KaDcyLa™ (ado-trastuzumab emtansine) is the first fDa-approved antibody-Drug conjugate (aDc)
`for her2-Positive Metastatic Breast cancer
`
`Disease state Overview
`
`• In 2013, 232,340 women are expected to be diagnosed with breast cancer in the U.S., and 39,630 are expected to die from it.1
`• Breast cancer is the most frequently diagnosed cancer in women* and is the second leading cancer killer among women.1 From 2005 – 2009, the median age
`at diagnosis for cancer of the breast was 61 years of age.2 Approximately 5% of breast cancer cases are metastatic at diagnosis.2 Approximately 25% of breast
`cancers exhibit overexpression of the HER2 protein, amplification of the HER2 gene, or both.3,4 Untreated metastatic HER2-positive breast cancer presents
`with an aggressive disease progression profile and poor patient outcomes.5
`• In 2013, an estimated 13,000 women may require treatment for HER2-positive metastatic breast cancer following recurrence with first-line treatment.6
`• 7–8% of HER2-positive adjuvant breast cancer patients (up to 576 patients) are estimated to develop disease recurrence during or within 6 months of
`completing adjuvant therapy.7
`*Excluding cancers of the skin
`
`inDicatiOn anD DOsing
`
`• KADCYLA™ (ado-trastuzumab emtansine) injection, for intravenous use, as a single agent, is indicated 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.8
`• The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle).8 There is no loading dose required.
`• KADCYLA should be continued until disease progression or until unacceptable toxicity.8
`
`PrOPOseD MechanisM Of actiOn
`
`• KADCYLA is a HER2-targeted ADC that exhibits the mechanisms of trastuzumab and the intracellular cytotoxic activity of DM1.8
`• Based on preclinical models, KADCYLA has been shown to work via the following steps:8
` − HER2 binding: KADCYLA selectively binds to HER2 receptor at subdomain IV
` − Trastuzumab activity: inhibits HER2 signaling, triggers the ADCC* immune response, and inhibits HER2 shedding
` − Internalization: once bound, the KADCYLA/HER2 receptor complex is internalized via endocytosis
` − DM1† release: KADCYLA is degraded inside the cell 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
`†The primary DM1-containing cytotoxic catabolite released is lysine-MCC-DM1
`
`PrODuct efficacy
`• EMILIA, a pivotal randomized, multicenter, open-label, Phase III study (N=991), demonstrated statistically significant improvements in overall and
`progression-free survival in HER2-positive mBC patients previously treated with trastuzumab and a taxane.8
`• The median age of patients in the pivotal study was approximately 53 years (range 24 – 84 years).8
`• KADCYLA demonstrated a 5.8-month improvement in median overall survival (OS) and a 3.2-month improvement in median progression-free survival (PFS)
`as assessed by an independent review committee (IRC).8
`
`Primary endpoints
`
`KaDcyLa (n = 495)
`
`Lapatinib + capecitabine (n = 496)
`
`hr (95% ci)
`0.682
`(0.548, 0.849)
`0.650
`(0.549, 0.771)
`• Patient demographics and baseline tumor characteristics were balanced between treatment arms. A treatment benefit with KADCYLA in terms of PFS and
`OS was observed in patient subgroups based on stratification factors, key baseline demographic and disease characteristics, and prior treatments.8
`
`Overall survival (median months)
`
`Progression-free survival
`(median months)
`
`30.9
`
`9.6
`
`25.1
`
`6.4
`
`P value
`
`0.0006
`
`< 0.0001
`
`BOXeD warnings
`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 reverse for additional important safety information and accompanying full Prescribing information, including Boxed warnings.
`
`IMMUNOGEN 2145, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`aDDitiOnaL iMPOrtant safety infOrMatiOn
`
`• 43.1% of patients experienced ≥ Grade 3 adverse events in the KADCYLA-treated group compared with 59.2% of patients in the lapatinib +
`capecitabine-treated group.8
`• 6.5% discontinued KADCYLA due to an adverse event, compared with 8.4% who discontinued lapatinib and 10.5% who discontinued capecitabine
`due to an adverse event.8
`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.
`
`suPPL y anD DistriButiOn
`• KADCYLA (ado-trastuzumab emtansine) is available through authorized specialty distributors and wholesalers.
`
`• KADCYLA is supplied as a lyophilized powder in single-use vials: 100 mg per vial (NDC 50242-088-01) or 160 mg per vial (NDC 50242-087-01).
`Store vials in a refrigerator at 2-8°C (36-46°F) until time of use.8
`
`Please see KaDcyLa full Prescribing information including Boxed warnings for additional important safety information.
`
`References: 1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013. 2. SEER Stat Fact Sheets: Breast. National Cancer Institute Web
`site. http://seer.cancer.gov/statfacts/html/breast.html. Accessed February 14, 2013. 3. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival
`with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182. 4. 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. 5. Wolff AC, Hammond ME, Schwartz 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):118-145. 6. Data on file, Genentech, Inc. 7. Slamon
`DJ, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-83. 8. KADCYLA™ (ado-trastuzumab emtansine) full
`prescribing information. Genentech, Inc., February 2013.
`
`©2013 Genentech, Inc., So. San Francisco, CA TDM0001305100 2/13
`
`IMMUNOGEN 2145, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`