndrome.
`*Most common ARs (>25% [all grades] or >2% [Grades ≥3] in either study arm) are included. ARs categorized according to NCI-CTCAE (version 3).
`References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Data on file. Genentech, Inc.
`Please see full Prescribing Information at this booth for additional important safety information, including Boxed WARNINGS.
`
`© 2013 Genentech USA, Inc. All rights reserved. TDM0002134300 (10/13)
`
`IMMUNOGEN 2229, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`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
`
`Additional Important Safety
`Information
`Left Ventricular Dysfunction (LVD)
`• Patients treated with KADCYLA are at increased risk
`of developing LVD. In EMILIA, LVD occurred in 1.8% of
`patients in the KADCYLA-treated group and in 3.3% in the
`comparator group. Permanently discontinue KADCYLA if
`LVEF has not improved or has declined further
`Pregnancy Registry
`• Advise patients to contact their healthcare provider
`immediately if they suspect they may be pregnant.
`Encourage women who may be exposed to KADCYLA during
`pregnancy to enroll in the MotHER Pregnancy Registry by
`contacting 1-800-690-6720
`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. Patients should be closely monitored
`for IRR reactions, especially during the first infusion
`Thrombocytopenia
`• In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia
`was 14.5% in the KADCYLA-treated group and 0.4% in
`the comparator group (overall incidence 31.2% and 3.3%,
`respectively)
`• 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 (overall incidence 21.2% and 13.5%,
`respectively)
`• 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.
`Specific treatment for KADCYLA extravasation is unknown
`Nursing Mothers
`• Discontinue nursing or discontinue KADCYLA taking into
`consideration the importance of the drug to the mother
`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 full Prescribing Information at this booth for additional important safety information, including Boxed WARNINGS.
`
`© 2013 Genentech USA, Inc. All rights reserved. TDM0002134300 (10/13)
`
`IMMUNOGEN 2229, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`