Trastuzumab emtansine

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Trastuzumab emtansine
Trastuzumab emtansine.svg
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Clinical data
Trade names Kadcyla
Other namesado-trastuzumab emtansine, trastuzumab-DM1, T-DM1
AHFS/Drugs.com Monograph
MedlinePlus a613031
License data
Pregnancy
category
Routes of
administration 		Intravenous infusion
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability N/A
Protein binding 93% (in vitro)
Metabolism Liver (CYP3A4/3A5-mediated)
Elimination half-life 4 days
Identifiers
CAS Number
PubChem SID
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6448H9948N1720O2012S44·(C47H62ClN4O13S)n[ citation needed ]
Molar mass 148.5kg/mol[ citation needed ]
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Trastuzumab emtansine, [7] [8] sold under the brand name Kadcyla, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the cytotoxic agent DM1. [9] [10] [11] [12] Trastuzumab alone stops growth of cancer cells by binding to the HER2 receptor, whereas trastuzumab emtansine undergoes receptor-mediated internalization into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bind tubulin to cause mitotic arrest and cell death. [13] Trastuzumab binding to HER2 prevents homodimerization or heterodimerization (HER2/HER3) of the receptor, ultimately inhibiting the activation of MAPK and PI3K/AKT cellular signalling pathways. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the cytotoxic agent DM1 specifically to tumor cells. [14] The conjugate is abbreviated T-DM1.

Contents

In the EMILIA clinical trial [15] of women with advanced HER2 positive breast cancer who were already resistant to trastuzumab alone, it improved median overall survival by 5.8 months (30.9 months vs. 25.1 months) compared to the combination of lapatinib and capecitabine. [14] Based on that trial, the U.S. Food and Drug Administration (FDA) approved marketing on 22 February 2013. [16] [17] [18]

Trastuzumab emtansine was developed by Genentech, and is manufactured by Lonza. [19]

Medical uses

In the United States, trastuzumab emtansine was approved specifically for treatment of HER2-positive metastatic breast cancer (mBC) in patients who have been treated previously with trastuzumab and a taxane (paclitaxel or docetaxel), and who have already been treated for mBC or developed tumor recurrence within six months of adjuvant therapy. [20] [5]

Approval was based on the EMILIA study, [15] a phase III clinical trial that compared trastuzumab emtansine versus capecitabine (Xeloda) plus lapatinib (Tykerb) in 991 people with unresectable, locally advanced or metastatic HER2-positive breast cancer who had previously been treated with trastuzumab and taxane chemotherapy. [15] This trial showed improved progression-free survival in patients treated with trastuzumab emtansine (median 9.6 vs. 6.4 months), along with improved overall survival (median 30.9 vs. 25.1 months) and safety. [14]

Adverse effects

During clinical trials, the most common adverse effects of trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia (low platelet counts), headache, increased liver enzyme levels, and constipation. [5]

Severe adverse events identified during the EMILIA trial included hepatotoxicity (liver damage), including rare cases of liver failure, hepatic encephalopathy, and nodular regenerative hyperplasia; heart damage (dysfunction of the left ventricle); interstitial lung disease, including acute interstitial pneumonitis; thrombocytopenia; and peripheral neuropathy. [5] Overall, trastuzumab emtansine was better tolerated than the control treatment, a combination of lapatinib (Tykerb) and capecitabine (Xeloda), with 43% of patients in the trastuzumab emtansine group experiencing severe toxic effects, versus 59% of those who received lapatinib/capecitabine; furthermore, fewer patients had to stop treatment due to adverse effects than with lapatinib or capecitabine. [5] Anemia, low platelet counts, and peripheral neuropathy were more common among patients who received trastuzumab emtansine, whereas heart damage and gastrointestinal effects, such as vomiting, diarrhea, and stomatitis, were more common with lapatinib/capecitabine. [5]

In the United States, trastuzumab emtansine carries black box warnings for liver toxicity, heart damage (reduction in left ventricular ejection fraction), and fetal harm if given to pregnant women. [5] [18]

Chemical properties

Schematic representation of trastuzumab emtansine. The maytansine skeleton is shown in black at left. The thioether group that makes mertansine is shown in red. The linker group that makes emtansine is shown in blue at right, bound to the amino group (HN-) of a lysine residue in the trastuzumab molecule (-mab). Emtansine mab structure coloured.svg
Schematic representation of trastuzumab emtansine. The maytansine skeleton is shown in black at left. The thioether group that makes mertansine is shown in red. The linker group that makes emtansine is shown in blue at right, bound to the amino group (HN–) of a lysine residue in the trastuzumab molecule (–mab).

Trastuzumab emtansine is an antibody-drug conjugate (ADC), a combination between a monoclonal antibody and a small-molecule drug. Each molecule of trastuzumab emtansine consists of a single trastuzumab molecule with several molecules of DM1, a cytotoxic maytansinoid, attached. [21] SMCC, or succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate, is a heterobifunctional crosslinker, a type of chemical reagent that contains two reactive functional groups, a succinimide ester and a maleimide. The succinimide group of SMCC reacts with the free amino group of a lysine residue in the trastuzumab molecule[ failed verification ] and the maleimide moiety of SMCC links to the free sulfhydryl group of DM1, forming a covalent bond between the antibody and the DM1. Each trastuzumab molecule may be linked to zero to eight DM1 molecules (3.5 on average). [21] [22] DM1 binds at plus ends of cellular microtubules and thereby inhibits cell division in the target tumor cells. [23]

History

In 2013, trastuzumab emtansine was approved in the United States for the treatment of adults with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. [18] [20]

Referred to as T-DM1 during clinical research, trastuzumab emtansine was reviewed under the FDA's priority review program. [18]

The safety and effectiveness of trastuzumab emtansine were evaluated in a clinical study of 991 patients randomly assigned to receive trastuzumab emtansine or lapatinib plus capecitabine, another chemotherapy drug. [18] Patients received treatment until either the cancer progressed or the side effects became intolerable. [18] The study was designed to measure progression-free survival, the length of time patients lived without the cancer progressing, and overall survival, the length of time patients lived before death. [18]

Results showed that patients treated with trastuzumab emtansine had a median progression-free survival of 9.6 months compared to 6.4 months in patients treated with lapatinib plus capecitabine. [18] The median overall survival was 30.9 months in the trastuzumab emtansine group and 25.1 months in the lapatinib plus capecitabine group. [18]

The U.S. Food and Drug Administration (FDA) approved trastuzumab emtansine in February 2013, and granted the application for Kadcyla to Genentech. [18] The FDA granted the application for trastuzumab emtansine priority review and breakthrough therapy designations. [24]

In 2013, trastuzumab emtansine was approved in the UK, [3] and the EU. [6]

In 2019, trastuzumab emtansine was approved in the United States for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. [24]

Approval was based on KATHERINE (NCT01772472 [25] ), a randomized, multicenter, open-label trial of 1486 patients with HER2-positive EBC. [24] Breast tumor samples were required to demonstrate HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined at a central laboratory using Ventana's PATHWAY anti-HER2-/neu (4B5) Rabbit Monoclonal Primary Antibody or INFORM HER2 Dual ISH DNA Probe Cocktail assays. [24] Patients were required to have had neoadjuvant taxane and trastuzumab-based therapy with residual invasive tumor in the breast and/or axillary lymph nodes. [24] Patients received radiotherapy and/or hormonal therapy concurrent with study treatment per local guidelines. [24] Patients were randomized (1:1) to receive trastuzumab emtansine 3.6 mg/kg intravenously or trastuzumab 6 mg/kg intravenously on day 1 of a 21-day cycle for 14 cycles. [24]

The trial's primary endpoint was invasive disease-free survival (IDFS), defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. [24] After a median follow-up of 40 months, the trial demonstrated a statistically significant improvement in IDFS in patients who received trastuzumab emtansine compared with those who received trastuzumab (HR 0.50; 95% CI: 0.39, 0.64; p<0.0001). [24] Overall survival data were not mature at the time of the IDFS analysis. [24]

Society and culture

Economics

In the UK, trastuzumab emtansine was not recommended for use by the National Health Service by advisory body NICE, reportedly because an acceptable pricing agreement could not be reached with Roche. [26] Originally it cost £5,900 a month. [27] and NICE estimated it cost £166,000 per QALY [28] (well over the usual maximum). It has been funded by the English NHS Cancer Drugs Fund but in January 2015 it was proposed to remove it from the approved list. [29] After a secret discount was agreed by Roche the Cancer Drugs Fund will continue to fund it. [27]

In June 2017, the NHS Confederation and NHS Chief Executive Simon Stevens announced that the NHS would be offering trastuzumab emtansine to a limited number of women after striking a deal with Roche on the price. [30]

Names

In 2013, trastuzumab emtansine was approved in the United States with the generic name "ado-trastuzumab emtansine", [18] [20] rather than the original United States Adopted Name (USAN) issued in 2009, "trastuzumab emtansine". [20] Trastuzumab is the anti-HER2 antibody; emtansine refers to the linker-drug (SMCC-DM1). The "ado-" prefix was added at the request of the FDA to help prevent dispensing errors. [31] [20] [32] During preclinical development and clinical trials, the drug was also known as trastuzumab-DM1 or trastuzumab-MCC-DM1 (after the codename for emtansine), both abbreviated T-DM1, and by the codename PRO132365. [11]

Research

Clinical trials

Since 2013 there have been some more clinical trials:

Related Research Articles

Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within Roche. Historically, the company is regarded as the world's first biotechnology company.

<span class="mw-page-title-main">Trastuzumab</span> Medication

Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together with other chemotherapy medication. Trastuzumab is given by slow injection into a vein and injection just under the skin.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

<span class="mw-page-title-main">Pertuzumab</span> Pharmaceutical drug

Pertuzumab, sold under the brand name Perjeta, is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer; it also used in the same combination as a neoadjuvant in early HER2-positive breast cancer.

Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

<span class="mw-page-title-main">Mertansine</span> Chemical compound

Mertansine, also called DM1, is a thiol-containing maytansinoid that for therapeutic purposes is attached to a monoclonal antibody through reaction of the thiol group with a linker structure to create an antibody-drug conjugate (ADC).

<span class="mw-page-title-main">Neratinib</span> Chemical compound

Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.

Glembatumumab vedotin is an antibody-drug conjugate (ADC) that targets cancer cells expressing transmembrane glycoprotein NMB (GPNMB).

<span class="mw-page-title-main">Plant sources of anti-cancer agents</span>

Plant sources of anti-cancer agents are plants, the derivatives of which have been shown to be usable for the treatment or prevention of cancer in humans.

<span class="mw-page-title-main">Antibody–drug conjugate</span> Class of biopharmaceutical drugs

Antibody–drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.

Margetuximab, sold under the brand name Margenza, is a chimeric IgG monoclonal antibody medication against HER2 used for the treatment of cancer.

ImmunoGen, Inc. was a biotechnology company focused on the development of antibody-drug conjugate (ADC) therapeutics for the treatment of cancer. ImmunoGen was founded in 1981 and was headquartered in Waltham, Massachusetts.

<span class="mw-page-title-main">Copanlisib</span> Chemical compound

Copanlisib, sold under the brand name Aliqopa, is a medication used for the treatment of adults experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies.

<span class="mw-page-title-main">Sacituzumab govitecan</span> Antibody-drug conjugate

Sacituzumab govitecan, sold under the brand name Trodelvy by Gilead Sciences, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.

<span class="mw-page-title-main">Tucatinib</span> Chemical compound

Tucatinib, sold under the brand name Tukysa, is an anticancer medication used for the treatment of HER2-positive breast cancer. It is a small molecule inhibitor of HER2. It was developed by Array BioPharma and licensed to Cascadian Therapeutics.

<span class="mw-page-title-main">Trastuzumab deruxtecan</span> Medication

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.

Trastuzumab/hyaluronidase, sold under the brand name Herceptin SC among others, is a fixed-dose combination medication for the treatment of HER2-overexpressing breast cancer in adults. It is a combination of trastuzumab and hyaluronidase.

Nancy Lin is an American oncologist who works at the Dana-Farber Cancer Institute and is an Associate Professor of Medicine at Harvard Medical School. Her research considers new diagnostic strategies and treatment pathways for HER2 positive breast cancer.

Xavier Pivot is a French oncologist, university professor, breast cancer specialist and general director of the Strasbourg Cancer Institute.⁣⁣ He is best known for his research on treatments with trastuzumab in HER2-positive breast cancers.

References

  1. ↑ Use During Pregnancy and Breastfeeding
  2. ↑ "Kadcyla® (trastuzumab emtansine)". www.guildlink.com.au. Retrieved 27 July 2024.
  3. 1 2 "Kadcyla 100 mg Powder for Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC)". electronic medicines compendium (emc). 19 November 2019. Archived from the original on 4 December 2019. Retrieved 3 December 2019.
  4. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  5. 1 2 3 4 5 6 7 "Kadcyla- ado-trastuzumab emtansine injection, powder, lyophilized, for solution". DailyMed . 16 May 2019. Retrieved 4 December 2019.
  6. 1 2 "Kadcyla EPAR". European Medicines Agency (EMA). 17 September 2018.
  7. ↑ Niculescu-Duvaz I (June 2010). "Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2+ metastatic breast cancer". Curr. Opin. Mol. Ther. 12 (3): 350–60. PMID   20521224.
  8. ↑ USAN Council (2009). "Statement On A Nonproprietary Name Adopted By The Usan Council: Trastuzumab Emtansine" (PDF). American Medical Association. Archived from the original (PDF) on 28 September 2012. Retrieved 22 February 2013.
  9. ↑ LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX (October 2011). "Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer". Clin. Cancer Res. 17 (20): 6437–47. doi: 10.1158/1078-0432.CCR-11-0762 . PMID   22003071.
  10. ↑ Poon, Kirsten Achilles (6 May 2010). Safety Assessment of Antibody Drug Conjugates (PDF). Drug Development: From Small Molecules to Biologics. NorCal Society of Toxicology 2010 Spring Meeting. Archived from the original (PDF) on 13 April 2014. Retrieved 23 February 2013.
  11. 1 2 "Trastuzumab emtansine". National Cancer Institute (NCI). Retrieved 23 February 2013.
  12. ↑ "FDA denies accelerated approval of Genentech's trastuzumab-DM1 (T-DM1) BLA for metastatic breast cancer" (Press release). Genentech. 27 August 2010. Retrieved 23 February 2013.
  13. ↑ Teicher BA, Doroshow JH (November 2012). "The promise of antibody-drug conjugates". N. Engl. J. Med. 367 (19): 1847–8. doi:10.1056/NEJMe1211736. PMID   23134386.
  14. 1 2 3 Verma S, Miles D, Gianni L, et al. (November 2012). "Trastuzumab emtansine for HER2-positive advanced breast cancer". N. Engl. J. Med. 367 (19): 1783–91. doi:10.1056/NEJMoa1209124. PMC   5125250 . PMID   23020162.
  15. 1 2 3 Clinical trial number NCT00829166 for "A Study of Trastuzumab Emtansine Versus Capecitabine + Lapatinib in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (EMILIA)" at ClinicalTrials.gov
  16. ↑ "New data from Phase III EMILIA study showed Roche's trastuzumab emtansine (T-DM1) significantly improved survival of people with HER2-positive metastatic breast cancer" (Press release). Hoffmann-La Roche. 27 August 2012. Archived from the original on 4 November 2021. Retrieved 23 February 2013.
  17. ↑ Pollack A (22 February 2013). "F.D.A. Approves a New Drug for Advanced Breast Cancer". The New York Times . Retrieved 22 February 2013.
  18. 1 2 3 4 5 6 7 8 9 10 11 "FDA approves new treatment for late-stage breast cancer" (Press release). U.S. Food and Drug Administration (FDA). 22 February 2013. Archived from the original on 12 January 2017. Retrieved 22 February 2013.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  19. ↑ Franklin J (24 July 2014). "Lonza profit boosted by drug production outsourcing". Reuters . Retrieved 28 July 2014.
  20. 1 2 3 4 5 "Drug Approval Package: ado-trastuzumab emtansine". U.S. Food and Drug Administration (FDA). 22 February 2013. Archived from the original on 4 December 2019. Retrieved 3 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  21. 1 2 Girish S, Gupta M, Wang B, et al. (May 2012). "Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer". Cancer Chemother. Pharmacol. 69 (5): 1229–40. doi:10.1007/s00280-011-1817-3. PMC   3337408 . PMID   22271209.
  22. ↑ Lewis Phillips GD, Li G, Dugger DL, et al. (November 2008). "Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate". Cancer Res. 68 (22): 9280–90. doi: 10.1158/0008-5472.CAN-08-1776 . PMID   19010901.
  23. ↑ Lopus M (August 2011). "Antibody-DM1 conjugates as cancer therapeutics". Cancer Letters. 307 (2): 113–118. doi:10.1016/j.canlet.2011.03.017. PMC   3105156 . PMID   21481526.
  24. 1 2 3 4 5 6 7 8 9 10 "FDA approves ado-trastuzumab emtansine for early breast cancer". U.S. Food and Drug Administration (FDA) (Press release). 6 May 2019. Archived from the original on 28 September 2019. Retrieved 3 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  25. ↑ Clinical trial number NCT01772472 for "A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE)" at ClinicalTrials.gov
  26. ↑ Triggle N (8 August 2014). "NHS says no to new breast cancer drug Kadcyla". BBC News Online . Retrieved 8 August 2014.
  27. 1 2 Breast cancer drug Kadcyla to remain on NHS after manufacturer lowers price. Nov 2015
  28. ↑ "Pressure grows on Roche to lower breast cancer drug price. Aug 2014". Archived from the original on 9 June 2021. Retrieved 13 November 2015.
  29. ↑ "David Cameron's flagship Cancer Drugs Fund 'is a waste of NHS cash'". Guardian. 10 January 2015. Retrieved 11 January 2015.
  30. ↑ "NHS U-turn sees breast cancer drug Kadcyla approved for use". NursingNotes. 16 June 2017. Archived from the original on 3 June 2019. Retrieved 16 June 2017.
  31. ↑ "Drug Safety Communication: FDA warns about potential medication errors resulting from confusion regarding nonproprietary name for breast cancer drug Kadcyla (ado-trastuzumab emtansine)". U.S. Food and Drug Administration (FDA). 16 January 2016. Archived from the original on 4 December 2019. Retrieved 3 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  32. ↑ Kim TE, Pazdur R (2013). Summary Review for Regulatory Action (PDF) (Technical report). U.S. Food and Drug Administration. p. 8. Retrieved 22 February 2013.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  33. ↑ Clinical trial number NCT01120184 for "A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab (Herceptin) Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE)" at ClinicalTrials.gov. Retrieved 23 February 2013.
  34. ↑ Roche provides update on Phase III MARIANNE study in people with previously untreated advanced HER2-positive breast cancer (PDF), 2014, archived from the original (PDF) on 24 September 2015, retrieved 16 January 2015
  35. ↑ Clinical trial number NCT01641939 for "A Study of Trastuzumab Emtansine Versus Taxane in Patients With Advanced Gastric Cancer" at ClinicalTrials.gov. Retrieved 23 February 2013.
  36. ↑ "Roche's Kadcyla Fails Phase II/III Trial for Gastric Cancer". Genetic Engineering & Biotechnology News. 22 October 2015. Archived from the original on 24 October 2015. Retrieved 26 May 2017.
  37. ↑ Clinical trial number NCT01419197 for "A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-Positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-Directed Therapy (TH3RESA)" at ClinicalTrials.gov. Retrieved 23 February 2013.
  38. ↑ TDM-1 Heavy Hitter in Heavily Treated Breast Cancer. Oct 2013
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