Kadcyla (Ado-Trastuzumab Emtansine):
`First Antibody-Drug Conjugate Approved for
`the Treatment of HER2-Positive Metastatic
`Breast Cancer
`Approximately 25% of women who are diagnosed
`
`13,000 patients with HER2-positive metastatic breast
`cancer will have disease recurrence after trastuzumab
`treatment.7 Concerted efforts are under way to identify
`the mechanisms of trastuzumab resistance, as well as
`novel “druggable” targets for this patient population.8
`Currently, treatment strategies for patients with tras-
`tuzumab-resistant HER2-positive breast cancer are se-
`lected on the basis of patient-specific factors (ie, age,
`comorbidities), disease- related factors, and cost.9 Thera-
`py alternatives include the combination of pertuzumab,
`trastuzumab, and a taxane; lapatinib plus trastuzumab;
`lapatinib plus capecitabine; and the continued use of
`trastuzumab plus chemotherapy.10
`
`FDA Approval of Ado-Trastuzumab Emtansine Fills
`an Unmet Need
`In February 2013, the US Food and Drug Administra-
`tion (FDA) granted accelerated approval for ado-trastu-
`zumab emtansine (Kadcyla; Genentech, Inc), also known
`as T-DM1, for the treatment of patients with HER2-pos-
`itive metastatic breast cancer who were previously treated
`with trastuzumab and with taxanes.11 The approval was
`based on the result of a single, open-label trial of patients
`with HER2-positive metastatic breast cancer: T-DM1
`demonstrated a significant 5.8-month improvement in
`median OS and a 3.2-month improvement in median
`progression-free survival (PFS) compared with the com-
`bination of lapatinib plus capecitabine.12
`In an interview regarding T-DM1, Hope S. Rugo,
`MD, Director, Breast Oncology Clinical Trials Program,
`University of California, San Francisco, stated, “Use of
`the immunoconjugate—trastuzumab linked to a micro-
`tubule inhibitor [DM1]—was shown in trials to be better
`in every way: response, progression-free survival, overall
`survival, and tolerability.”9
`According to the drug manufacturer, 1 cycle (once in
`21 days) of T-DM1 costs $9800.
`
`Dosing and Administration
`T-DM1 is administered intravenously at 3.6 mg/kg on
`day 1 of a 21-day cycle. No loading dose or premedica-
`
`1
`
`By Lisa A. Raedler, PhD, RPh
`
`with breast cancer have HER2-positive tumors.
`The HER2 gene, which resides on chromosome
`17, directs tumor cells to manufacture HER2 protein.
`This protein is a cell-surface receptor that compels the
`tumor cell to grow and to divide more frequently than
`normal, making HER2-positive breast cancer an aggres-
`sive phenotype.
`Before the advent of HER2-directed therapies, pa-
`tients diagnosed with HER2-positive disease had signifi-
`cantly shorter disease-free survival compared with pa-
`tients with other breast cancer subtypes.1
`
`Unmet Need in Trastuzumab-Resistant Breast Cancer
`The American Cancer Society estimates that ap-
`proximately 232,340 women will be diagnosed with
`invasive breast cancer, and approximately 39,620
`deaths will occur from the disease in 2013.2 Since 1989,
`death rates from breast cancer have declined, with rel-
`atively larger decreases in women aged <50 years, in
`part as a result of earlier detection and increasingly
`improved treatments.2
`Much of the increased survival for patients with
`HER2-positive breast cancer is attributed to the develop-
`ment of HER2-targeted therapies, including trastuzumab
`(Herceptin), pertuzumab (Perjeta), and
`lapatinib
`(Tykerb).3 The first phase 3 clinical trial that compared
`trastuzumab plus chemotherapy versus chemotherapy
`alone in patients with HER2-positive metastatic breast
`cancer demonstrated robust improvements in response
`rate (50% vs 32%, respectively), median time to progres-
`sion (7.4 months vs 4.6 months, respectively), and medi-
`an overall survival ([OS] 25.1 months vs 20.3 months,
`respectively) with the addition of trastuzumab.4 In addi-
`tion, 2 meta-analyses have confirmed the OS benefit of
`adding HER2-targeted therapy to standard treatment in
`patients with early-stage or metastatic HER2-positive
`breast cancer.5,6
`However, primary and secondary resistance to trastu-
`zumab occurs in the advanced breast cancer setting:
`none of these patients is cured. In 2013, approximately
`
`IMMUNOGEN 2119, 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`tions are required. Treatment with T-DM1 should be
`continued until disease progression or until unacceptable
`toxicity occurs.
`For the first infusion, T-DM1 should be administered
`over 90 minutes. Patients should be observed during the
`infusion and for at least 90 minutes after the initial dose
`for fever, chills, or other infusion-related reactions. For
`subsequent infusions, T-DM1 can be administered over
`30 minutes if previous infusions were well tolerated. Pa-
`tients should be observed during the infusion and for at
`least 30 minutes after.
`T-DM1 should not be administered at doses greater
`than 3.6 mg/kg. T-DM1 should not be substituted for or
`coadministered with trastuzumab.12
`
`Dose Modifications Based on Toxicity
`The dose of T-DM1 may be modified if hematologic or
`nonhematologic toxicities occur, including grade 3 or 4
`cytopenias; cardiac, hepatic, or renal toxicities; pulmonary
`complications; neurotoxicity; or other toxicities. In gener-
`al, T-DM1 is withheld until resolution, followed by re-
`starting therapy at the same dose or at a reduced dose,
`depending on the type of toxicity and whether it was at-
`tributable to T-DM1.12
`
`Mechanism of Action
`T-DM1 is a HER2-targeted antibody drug conjugate.
`The antibody is the humanized anti-HER2 immunoglob-
`ulin G1, ado-trastuzumab. The small-molecule drug
`DM1 is a microtubule inhibitor. On binding to subdo-
`main IV of the HER2 receptor, T-DM1 undergoes recep-
`tor-mediated internalization and lysosomal degradation,
`resulting in intracellular release of DM1-containing cy-
`totoxic catabolites. Binding of DM1 to tubulin disrupts
`microtubule networks in the cell, resulting in cell-cycle
`arrest and cell death. In vitro studies have shown that
`similar to trastuzumab, T-DM1 inhibits HER2 receptor
`signaling, mediates antibody-dependent cell-mediated
`cytotoxicity, and inhibits shedding of the HER2 extra-
`cellular domain in human breast cancer cells that over-
`express the HER2 gene.12
`The availability of an antibody drug conjugate for se-
`lected patients with breast cancer offers an exciting and
`novel approach, particularly for women who wish to
`avoid the side effects of chemotherapy. According to
`Julie R. Gralow, MD, Director, Breast Medical Oncolo-
`gy, Seattle Cancer Care Alliance, WA, T-DM1 “is a true
`magic bullet. For the 20% to 25% of breast cancer pa-
`tients that have HER2-positive breast cancer (HER2-ex-
`pressing breast cancer), this is an antibody that can take
`chemotherapy directly to the tumor cell and deliver it
`inside the cell. Then the bulk of the body does not get
`exposed to the chemotherapy.”13
`
`EMILIA: A Phase 3 Clinical Trial
`T-DM1 was approved by the FDA based on the re-
`sults of the EMILIA trial, a randomized, multicenter,
`open-label trial of 991 patients with HER2-positive,
`unresectable, locally advanced or metastatic breast can-
`cer.15 Previous taxane- and trastuzumab- based therapies
`were required before trial enrollment. Patients who had
`only received previous adjuvant therapy were required to
`have disease recurrence during or within 6 months of
`completing adjuvant therapy. Tumor samples were re-
`quired to show evidence of HER2 overexpression, de-
`fined as 3+ immunohistochemistry by Dako’s HercepT-
`est, or evidence of HER2 overexpression defined as a
`fluo rescence in situ hybridization (FISH) amplification
`ratio of ≥2.0 by Dako’s HER2 FISH pharmDx test kit.12,14
`Trial Design and Patient Popu lation. Patients in the
`EMILIA trial were randomized to T-DM1 or to lapatinib
`plus capecitabine.12 Ran domization was stratified by
`world region (ie, United States, Western Europe, or
`other), the number of previous chemotherapy regimens
`used for unresectable locally advanced or metastatic dis-
`ease, and by visceral versus nonvisceral disease as deter-
`mined by the investigators.
`T-DM1 was given intravenously at 3.6 mg/kg on day
`1 of a 21-day cycle. Lapatinib was administered orally at
`1250 mg once daily in a 21-day cycle. Capecitabine was
`administered orally at 1000 mg/m2 twice daily on days 1
`through 14 of a 21-day cycle.
`Patients were treated with T-DM1 or with lapatinib
`plus capecitabine until disease progression, consent with-
`drawal, or until reaching an unacceptable toxicity level.12
`The patient demographics and baseline tumor charac-
`teristics were balanced between treatment arms in the
`EMILIA trial.12 All patients had metastatic disease at
`study entry. The median age was approximately 53 years
`(range, 24-84 years); 74% of patients were white, 18%
`were Asian, and 5% were black. All but 5 patients were
`women. Tumor prognostic characteristics, including hor-
`mone receptor status (positive, 55%; negative, 43%),
`presence of visceral disease (68%) and nonvisceral dis-
`ease only (33%), and the number of metastatic sites (<3,
`61%; ≥3, 37%), were similar in the study arms.12
`Efficacy. Of the 991 patients who were enrolled in the
`EMILIA trial, 978 received treatment.15 The median
`dose intensity was 99.9% for patients receiving T-DM1,
`77.2% for patients receiving capecitabine, and 93.4% for
`patients treated with lapatinib. The key study findings
`are summarized in Table 1.
`Dose reduction was necessary for 16.3% of patients
`in the T-DM1 arm; capecitabine doses and lapatinib
`doses were reduced for 53.4% and 27.3% of the pa-
`tients, respectively.15
`At the time of the primary efficacy analysis, median
`
`2
`
`IMMUNOGEN 2119, 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`time with therapy was 5.7 months for T-DM1, 4.9
`months for lapatinib, and 4.8 months for capecitabine.12
`The coprimary efficacy end points were PFS based on
`tumor response assessments by an independent review
`committee and on OS.
`PFS was defined as the time from the date of random-
`ization 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 investiga-
`tor tumor response assessments, objective response rate,
`duration of response, and time to symptom progression.12
`Subgroup analyses using baseline patient characteris-
`tics indicated that the use of single-agent T-DM1 was
`superior to lapatinib plus capecitabine for all patient
`subsets except those aged ≥65 years.14 A subsequent bio-
`marker analysis demonstrated that patients in EMILIA
`whose tumors expressed high HER2 messenger RNA
`levels derived more benefit from T-DM1 than patients
`with lower levels of expression. In high HER2 express ors,
`the median PFS was 34.1 months with T-DM1 versus
`24.8 months with lapatinib plus capecitabine.16
`
`Safety Profile
`Single-agent T-DM1 has been evaluated in 884 pa-
`tients with HER2-positive metastatic breast cancer.12
`These patients received a median of 7.6 months of
`T-DM1 treatment. The most common (frequency,
`≥25%) drug-related adverse events (AEs) seen in pa-
`tients receiving T-DM1 were fatigue, nausea, musculo-
`skeletal pain, thrombocytopenia, headache, increased
`transaminases, and constipation. Grades 3 and 4 AEs
`were reported in 43.1% of patients receiving T-DM1
`and in 59.2% of patients receiving lapatinib plus
`capecitabine.
`Overall, 32 (6.5%) patients discontinued T-DM1 as a
`result of an AE. The most common AEs leading to
`T-DM1 withdrawal were thrombocytopenia and in-
`creased transaminases.
`Eighty (16.3%) patients receiving T-DM1 experi-
`enced AEs leading to dose reductions. These AEs includ-
`ed thrombocytopenia, increased transaminases, and pe-
`ripheral neuropathy.
`AEs that led to dose delays occurred in 23.7% of pa-
`tients receiving T-DM1 and included neutropenia,
`thrombocytopenia, leukopenia, fatigue, increased trans-
`aminases, and pyrexia.12
`Hepatotoxicity. Serious hepatotoxicity has been re-
`ported, including liver failure and death, in patients re-
`ceiving T-DM1. Serum transaminases and bilirubin
`should be monitored before the initiation of T-DM1
`treatment and before each T-DM1 dose. The dose of
`
`304 (61.3)
`265 (53.5)
`6.4
`9.6
`0.650 (0.549-0.771)
`<.001
`
`182 (36.7)
`149 (30.1)
`25.1
`30.9
`0.682 (0.548-0.849)
`.006
`
`389
`397
`120 (30.8)
`173 (43.6)
`12.7 (6.0-19.4)
`
`
`
`Table 1
`
` EMILIA: Efficacy End Points of Ado-Trastuzumab
`Emtansine versus Lapatinib plus Capecitabine
`Ado-trastuzumab
`Lapatinib plus
`emtansine
`capecitabine
`(N = 495)
`(N = 496)
`
`Outcome parameter
`PFS (independent review)
`Patients, N (%)
`Median PFS, mo
`
`Hazard ratio, stratifieda
`(95% CI)
`P value (log-rank test,
`stratifieda)
`Overall survivalb
`Patients, N (%)
`Median survival, mo
`Hazard ratio, stratifieda
`(95% CI)
`P value (log-rank testa)
`OR rate (independent review)
`Patients with measurable
`disease, N
`Patients with OR, N (%)
`Difference (95% CI)
`Duration of OR, mo
`Patients with OR, N
`120
`173
`Median duration,
`mo (95% CI)
`6.5 (5.5-7.2)
`12.6 (8.4-20.8)
`aStratified by world region (ie, United States, Western Europe, or
`other), number of previous chemotherapeutic regimens for locally
`advanced or metastatic disease (0-1 vs >1), and visceral versus non-
`visceral disease.
`bThe second interim analysis for OS was conducted when 331
`events were observed. The results are presented in this table.
`CI indicates confidence interval; OR, objective response; PFS,
`progression- free survival.
`Source: Kadcyla (ado-trastuzumab emtansine) for injection [pre-
`scribing information]. South San Francisco, CA: Genentech, Inc;
`February 2013.
`
`T-DM1 should be reduced or discontinued as appropri-
`ate in cases of increased serum transaminases or in-
`creased total bilirubin.12
`Cardiac Toxicity. T-DM1 administration may lead to
`reductions in left-ventricular ejection fraction. Left-ven-
`tricular function should be evaluated in all patients be-
`fore and during treatment with T-DM1. Treatment
`should be withheld if a clinically significant decrease in
`left-ventricular function is detected.12
`
`Warnings and Precautions
`A number of adverse reactions associated with T-DM1
`are discussed in the “Warnings and Precautions” section
`of the prescribing information and are summarized in
`Table 2.12
`
`3
`
`IMMUNOGEN 2119, 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`Table 2 Ado-Trastuzumab Emtansine: Warnings and Precautions
`Warnings and
`precautions
`Infusion reactions
`
`Description
`• Occurred in 1.4% of patients receiving the drug; 1 case of a serious, allergic/anaphylactic-like
`reaction was reported
`• Characterized by flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm,
`tachycardia
`• Monitor patients closely for infusion reactions, particularly during first infusion
`• Occurs within 24 hours of infusion
`• Characterized by mild erythema, tenderness, skin irritation, pain, swelling at the infusion site
`• Monitor the infusion site closely for possible subcutaneous infiltration during administration
`• Occurred in 31.2% of patients; 14.5% were grade 3/4
`• Higher incidence and severity of thrombocytopenia were noted in Asian patients
`• Monitor platelet counts frequently
`• Occurred in 21.2% of patients; 2.2% were grade 3/4
`• Monitor frequently for signs and symptoms of neurotoxicity
`• Mainly asymptomatic transient increases in serum transaminase concentrations
`• Because T-DM1 can cause elevated serum transaminases and bilirubin, liver enzymes should be
`monitored frequently
`• Serious hepatobiliary disorders, including ≥2 deaths resulting from severe drug-induced liver
`injury and associated hepatic encephalopathy, were reported
`• Of 884 patients in T-DM1 clinical trials, 3 had NRH of the liver identified from liver biopsies;
`consider NRH in patients with clinical symptoms of portal hypertension, normal transaminases,
`and no manifestations of cirrhosis
`• A decrease of LVEF to <40% has been observed in patients treated with T-DM1
`• Left-ventricular dysfunction occurred in 1.8% of patients receiving T-DM1 and in 3.3% of
`patients treated with lapatinib plus capecitabine in the randomized trial
`• Assess LVEF before initiation of T-DM1 and at regular intervals (eg, every 3 months) during
`treatment to ensure LVEF is within the institution’s normal limits
`
`Extravasation
`
`Thrombocytopenia
`
`Peripheral
`neuropathy
`Hepatic toxicity
`and hepatic failure
`
`Left-ventricular
`dysfunction
`
`Pulmonary toxicity
`
`• Cases of interstitial lung disease (eg, pneumonitis), including some leading to acute respiratory
`distress syndrome or death, have been reported
`• Pneumonitis incidence was 0.8% in clinical trials, including 1 case of grade 3
`• Exposure to T-DM1 can result in embryo-fetal death or birth defects
`Embryo-fetal
`• Patients should be advised of this risk and the need for effective contraception
`toxicity
`LVEF indicates left-ventricular ejection fraction; NRH, nodular regenerative hyperplasia; T-DM1, ado-trastuzumab emtansine.
`Source: Kadcyla (ado-trastuzumab emtansine) for injection [prescribing information]. South San Francisco, CA:
`Genentech, Inc; February 2013.
`
`The FDA has issued a warning to prescribers advising
`that they should add “ado-” to the nonproprietary name
`“trastuzumab” when discussing T-DM1 to avoid confu-
`sion between Herceptin and Kadcyla, which was report-
`ed in clinical trials.17
`
`Conclusion
`T-DM1, which several experts have called a “magic
`bullet,” combines trastuzumab and DM1 without caus-
`ing traditional chemotherapy side effects, such as alo-
`pecia, neutropenia, or vomiting. For first-, second-, and
`third-line patients with HER2-positive metastatic
`breast cancer who are resistant to trastuzumab and to
`taxanes, single-agent T-DM1 offers clinically and sta-
`tistically significant OS and PFS benefits, with a favor-
`
`able tolerability profile on a convenient, once-every-3-
`week dosing schedule. n
`
`References
`1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of re-
`lapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:
`177-182.
`2. American Cancer Society. Breast cancer: what are the key statistics about breast
`cancer? February 26, 2013. www.cancer.org/cancer/breastcancer/detailedguide/
`breast-cancer-key-statistics. Accessed May 13, 2013.
`3. Swain SM, Kim S-B, Cortes J, et al. Confirmatory overall survival (OS) analysis of
`CLEOPATRA: a randomized, double-blind, placebo-controlled phase 3 study with
`pertuzumab (P), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-pos-
`itive first-line (1L) metastatic breast cancer (MBC). Cancer Res. 2012;72 (24 suppl
`3):Abstract P5-18-26.
`4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclo-
`nal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
`N Engl J Med. 2001;344:783-792.
`5. Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of
`HER2-positive early breast cancer: a meta-analysis of published randomized trials.
`BMC Cancer. 2007;7:153.
`
`4
`
`IMMUNOGEN 2119, 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`6. Harris CA, Ward RL, Dobbins TA, et al. The efficacy of HER2-targeted agents in
`metastatic breast cancer: a meta-analysis. Ann Oncol. 2011;22:1308-1317.
`7. Genentech. Kadcyla (ado-trastuzumab emtansine) is the first FDA-approved anti-
`body-drug conjugate (ADC) for HER2-positive metastatic breast cancer. Kadcyla fact
`sheet. February 2013. www.genentech-forum.com/files/documents/kadcyla-fact-sheet.
`pdf. Accessed May 21, 2013.
`8. Tsang RY, Finn RS. Beyond trastuzumab: novel therapeutic strategies in
`HER2-positive metastatic breast cancer. Br J Cancer. 2012;106:6-13.
`9. Patient Power. ASCO update: the latest news in advanced breast cancer. YouTube.
`June 15, 2012. www.youtube.com/watch?v=ET8upnD1ujw. Accessed May 21, 2013.
`10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in
`Oncology (NCCN Guidelines)®: Breast Cancer. Version 3.2013. May 3, 2013. www.
`nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 21, 2013.
`11. US Center for Drug Evaluation and Research. Kadcyla approval letter. February 22,
`2013. www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125427Orig1s000Approv.pdf.
`Accessed May 21, 2013.
`12. Kadcyla (ado-trastuzumab emtansine) for injection [prescribing information].
`
`South San Francisco, CA: Genentech, Inc; February 2013.
`13. Patient Power. What does new HER-2 positive drug approval mean for advanced
`breast cancer? YouTube. March 13, 2013. www.youtube.com/watch?v=WkNLKKf-
`WHB8. Accessed May 21, 2013.
`14. Verma S, Miles D, Gianni L, et al, for the EMILIA Study Group. Trastuzumab em-
`tansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367:1783-1791.
`15. EMILIA: T-DM1 demonstrates greater safety, efficacy for advanced HER2-positive
`breast cancer. ASCO Daily News. June 2012. http://chicago2012.asco.org/ASCO
`DailyNews/LBA1.aspx. Accessed May 21, 2013.
`16. Baselga J, Verma S, Ro J, et al. Relationship between tumor biomarkers (BM) and
`efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-pos-
`itive metastatic breast cancer (MBC). Abstract presented at the 2013 AACR Annual
`Meeting; April 6-10, 2013; Washington, DC. Abstract LB-63.
`17. US Food and Drug Administration. FDA warns about potential medication errors
`resulting from confusion regarding nonproprietary name for breast cancer drug Kadc-
`yla (ado-trastuzumab emtansine). Podcast; updated May 7, 2013. www.fda.gov/Drugs/
`DrugSafety/DrugSafetyPodcasts/ucm351075.htm. Accessed May 23, 2013.
`
`5
`
`IMMUNOGEN 2119, 5
`Phigenix v. Immunogen
`IPR2014-00676