HPK0001792100  
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`Introduction
`
`Hello. My name is <<name>>. I’m an oncology clinical coordinator (OCC) with
`Genentech. Today there will be back-to-back presentations focusing on PERJETA and
`KADCYLA, which are treatment options for human epidermal growth factor receptor 2
`positive (HER2+) metastatic breast cancer (MBC).
`
`This program is presented on behalf of Genentech, and the information presented is
`consistent with FDA guidelines.
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`PERJETA (Pertuzumab): Indications and Usage
`•  Review as stated
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc;
`April 2013.
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`KADCYLA (Ado-trastuzumab Emtansine): Indication and Usage
`•  Review as stated
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
`
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`KADCYLA (Ado-trastuzumab Emtansine): Boxed WARNINGS
`•  Review as stated
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
`
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`Metastatic Breast Cancer
`Breast cancer is the most frequently diagnosed cancer in women.1 In the United States,
`•  60% of breast cancers are detected when the cancer is localized to the breast.2
`•  MBC is the initial diagnosis in approximately 5% of women with breast cancer.2
`•  Regional breast cancer, in which the cancer has spread to regional lymph nodes, is the initial
`diagnosis in approximately 33% of women with breast cancer. In the remaining 2% of women,
`the cancer stage/localization is unknown at the time of diagnosis.2
`•  HER2 protein overexpression or HER2 gene amplification is observed in approximately 25% of
`breast cancer cases.3
`Metastasis is the spread of tumor cells from the primary tumor to distant sites in the body.
`•  Breast cancer can spread to almost any organ.4
`•  The most common sites for breast cancer metastasis are bone, brain, lung, and liver.4
`•  HER2+ tumors are most likely to recur in the viscera.5
`MBC is considered treatable but not curable.4
`•  Treatment for MBC aims to improve treatment outcomes, including slowing disease
`progression.4
`References: 1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American
`Cancer Society; 2012. 2. SEER stat fact sheets: breast. NCI website. http://seer.cancer.gov/
`statfacts/html/breast.html. Updated November 10, 2011. Accessed November 28, 2012. 3.
`Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer:
`correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science.
`1987;235(4785):177-182. 4. Foxson SB, Lattimer JG, Felder B. Breast cancer. In: Yarbro CH,
`Wujcik D, Gobel BH, eds. Cancer Nursing: Principles and Practice. 7th ed. Sudbury, MA: Jones
`and Bartlett; 2011:1091-1145. 5. Ross JS, Slodkowska EA, Symmans WF, et al. HER-2 receptor
`and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.
`Oncologist. 2009;14:320-368.
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`HER2 Signaling
`
` •
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`  Review as stated
`
`
`References: 1. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu
`proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707-712.
`2. PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013. 3. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and
`discovering ERBB3. Nat Rev Cancer. 2009;9:463-475.
`
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`HER2 Overexpression in MBC
`
` •
`
`  Review as stated
`
`
`References: 1. Foxson SB, Lattimer JG, Felder B. Breast cancer. In: Yarbro CH, Wujcik
`D, Gobel BH, eds. Cancer Nursing: Principles and Practice. 7th ed. Sudbury, MA: Jones
`and Bartlett; 2011:1091-1145. 2. PERJETA [package insert]. South San Francisco, CA:
`Genentech USA, Inc; April 2013. 3. Baselga J, Swain SM. Novel anticancer targets:
`revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9:463-475. 4. Witton
`CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1-4 family of
`receptor tyrosine kinases in breast cancer. J Pathol. 2003;200(3):290-297. 5. Wolff AC,
`Hammond EH, Schwarz JN, et al. American Society of Clinical Oncology/College of
`American Pathologists guideline recommendations for human epidermal growth factor
`receptor 2 testing in breast cancer. J Clin Oncol. 2007;25(1):1-28.
`
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`Introduction
`This portion of the presentation will discuss PERJETA, a first-line treatment for HER2-positive
`metastatic breast cancer (MBC).
`
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`Proposed Mechanism of Action of PERJETA With Herceptin: A More Comprehensive
`Blockade of HER2 Signaling
`
` •
`
`  Review as stated
`
`
`References: 1. Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-
`amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878-5887. 2.
`Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced
`antitumor activity of Herceptin and pertuzumab combination treatment on HER2-positive human
`xenograft tumor models. Cancer Res. 2009;69:9330-9336. 3. PERJETA [package insert]. South
`San Francisco, CA: Genentech USA, Inc; April 2013. 4. Hynes NE, Lane HA. ERBB receptors
`and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341-354. 5. Yarden Y,
`Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127-137.
`6. Hsieh AC, Moasser MM. Targeting HER proteins in cancer therapy and the role of the non-
`target HER3. Br J Cancer. 2007;97:453-457.
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`KEY POINT: The results of the pivotal phase 3 trial CLEOPATRA supported the approval of
`PERJETA as a first-line treatment for MBC.
`CLEOPATRA was a randomized, double-blind, placebo-controlled, phase 3 clinical trial that compared
`PERJETA plus Herceptin plus docetaxel to placebo plus Herceptin plus docetaxel.
`• 
`It was conducted in 808 patients with HER2+ locally recurrent, unresectable, or metastatic breast
`cancer
`•  Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free
`interval of ≥ 12 months before enrollment into the trial
`•  Patients were required to have evidence of HER2 overexpression defined as IHC 3+ by
`Dako HercepTest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH pharmDx™ Kit
`•  Patients were stratified by prior treatment status (de novo vs prior adjuvant/neoadjuvant
`therapy) and geographic region
`•  Patients were treated with either PERJETA plus Herceptin plus docetaxel or placebo plus Herceptin
`plus docetaxel every 3 weeks
`•  Treatment continued until disease progression, unmanageable toxicity, or withdrawal of consent
`•  The primary end point was progression-free survival (PFS), assessed by an independent review
`facility (IRF)
`•  Additional end points were overall survival (OS), objective response rate (ORR), duration of
`response (DoR), and safety
`HER2 overexpression was defined as IHC 3+ or FISH amplification ratio of 2.0 or greater. IHC 3+ is
`defined as uniform, intense membrane staining in more than 10% of tumor cells.1,2
`[click] Per protocol, one prior hormonal treatment for MBC was allowed.1,2 Adjuvant treatment with
`chemotherapy and/or Herceptin was also allowed. Patients with prior adjuvant or neoadjuvant therapy
`were required to have a disease-free interval of ≥ 12 months to be eligible for enrollment in the trial.1,2
`Randomization was stratified by prior treatment status (de novo or prior adjuvant/neoadjuvant therapy)
`and geographic region (Europe, North America, South America, and Asia).
`References: 1. PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus Herceptin
`plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
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`HPK0001792100  
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`KEY POINT: The results of the pivotal phase 3 trial CLEOPATRA supported the approval of
`PERJETA as a first-line treatment for MBC.
`CLEOPATRA was a randomized, double-blind, placebo-controlled, phase 3 clinical trial that compared
`PERJETA plus Herceptin plus docetaxel to placebo plus Herceptin plus docetaxel.
`• 
`It was conducted in 808 patients with HER2+ locally recurrent, unresectable, or metastatic breast
`cancer
`•  Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free
`interval of ≥ 12 months before enrollment into the trial
`•  Patients were required to have evidence of HER2 overexpression defined as IHC 3+ by
`Dako HercepTest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH pharmDx™ Kit
`•  Patients were stratified by prior treatment status (de novo vs prior adjuvant/neoadjuvant
`therapy) and geographic region
`•  Patients were treated with either PERJETA plus Herceptin plus docetaxel or placebo plus Herceptin
`plus docetaxel every 3 weeks
`•  Treatment continued until disease progression, unmanageable toxicity, or withdrawal of consent
`•  The primary end point was progression-free survival (PFS), assessed by an independent review
`facility (IRF)
`•  Additional end points were overall survival (OS), objective response rate (ORR), duration of
`response (DoR), and safety
`HER2 overexpression was defined as IHC 3+ or FISH amplification ratio of 2.0 or greater. IHC 3+ is
`defined as uniform, intense membrane staining in more than 10% of tumor cells.1,2
`[click] Per protocol, one prior hormonal treatment for MBC was allowed.1,2 Adjuvant treatment with
`chemotherapy and/or Herceptin was also allowed. Patients with prior adjuvant or neoadjuvant therapy
`were required to have a disease-free interval of ≥ 12 months to be eligible for enrollment in the trial.1,2
`Randomization was stratified by prior treatment status (de novo or prior adjuvant/neoadjuvant therapy)
`and geographic region (Europe, North America, South America, and Asia).
`References: 1. PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus Herceptin
`plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
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`PERJETA Extended PFS to 18.5 Months From 12.4 Months
`The primary end point in CLEOPATRA was PFS, as assessed by an IRF. (PFS is the time from
`when the patient was randomly assigned to a treatment arm in CLEOPATRA until death or
`disease progression.)
`•  Median PFS, the time when 50% (half) of patients have progressed or died in a specified arm
`of the study and half continue to be progression-free or alive, was 12.4 months in the placebo
`plus Herceptin plus docetaxel arm vs 18.5 months in the PERJETA-containing arm, an
`increase of 6.1 months.
`At the time of the final PFS analysis OS was not mature and the first interim OS analysis results
`did not meet the pre-specified stopping boundary for statistical significance.
`At the time of PFS analysis, 191 patients (47.5%) had experienced a PFS event in the PERJETA
`plus Herceptin plus docetaxel arm, compared with 242 patients (59.6%) in the placebo plus
`Herceptin plus docetaxel arm.
`•  The hazard ratio for PFS with the addition of PERJETA was 0.62.
`Consistent results were observed across several patient subgroups including age (< 65 or ≥ 65
`years), race, geographic region, prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy
`(yes or no), and prior adjuvant/neoadjuvant trastuzumab (yes or no).1,2
`
`References: 1. PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus
`Herceptin plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
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`HPK0001792100  
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`CLEOPATRA: Consistent PFS Benefit Seen Across a Broad Range of Patients
`
` •
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`  Review as stated
`
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc;
`April 2013.
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`CLEOPATRA: Consistent PFS Benefit Seen Across a Broad Range of Patients
`(cont)
`
` •
`
`  Review as stated
`
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc;
`April 2013.
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`KEY POINT: At the time of the second interim analysis, median OS had not been
`reached in the PERJETA + Herceptin + docetaxel arm because more than half of
`the patients were still alive.
`
`The graph shows the Kaplan-Meier curves for OS data at the second interim analysis,
`conducted 1 year following the first interim analysis
`•  Median follow-up was 30 months (1 year following the first interim analysis) for both
`the PERJETA-based regimen and the placebo + Herceptin + docetaxel arm (Kaplan-
`Meier estimate)1
`•  More than 50% of patients in the PERJETA + Herceptin + docetaxel arm were alive at
`the time of the second interim analysis, thereby indicating that the median OS for this
`arm has not yet been reached1
`•  At the time of the second interim analysis, there were 113 (28.1%) and 154 (37.9%)
`deaths in the PERJETA + Herceptin + docetaxel arm and the placebo + Herceptin +
`docetaxel arm, respectively1
`•  The hazard ratio and P value demonstrated a statistically significant improvement in
`OS (HR = 0.66; P = .0008).1,2 The hazard ratio and P value for the second interim
`analysis of OS crossed the pre‑defined efficacy stopping boundary.
`
`References: 1. PERJETA [package insert]. South San Francisco, CA: Genentech USA,
`Inc; April 2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group.
`Pertuzumab plus Herceptin plus docetaxel for metastatic breast cancer. N Engl J Med.
`2012;366:109-119.
`
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`CLEOPATRA: Consistent OS Benefit Demonstrated Across Several HER2+ MBC
`Patient Subgroups
`
` •
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`  Review as stated
`
`
`OS results in patient subgroups were consistent with those observed for IRF-assessed
`PFS with the exception of the subgroup of patients with disease limited to nonvisceral
`metastasis (HR = 1.42; 95% CI, 0.71-2.84).
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc;
`April 2013.
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`CLEOPATRA: Consistent OS Benefit Demonstrated Across Several HER2+ MBC
`Patient Subgroups (cont)
`
` •
`
`  Review as stated
`
`
`OS results in patient subgroups were consistent with those observed for IRF-assessed
`PFS with the exception of the subgroup of patients with disease limited to nonvisceral
`metastasis (HR = 1.42; 95% CI, 0.71-2.84).
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc;
`April 2013.
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`Boxed WARNING: Embryo-Fetal Toxicity
`
` •
`
`  Review as stated
`
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
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`Warnings and Precautions: Cardiotoxicity
`Decreases in left ventricular ejection fraction (LVEF) have been reported with drugs that block
`HER2 activity, including PERJETA.
`In CLEOPATRA, the addition of PERJETA to the combination of Herceptin and docetaxel was not
`associated with increases in left ventricular dysfunction, including cases of congestive heart
`failure (CHF). The incidence of left ventricular dysfunction in the PERJETA-based arm was 4.4%,
`compared with 8.3% in the arm with Herceptin + docetaxel alone.
`It is important to carefully select patients for PERJETA therapy and monitor them closely.
`Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during
`treatment to ensure that LVEF is within the institution’s normal limits.
`• 
`[click] Withhold PERJETA and Herceptin for at least 3 weeks if LVEF is less than 40% or if
`LVEF is 40% to 50% and is 10 percentage points or more below baseline value.
`•  Repeat LVEF assessment within 3 weeks.
`•  You can resume PERJETA and Herceptin if LVEF is greater than 45% or if LVEF is 40% to
`45% and is less than 10 percentage points below baseline. Discontinuation should be strongly
`considered if LVEF has not improved or has declined further, unless the benefits for the
`individual are deemed to outweigh the risks.
`•  PERJETA should be withheld or discontinued if Herceptin treatment is withheld or
`discontinued.
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
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`Warnings and Precautions: Infusion Reactions
`
` •
`
`  Review as stated
`
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
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`Warnings and Precautions: HER2 Testing
`
` •
`
`  Review as stated
`
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
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`Most Common Adverse Reactions (All Grades > 30% or Grades 3-4 > 2%) in CLEOPATRA
`•  Review as stated
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
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`HPK0001792100  
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`Most Common Adverse Reactions (All Grades > 30% or Grades 3-4 > 2%) in CLEOPATRA
`•  Review as stated
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
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`PERJETA Dosing and Administration
`PERJETA is administered as a fixed dose.
`PERJETA requires a loading dose of 840 mg, given intravenously over 60 minutes; subsequent
`doses are 420 mg every 3 weeks (q3w) given over a 30 to 60 minute period. Close observation of
`the patient for 60 minutes after first infusion and 30 minutes after subsequent infusions is
`recommended.
`Herceptin (trastuzumab) also requires a loading dose. For Herceptin, the loading dose is 8 mg/kg
`given intravenously over 90 minutes; subsequent doses are 6 mg/kg q3w given intravenously
`over a 30 to 60 minute period.
`[click]
`If docetaxel is discontinued, treatment with PERJETA and Herceptin should continue until
`progressive disease or unmanageable toxicity.
`PERJETA should be withheld or discontinued if Herceptin is withheld.
`
`PERJETA, trastuzumab, and docetaxel should be administered sequentially. PERJETA and
`trastuzumab can be given in any order. Docetaxel should be administered after PERJETA and
`trastuzumab. An observation period of 30 to 60 minutes is recommended after each PERJETA
`infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel [see
`Warnings and Precautions (5.3)].
`
`
`Reference: PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
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`If a Delayed or Missed Dose of PERJETA Occurs
`
`For delayed or missed doses of PERJETA, if the time between 2 sequential infusions is less than
`6 weeks, the 420-mg dose of PERJETA should be administered. Do not wait until the next
`planned dose.
`If the time between 2 sequential infusions is 6 weeks or more, the initial dose of 840 mg of
`PERJETA should be readministered as a 60-minute IV infusion followed every 3 weeks thereafter
`by a dose of 420 mg administered over 30 to 60 minutes.1
`[click] In CLEOPATRA, if the time between sequential infusions of Herceptin (trastuzumab) was 6
`weeks or more, a reloading dose (8 mg/kg) was administered.2
`[click] As directed in the prescribing information, instances for PERJETA dose interruption or
`discontinuation include the following:
`•  Left ventricular dysfunction
`•  Significant infusion reaction
`•  Herceptin: If Herceptin is discontinued, PERJETA should be discontinued
`•  Nursing mothers: In this situation, assess the importance of PERJETA to the mother and
`advise her to either discontinue nursing or discontinue PERJETA
`
`
`References: 1. PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus
`Herceptin plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
`
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`Summary
`
` •
`
`  Review as stated
`
`
`Reference: 1. PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; April
`2013.
`
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`IMMUNOGEN 2204, pg. 27
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`HPK0001792100  
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`Introduction
`This portion of the presentation will discuss KADCYLA, a treatment for HER2-positive
`metastatic breast cancer (MBC).
`
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`KADCYLA (Ado-trastuzumab Emtansine) Indication and Usage
`Review as stated.
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
`
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`KADCYLA: Boxed WARNINGS
`Review as stated.
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
`
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`KADCYLA: Warnings and Precautions
`Review as stated.
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
`
`
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`KADCYLA: Additional Important Safety Information
`Review as stated.
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`KADCYLA: Structure
`KADCYLA (ado-trastuzumab emtansine) is a HER2-targeted antibody-drug conjugate
`(ADC).
`
`[[Click]] KADCYLA contains the anti-HER2 antibody trastuzumab.
`
`[[Click]] In KADCYLA, trastuzumab is covalently linked to a microtubule inhibitory drug,
`DM1.
`•  KADCYLA contains an average of 3.5 DM1 molecules per antibody.
`
`[[Click]] DM1 is linked to trastuzumab with the stable linker MCC (4-[N-maleimidomethyl]
`cyclohexane-1-carboxylate).
`
`[[Click]] The MCC-DM1 complex is referred to as emtansine.
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`KADCYLA: Proposed Mechanism of Action
`KADCYLA has the mechanisms of action of both trastuzumab and DM1.
`
`KADCYLA, like trastuzumab, binds to subdomain IV of the HER2 extracellular domain
`(ECD).
`
`In vitro studies have shown that KADCYLA, like trastuzumab, inhibits HER2 receptor
`signaling, mediates antibody-dependent cell-mediated cytotoxicity (ADCC), and inhibits
`shedding of the HER2 ECD in human breast cancer cells that overexpress HER2.
`
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`KADCYLA: Proposed Mechanism of Action
`KADCYLA has the mechanisms of action of both trastuzumab and DM1.
`
`After binding to the HER2 protein, KADCYLA is internalized by receptor-mediated
`endocytosis.
`
`KADCYLA then undergoes lysosomal degradation, resulting in intracellular release of
`DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1).
`
`DM1, the cytotoxic component of KADCYLA, binds to tubulin. Binding of DM1 to tubulin
`disrupts microtubule networks in the cell, which results in cell-cycle arrest and apoptotic
`cell death.
`
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`EMILIA Was the Pivotal Trial for KADCYLA
`The efficacy and safety profile of KADCYLA were evaluated in a randomized,
`multicenter, open-label trial of 991 patients with HER2-positive, unresectable locally
`advanced breast cancer (LABC) or MBC. Prior taxane- and trastuzumab-based therapy
`was required before trial enrollment.
`
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`EMILIA Trial: Study Design
`•  Enrolled patients had
`•  Unresectable LABC or MBC.
`•  Prior taxane- and trastuzumab-based therapy, including prior therapy with trastuzumab and a
`taxane in the neoadjuvant or adjuvant setting, and relapse within 6 months of completing
`adjuvant therapy.
`•  HER2+ cancer based on a central laboratory assay result.
`•  Breast tumor samples were required to show HER2 overexpression defined as 3+
`immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) amplification
`ratio greater than or equal to 2.0.
`•  Patients were randomized 1:1 to receive either lapatinib plus capecitabine or KADCYLA.
`•  Randomization was stratified by world region, number of prior chemotherapy regimens for
`unresectable locally advanced or metastatic disease (0 to 1, or more than 1), and visceral vs
`nonvisceral disease.
`•  The primary end points were progression-free survival (PFS) based on tumor-response assessments by
`an independent review committee (IRC), overall survival (OS), and safety.
`•  PFS was defined as the time from the date of randomization to the date of disease progression or
`death from any cause (whichever occurred earlier).
`•  OS was defined as the time from the date of randomization to the date of death from any cause.
`•  Secondary end points included PFS based on investigator tumor-response assessments, objective
`response rate (ORR), duration of response (DOR), and time to symptom progression.
`Dosing information
`•  KADCYLA was given intravenously at 3.6 mg/kg on day 1 of a 21-day cycle. There were no
`recommended premedications.
`•  Lapatinib was administered at 1250 mg orally once per day of a 21-day cycle, and capecitabine was
`administered at 1000 mg/m2 orally twice daily on days 1 through 14 of a 21-day cycle.
`•  Patients were treated with either KADCYLA or lapatinib plus capecitabine until progression of disease,
`withdrawal of consent, or unacceptable toxicity.
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San Francisco, CA: Genentech
`USA, Inc; February 2013.
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`EMILIA Trial: Selected Patient Demographics and Baseline Tumor
`Characteristics1,2
`Patient demographics and baseline tumor characteristics were balanced between
`treatment arms.
`•  All but 5 patients were women.
`
`
`References: 1. KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013. 2. Verma S, Miles D, Gianni L, et
`al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med.
`2012;367(19):1783-1791.
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`EMILIA Trial: Patient Prior Treatment1,2,3
`Patients were balanced between treatment arms with respect to factors including type,
`number, and setting of prior systemic treatments for breast cancer.
`
`
`References: 1. KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013. 2. Verma S, Miles D, Gianni L, et
`al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med.
`2012;367(19):1783-1791. 3. Blackwell K, Miles D, Gianni L, et al. Primary results from
`EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X)
`and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC)
`previously treated with trastuzumab (T) and a taxane. Abstract presented at: ASCO 2012
`Annual Meeting; June 1-5, 2012; Chicago, IL.
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`EMILIA Trial: Primary Efficacy End Point, OS
`At the time of PFS analysis, 223 patients had died. More deaths occurred in the
`lapatinib-plus-capecitabine arm (26%) compared with the KADCYLA arm (19%);
`however, the results of this interim OS analysis did not meet the prespecified boundary
`for statistical significance.
`
`At the time of the second interim OS analysis, 331 events had occurred. The coprimary
`end point of OS was met; OS was significantly improved in patients receiving KADCYLA
`vs lapatinib plus capecitabine (HR = 0.682 [95% CI, 0.548-0.849], P = 0.0006). The
`median duration of survival was 30.9 months in the KADCYLA arm vs 25.1 months in the
`lapatinib-plus-capecitabine arm.
`
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`EMILIA Trial: Primary Efficacy End Point, PFS by IRC
`In the EMILIA trial, a statistically significant improvement in IRC-assessed PFS was
`observed in the KADCYLA-treated group vs the lapatinib-plus-capecitabine-treated
`group (HR = 0.650 [95% CI, 0.549-0.771], P < 0.0001), with an increase in median PFS
`of 3.2 months (median PFS of 9.6 months in the KADCYLA-treated group vs 6.4 months
`in the lapatinib-plus-capecitabine group).
`
`The results for PFS based on investigator assessments were similar to those observed
`for IRC-assessed PFS.
`
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`EMILIA Trial: Secondary End Points (ORR, DOR)
`Review as stated.
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`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`EMILIA Trial: Most Common Adverse Reactions
`Review as stated.
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`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`EMILIA Trial: Selected Laboratory Abnormalities
`Review as stated.
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`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`[[Slide builds]]
`EMILIA Trial: KADCYLA Dose Reductions and Discontinuations
`Review as stated.
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`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: Genentech USA, Inc; February 2013.
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`[[Slide builds]]
`EMILIA Trial: Summary
`Review as stated.
`
`Reference: KADCYLA (ado-trastuzumab emtansine) [package insert]. South San
`Francisco, CA: