KADCYLA™ (ado-trastuzumab emtansine) for the Treatment of HER2-Positive
`Metastatic Breast Cancer in Patients Previously Treated With Trastuzumab and a
`Taxane
`
`
`1
`
`IMMUNOGEN 2237, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`Metastatic Breast Cancer in Patients Previously Treated With Trastuzumab and a
`Taxane
`
`
`1
`
`IMMUNOGEN 2237, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Indication
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`2
`
`IMMUNOGEN 2237, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Boxed WARNINGS
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`3
`
`IMMUNOGEN 2237, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`4
`
`IMMUNOGEN 2237, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Additional Important Safety Information
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`5
`
`IMMUNOGEN 2237, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Learning Objectives
`• Review as stated
`
`6
`
`IMMUNOGEN 2237, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Overview of HER2-Positive Metastatic Breast Cancer
`
`7
`
`IMMUNOGEN 2237, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`HER2-Positive Metastatic Breast Cancer
`• Review as stated1-3
`• HER2 overexpression or amplification is observed in approximately 20-25% of breast cancer
`cases.2,3
`• HER2-positive status is associated with more aggressive tumor behavior and poorer patient
`outcomes in untreated breast cancer.1,4
`– HER2 positivity in breast cancer has been associated with increased cell
`proliferation, cell motility, tumor invasiveness, local and regional spread,
`angiogenesis, and reduced apoptosis.1
`• HER2 is a predictive biomarker of response to HER2-targeted therapy.5-8
`References
`1. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten
`years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14(4):
`320-368. 2. Nahta R, Yu D, Hung M-C, et al. Mechanisms of Disease: understanding
`resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;
`3:269-280. 3. Burris HA III, Tibbitts J, Holden SN, Sliwkowski MX, Lewis Phillips GD.
`Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2 breast cancer. Clin Breast
`Cancer. 2011;11(5):275-282. 4. 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. 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. TYKERB [package insert]. Abbotsford, Victoria: GlaxoSmithKline
`Australia Pty Ltd; October, 2012. 7. Herceptin [package insert]. South San Francisco, CA:
`Genentech USA, Inc; October 29, 2010. 8. PERJETA [package insert]. South San Francisco,
`CA: Genentech USA, Inc; June, 2012.
`
`
`8
`
`IMMUNOGEN 2237, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`FDA Approval of HER2-Targeted Metastatic Breast Cancer Therapies
`
`Four HER2-targeted therapies are now FDA-approved to treat HER2-positive metastatic
`breast cancer.
`• Trastuzumab (Herceptin®), the first, was approved for use in the metastatic setting in
`1998. Further indications in the adjuvant setting followed in 2006 and 2008.
`• Lapatinib (TYKERB®), a tyrosine kinase inhibitor that targets HER2 intracellularly,
`gained approvals in the metastatic setting in 2007 and 2010.
`• Pertuzumab (PERJETA®), an antibody that targets a different domain of HER2 than
`trastuzumab, was approved to treat metastatic HER2-positive breast cancer in
`combination with trastuzumab and docetaxel in 2012.
`• ado-trastuzumab emtansine (KADCYLATM), the first antibody-drug conjugate targeting
`HER2, was approved for metastatic HER2-positive breast cancer as a single agent in
`2013.
`
`References
`1. KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013. 2. Herceptin [package insert]. South San Francisco, CA: Genentech USA, Inc;
`October 29, 2010. 3. PERJETA [package insert]. South San Francisco, CA: Genentech
`USA, Inc; June, 2012. 4. TYKERB [package insert]. Research Triangle Park, NC:
`GlaxoSmithKline Australia Pty Ltd; October, 2012.
`
`9
`
`IMMUNOGEN 2237, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`10
`
`Additional Genentech Product Information: Metastatic Breast Cancer Indications
`and Boxed WARNINGS
`
` •
`
` Review Herceptin indications, boxed WARNINGS, and additional important safety
`information as stated.
`• Package inserts (PIs) for both Herceptin and PERJETA will be handed out with this
`presentation.
`
`
`Reference
`Herceptin [package insert]. South San Francisco, CA: Genentech USA, Inc; October 29,
`2010.
`
`IMMUNOGEN 2237, pg. 10
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`11
`
`Additional Genentech Product Information: Metastatic Breast Cancer Indications
`and Boxed WARNINGS
`
` •
`
` Review PERJETA indication, boxed WARNING, and additional important safety
`information as stated.
`• Package inserts (PIs) for both Herceptin and PERJETA will be handed out with this
`presentation.
`
`
`Reference
`PERJETA [package insert]. South San Francisco, CA: Genentech USA, Inc; June, 2012.
`
`IMMUNOGEN 2237, pg. 11
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA (ado-trastuzumab emtansine): Proposed Mechanism of Action
`
`12
`
`IMMUNOGEN 2237, pg. 12
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: The First Antibody-Drug Conjugate (ADC) for HER2-Positive Metastatic
`Breast Cancer
`KADCYLA (ado-trastuzumab emtansine) is a HER2-targeted ADC.
`•
`[[Click]] The antibody is the humanized anti-HER2 IgG1, trastuzumab.
`• [[Click]] In KADCYLA, trastuzumab is covalently linked to a small molecule cytotoxic
`microtubule inhibitory drug, DM1.
`– DM1, the cytotoxic drug 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.
`– KADCYLA contains an average of 3.5 DM1 molecules per antibody.
`[[Click]] DM1 is covalently linked to trastuzumab with the stable thioether linker MCC
`(4-[N-maleimidomethyl] cyclohexane-1-carboxylate).
`– [[Click]] The MCC-DM1 complex is referred to as emtansine.
`
`•
`
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`13
`
`IMMUNOGEN 2237, pg. 13
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA has the Proposed Mechanisms of Action of Both Trastuzumab and DM1
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`14
`
`IMMUNOGEN 2237, pg. 14
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA has the Proposed Mechanisms of Action of Both Trastuzumab and DM1
`Upon binding to subdomain IV of the HER2 receptor, KADCYLA undergoes
`• [[Click]] receptor-mediated internalization (via endocytosis), and
`• [[Click]] subsequent lysosomal degradation, resulting in
`• [[Click]] intracellular release of DM1-containing cytotoxic catabolites.
`• [[Click]] Binding of DM1 to tubulin disrupts microtubule networks in the cell, which
`results in cell cycle arrest and apoptotic cell death.
`
`
`References
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`15
`
`IMMUNOGEN 2237, pg. 15
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA (ado-trastuzumab emtansine): EMILIA Clinical Trial
`
`16
`
`IMMUNOGEN 2237, pg. 16
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Study Design
`• Review as stated
`• Breast tumor samples were required to show HER2 overexpression defined as 3+ IHC or
`FISH amplification ratio ≥ 2.0 determined at a central laboratory.
`
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`17
`
`IMMUNOGEN 2237, pg. 17
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial Endpoints
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`18
`
`IMMUNOGEN 2237, pg. 18
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Selected Patient Demographics and Baseline Characteristics
`• Review as stated
`
`References
`1. KADCYLA [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.
`
`19
`
`IMMUNOGEN 2237, pg. 19
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Selected Patient Demographics and Baseline Characteristics,
`cont’d
`• Review as stated
`
`References
`1. KADCYLA [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.
`
`20
`
`IMMUNOGEN 2237, pg. 20
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Prior Therapy
`• Review as stated
`• The majority of patients (88%) had received prior systemic treatment in the metastatic
`setting.
`– Twelve percent of patients had prior treatment only in the neoadjuvant or
`adjuvant setting and had disease relapse within 6 months of treatment.
`• All but one patient received trastuzumab prior to study entry; approximately 85% of
`patients received prior trastuzumab in the metastatic setting.
`• Over 99% percent of patients had received a taxane, and 61% of patients had received
`an anthracycline prior to study entry.
`• Overall, patients received a median of 3 systemic agents in the metastatic setting.
`• Among patients with hormone receptor–positive tumors, 44.4% received prior adjuvant
`hormonal therapy and 44.8% received hormonal therapy for locally advanced/metastatic
`disease.
`
`
`References
`1. KADCYLA [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.
`
`21
`
`IMMUNOGEN 2237, pg. 21
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Progression-Free Survival (Independent Review Committee)
`• The randomized trial demonstrated a statistically significant improvement in independent review
`committee (IRC)-assessed PFS in the KADCYLA-treated group compared with the lapatinib plus
`capecitabine-treated (comparator) group (hazard ratio [HR] = 0.65, 95% confidence interval [CI],
`0.55-0.77, P < 0.0001), and 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 comparator group). The results for
`investigator-assessed PFS were similar to those observed for IRC-assessed PFS.
`– There were 265 events (53.5%) in the KADCYLA group vs 304 events (61.3%) in the
`comparator group.
`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.
`• In the subgroup of patients with hormone receptor–negative disease (n = 426), the HRs for PFS
`and OS were 0.56 (95% CI, 0.44-0.72) and 0.75 (95% CI, 0.54-1.03), respectively.
`• In the subgroup of patients with hormone receptor–positive disease (n = 545), the HRs for PFS
`and OS were 0.72 (95% CI, 0.58-0.91) and 0.62 (95% CI, 0.46-0.85), respectively.
`• In the subgroup of patients with non-measurable disease (n = 205), based on IRC assessments,
`the HRs for PFS and OS were 0.91 (95% CI, 0.59-1.42) and 0.96 (95% CI, 0.54-1.68),
`respectively; in patients with measurable disease the HRs were 0.62 (95% CI, 0.52-0.75) and
`0.65 (95% CI, 0.51-0.82), respectively.
`• The PFS and OS HRs in patients who were younger than 65 years old (n = 853) were 0.62 (95%
`CI, 0.52-0.74) and 0.66 (95% CI, 0.52-0.83), respectively. In patients ≥ 65 years old (n = 138), the
`HRs for PFS and OS were 1.06 (95% CI, 0.68-1.66) and 1.05 (95% CI, 0.58-1.91), respectively.
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February 2013.
`
`22
`
`IMMUNOGEN 2237, pg. 22
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Median Overall Survival
`• At the time of the confirmatory analysis, 331 events had occurred. The primary endpoint of OS
`was met; OS was significantly improved in patients receiving KADCYLA (HR = 0.68; 95% CI,
`0.55-0.85; P = 0.0006). This result crossed the pre-specified efficacy stopping boundary (HR =
`0.73 or P = 0.0037). The median duration of survival was 30.9 months in the KADCYLA arm vs
`25.1 months in the comparator arm.
`– There were 149 events (30.1%) in the KADCYLA group vs 182 events (36.7%) in the
`comparator group.
`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.
`• In the subgroup of patients with hormone receptor–negative disease (n = 426), the HRs for PFS
`and OS were 0.56 (95% CI, 0.44-0.72) and 0.75 (95% CI, 0.54-1.03), respectively.
`• In the subgroup of patients with hormone receptor–positive disease (n = 545), the HRs for PFS
`and OS were 0.72 (95% CI, 0.58-0.91) and 0.62 (95% CI, 0.46-0.85), respectively.
`• In the subgroup of patients with non-measurable disease (n = 205), the HRs for PFS and OS
`were 0.91 (95% CI, 0.59-1.42) and 0.96 (95% CI, 0.54-1.68), respectively; in patients with
`measurable disease the HRs were 0.62 (95% CI, 0.52-0.75) and 0.65 (95% CI, 0.51-0.82),
`respectively.
`• The PFS and OS HRs in patients who were younger than 65 years old (n = 853) were 0.62 (95%
`CI, 0.52-0.74) and 0.66 (95% CI, 0.52-0.83), respectively. In patients ≥ 65 years old (n = 138), the
`HRs for PFS and OS were 1.06 (95% CI, 0.68-1.66) and 1.05 (95% CI, 0.58-1.91), respectively.
`
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February 2013.
`
`23
`
`IMMUNOGEN 2237, pg. 23
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Overall Response Rate and Median Duration of Response
`• Objective response rate:
`– There were 397 and 389 patients in the KADCYLA and comparator groups,
`respectively, with measurable disease. Of these, 173 (43.6%) of 397 KADCYLA-
`treated and 120 (30.8%) of 389 comparator-treated patients had an objective
`response.
`• [[Click]] Duration of response:
`– Of the patients with an objective response (ie, 173 and 120 patients, above),
`median durations of response were as follows: [[click]] 12.6 months (95% CI,
`8.4-20.8) and 6.5 months (95% CI, 5.5-7.2) in the KADCYLA and comparator
`groups, respectively.
`
`
`References
`1. KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013. 2. Verma S, Miles D, Gianni L, et al. Updated overall survival results from EMILIA, a
`phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine and lapatinib in HER2-
`positive locally advanced or metastatic breast cancer. Oral presentation at: European
`Society for Medical Oncology Congress; September 28 to October 2, 2012; Vienna,
`Austria.
`
`
`24
`
`IMMUNOGEN 2237, pg. 24
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Most Common Adverse Reactions (ARs) Occurring in > 25% in
`Either Study Arm
`• Review as stated
`• The median duration of study treatment was 7.6 months for patients in the KADCYLA-
`treated group and 5.5 months and 5.3 months for patients treated with lapatinib and
`capecitabine, respectively.
`• Dose adjustments for KADCYLA were permitted.
`• The most common ARs seen with KADCYLA in the randomized trial (frequency > 25%)
`were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased
`transaminases, headache, and constipation.
`• The most common NCI–CTCAE (version 3) ≥ Grade 3 ARs (frequency >2%) were
`thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral
`neuropathy, and fatigue.
`
`
`In your packet, you will find a full summary of adverse drug reactions in the EMILIA
`trial.
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`25
`
`IMMUNOGEN 2237, pg. 25
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA (ado-trastuzumab emtansine): Dosing and Safety
`
`26
`
`IMMUNOGEN 2237, pg. 26
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Recommended Dose and Schedule
`• Review as stated
`• The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion
`every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
`
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`27
`
`IMMUNOGEN 2237, pg. 27
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Look-Alike/Sound-Alike Medication
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`28
`
`IMMUNOGEN 2237, pg. 28
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Dosing Schedule, Infusion-Related and Hypersensitivity Reactions
`• Review as stated
`• Closely monitor the infusion site for possible subcutaneous infiltration during drug
`administration.
`• Infusion-related reactions (IRRs), characterized by one or more of the following
`symptoms: flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm,
`and tachycardia have been reported in clinical trials of KADCYLA.
`• In the EMILIA clinical trial, the overall frequency of IRRs in patients treated with
`KADCYLA was 1.4%. In most patients, these reactions resolved over the course of
`several hours to a day after the infusion was terminated.
`• KADCYLA treatment should be interrupted in patients with severe IRR.
`• KADCYLA treatment should be permanently discontinued in the event of a life-
`threatening IRR.
`• Patients should be observed closely for IRRs, especially during the first infusion.
`• One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical
`trials of single-agent KADCYLA. Medications to treat such reactions, as well as
`emergency equipment should be available for immediate use.
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`29
`
`IMMUNOGEN 2237, pg. 29
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Dose Interruption, Reduction, and Discontinuation
`• Review as stated
`• Management of increased serum transaminases, hyperbilirubinemia, left ventricular
`dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require
`temporary interruption, dose reduction or treatment discontinuation of KADCYLA as per
`guidelines provided on slides.
`
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`30
`
`IMMUNOGEN 2237, pg. 30
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Dose Reductions
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`31
`
`IMMUNOGEN 2237, pg. 31
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Hepatotoxicity: Pre-assessment, Monitoring, and Management Guidelines
`• Review as stated
`• Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the
`concentrations of serum transaminases, has been observed in clinical trials with
`KADCYLA. Serious hepatobiliary disorders, including at least two fatal cases of severe
`drug-induced liver injury and associated hepatic encephalopathy, have been reported in
`clinical trials with KADCYLA. Some of the observed cases may have been confounded
`by comorbidities and/or concomitant medications with known hepatotoxic potential.
`– Monitor serum transaminases and bilirubin prior to initiation of KADCYLA
`treatment and prior to each KADCYLA dose. Patients with known active hepatitis
`B virus or hepatitis C virus were excluded from the EMILIA clinical trial.
`– Reduce the dose or discontinue KADCYLA as appropriate in cases of increased
`serum transaminases and/or total bilirubin.
`– Permanently discontinue KADCYLA treatment in patients with serum
`transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA
`has not been studied in patients with serum transaminases > 2.5 x ULN or
`bilirubin > 1.5 x ULN prior to the initiation of treatment.
`• In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the
`liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of
`these three cases of NRH were observed in the EMILIA clinical trial.
`– Upon diagnosis of NRH, KADCYLA treatment must be permanently
`discontinued.
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`
`32
`
`IMMUNOGEN 2237, pg. 32
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Left Ventricular Cardiac Dysfunction: Pre-assessment, Monitoring, and Management
`Guidelines
`• Review as stated
`• Patients treated with KADCYLA are at increased risk of developing left ventricular
`dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with
`KADCYLA.
`– In the EMILIA clinical trial, left ventricular dysfunction occurred in 1.8% of
`patients in the KADCYLA-treated group and 3.3% of patients in the comparator
`group.
`• Assess LVEF prior to initiation of KADCYLA and at regular intervals (eg, every 3 months)
`during treatment to ensure the LVEF is within the institution’s normal limits.
`– Perform standard cardiac assessment by echocardiogram or MUGA scan.2
`– Treatment with KADCYLA has not been studied in patients with LVEF < 50%
`prior to initiation of treatment.
`– Patients with a history of symptomatic congestive heart failure (CHF), serious
`cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6
`months were excluded from the EMILIA clinical trial.
`• Modify dose, as appropriate, according to dose reduction guidelines shown on the slide.
`
`References
`1. KADCYLA [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.
`
`
`33
`
`IMMUNOGEN 2237, pg. 33
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Thrombocytopenia: Pre-assessment, Monitoring, and Management Guidelines
`• Review as stated
`• In the EMILIA clinical trial, the overall frequency of thrombocytopenia was 31.2% in the
`KADCYLA-treated group and 3.3% in comparator group. The incidence of ≥ Grade 3
`thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the
`comparator group. In Asian patients, the incidence of > Grade 3 thrombocytopenia was
`45.1% in the KADCYLA-treated group and 1.3% in the comparator group.
`• Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose.
`– KADCYLA has not been studied in patients with platelet counts <100,000/mm3
`prior to initiation of treatment.
`• In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not
`administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3).
`• Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant
`treatment should be closely monitored during treatment with KADCYLA.
`• A reduction in dose is recommended in the case of grade 4 thrombocytopenia (platelets
`< 25,000/mm3).
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`34
`
`IMMUNOGEN 2237, pg. 34
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`35
`
`Pulmonary Toxicity and Neurotoxicity: Monitoring and Management Guidelines
`• Review as stated
`
` •
`
` 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. Signs and symptoms include dyspnea, cough, fatigue, and
`pulmonary infiltrates. These events may or may not occur as sequelae of infusion
`reactions. In the EMILIA clinical trial, the overall frequency of pneumonitis was 1.2%.
`– Patients with dyspnea at rest due to complications of advanced malignancy and
`co-morbidities may be at increased risk of pulmonary toxicity.
`
` •
`
` Neurotoxicity: In the EMILIA clinical trial, the overall frequency of peripheral neuropathy
`was 21.2% in the KADCYLA-treated group and 13.5% in the comparator group.
`– The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-
`treated group and 0.2% in the comparator group.
`
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`IMMUNOGEN 2237, pg. 35
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`36
`
`IMMUNOGEN 2237, pg. 36
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`37
`
`IMMUNOGEN 2237, pg. 37
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`38
`
`IMMUNOGEN 2237, pg. 38
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`39
`
`IMMUNOGEN 2237, pg. 39
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`40
`
`IMMUNOGEN 2237, pg. 40
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`41
`
`IMMUNOGEN 2237, pg. 41
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`42
`
`IMMUNOGEN 2237, pg. 42
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Important Safety Information, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`43
`
`IMMUNOGEN 2237, pg. 43
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Summary
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`44
`
`IMMUNOGEN 2237, pg. 44
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Summary, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`45
`
`IMMUNOGEN 2237, pg. 45
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Genentech Patient Resources
`• Review as stated
`
`Reference
`Patient access programs. Genentech website. http://www.gene.com/gene/products/
`access/. Accessed October 2, 2012.
`
`46
`
`IMMUNOGEN 2237, pg. 46
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Questions?
`
`
`47
`
`IMMUNOGEN 2237, pg. 47
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Supplemental Slides
`
`48
`
`IMMUNOGEN 2237, pg. 48
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Adverse Reactions
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`49
`
`IMMUNOGEN 2237, pg. 49
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Adverse Reactions, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`50
`
`IMMUNOGEN 2237, pg. 50
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Adverse Reactions, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`51
`
`IMMUNOGEN 2237, pg. 51
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Adverse Reactions, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`52
`
`IMMUNOGEN 2237, pg. 52
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Adverse Reactions, cont’d
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`53
`
`IMMUNOGEN 2237, pg. 53
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`EMILIA Clinical Trial: Selected Laboratory Abnormalities
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`54
`
`IMMUNOGEN 2237, pg. 54
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`Optional Slides for Pharmacy Audience
`
`55
`
`IMMUNOGEN 2237, pg. 55
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: How Supplied
`• KADCYLA is used as a single agent, not in combination with Herceptin.
`• In order to prevent medication errors it is important to check the vial labels to ensure that the drug
`being prepared and administered is KADCYLA (ado-trastuzumab emtansine) and not Herceptin
`(trastuzumab). Herceptin and KADCYLA vials look alike and the medication names sound alike.
`• Confirm vial label. KADCYLA (ADO-trastuzumab EMTANSINE) and Herceptin (trastuzumab) have
`similar generic names, but have important differences including dosing and indication.
`– Do not administer KADCYLA at doses greater than 3.6 mg/kg.
`– Do not substitute KADCYLA for or with trastuzumab.
`• In order to improve traceability of biological medicinal products, the tradename of the
`administered product should be clearly recorded (or stated) in the patient file.
`• There is no known antidote for overdose of KADCYLA. In clinical trials, overdose of KADCYLA
`has been reported at approximately two times the recommended dose which resulted in Grade 2
`thrombocytopenia (resolved 4 days later) and one death. In the fatal case, the patient incorrectly
`received KADCYLA at 6 mg/kg and died approximately 3 weeks following the overdose; a cause
`of death and a causal relationship to KADCYLA were not established.
`– Note that loading (8 mg/kg) and maintenance (6 mg/kg) doses of Herceptin are above or
`close to the dose at which overdose of KADCYLA has been reported (approximately 2
`times the recommended dose of 3.6 mg/kg).
`– Note that a loading dose is not used when administering KADCYLA.
`Reference
`1. KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February 2013.
`2. Herceptin [package insert]. South San Francisco, CA: Genentech USA, Inc; October 29, 2010.
`
`56
`
`IMMUNOGEN 2237, pg. 56
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA: Preparation for Administration
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`57
`
`IMMUNOGEN 2237, pg. 57
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA Storage and Handling
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`58
`
`IMMUNOGEN 2237, pg. 58
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA Preparation for Administration: Reconstitution
`• Review as stated
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`59
`
`IMMUNOGEN 2237, pg. 59
`Phigenix v. Immunogen
`IPR2014-00676
`
`
`
`KADCYLA Preparation for Administration: Dilution
`• Review as stated
`• The diluted KADCYLA infusion solution should be used immediately. If not used
`immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for
`up to 4 hours prior to use. Do not freeze or shake.
`
`
`Reference
`KADCYLA [package insert]. South San Francisco, CA: Genentech USA, Inc; February
`2013.
`
`60
`
`IMMUNOGEN 2237, pg. 60
`Phigenix v. Immunogen
`IPR2014-00676
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
