Trastuzumab Emtansine

Publication Details



Trastuzumab emtansine (also known as ado-trastuzumab emtansine) is a humanized monoclonal antibody to the human epidermal growth factor receptor-2 (HER2) conjugated with a microtubule inhibitor which is used in the therapy of advanced, metastatic breast cancer. Trastuzumab emtansine has been linked to frequent serum enzyme elevations during therapy, to occasional instance of acute clinically apparent liver injury and, when given chronically, to nodular regenerative hyperplasia and noncirrhotic portal hypertension.


Trastuzumab (tras tooz’ ue mab) emtansine (em tan’ seen) is a humanized monoclonal antibody to the human epidermal growth factor receptor-2 (HER2) conjugated to emtansine (DM1), a cytotoxic microtubule inhibitor, which is used in the therapy of advanced or metastatic forms of breast cancer that express HER2. The monoclonal antibody is linked by a cleavable tetrapeptide to the microtubule inhibitor which is released intracellularly after the conjugate binds to and is taken up by HER2 expressing cancer cells. Within the cancer cell, emtansine is released by lysosomal enzymes that cleave the linker molecule. The released emtansine then binds to microtubules causing cell cycle arrest and apoptotic cell death. This conjugate was shown to induce objective responses and improve survival in patients with unresectable or metastatic breast cancer who had progressed despite previous therapies, and it was approved for this indication in the United States in 2013. The antibody conjugate is available in single use vials of 100 mg per vial or 160 mg lyophilized powder under the brand name Kadcyla. The recommended dose is 3.6 mg/kg intravenously every 3 weeks until disease progression or intolerability. The antibody conjugate has a higher rate of adverse side effects than trastuzumab alone. The common adverse events include fatigue, nausea, vomiting, diarrhea, fever, myalgias, headache, constipation, serum enzyme elevations and thrombocytopenia. Less common but potential severe adverse events include hepatotoxicity, anaphylaxis, heart failure and embryo-fetal toxicity. Trastuzumab emtansine should be prescribed and administered only by health care workers with expertise and experience in cancer chemotherapy and management of its adverse events.


In large registration trials of trastuzumab emtansine for breast and other cancers, serum enzyme elevations occurred in 20% to 80% of patients and levels rose to above 5 times the upper limit of normal (ULN) in at least 5%. Some aminotransferase elevations were accompanied by serum bilirubin elevations. Subsequent to its approval and more widespread use, instances of acute liver injury including deaths from hepatic failure were reported with trastuzumab emtansine treatment, and it received a boxed warning about hepatotoxicity with recommendations for prospective monitoring of liver tests. Some cases appeared to represent acute sinusoidal obstruction syndrome and in other cases acute, direct hepatotoxic injury.

More recently, cases of noncirrhotic portal hypertension have been described in patients on long term trastuzumab emtansine. The typical presentation is with signs and symptoms of portal hypertension after months or years of therapy and usually with only modest increases in serum aminotransferase elevations and bilirubin. Strikingly, in patients who undergo liver biopsy, cirrhosis is not present, although mild-to-moderate fibrosis is present in some. This phenotype of injury is classified as noncirrhotic portal hypertension, but the underlying liver condition is usually nodular regenerative hyperplasia with elements of sinusoidal obstruction. Hepatic imaging shows a nodular and somewhat shrunken liver and prominent splenomegaly and varices. Typically, patients improve clinically once trastuzumab emtansine is dose-reduced or discontinued, although without chemotherapy the malignancy may return and progress. Another syndrome with somewhat similar clinical features associated with long term trastuzumab emtansine therapy is a disordered, nodular liver cause by shrinkage of necrotic hepatic metastases, sometimes referred to as “pseudocirrhosis.” These patients generally do not have symptoms of liver disease, and the diagnosis is made by hepatic imaging often done as a part of routine follow up of the metastatic liver disease.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the serum enzyme elevations during trastuzumab emtansine therapy is not known, but appears to be dose related and may be a mild direct toxicity of the infusions. The mechanism of the hepatotoxicity may be direct injury to endothelial cells and vasculature, possibly by their take up of the conjugate or the released microtubule inhibitor from other cells. Several instances of liver injury in patients taking trastuzumab emtansine have been attributed to sinusoidal obstruction syndrome, and mild forms of it may explain the frequent serum enzyme and bilirubin elevations during trastuzumab emtansine therapy. In other instances the underlying condition appears to be nodular regenerative hyperplasia, which is likely the result of acute or chronic vascular injury or both.

Outcome and Management

The product label for trastuzumab emtansine recommends monitoring of liver enzymes before starting and before each dose. The serum aminotransferase elevations that arise during trastuzumab emtansine therapy are usually mild-to-moderate in severity, self-limited in course, and not associated with symptoms or jaundice. In some instances, however, the injury persists or is more severe. Elevations of serum aminotransferase levels above 5 times ULN should lead to dose interruption or modification, but persistent elevations, appearance of symptoms or jaundice or evidence of sinusoidal obstruction syndrome should lead to discontinuation. Fatal instances of acute hepatic injury have been described with trastuzumab emtansine therapy. The chronic liver injury from the monoclonal-cytotoxic conjugate is generally persistent although signs and symptoms usually regress with drug discontinuation and sometimes with dose reduction alone. These clinically apparent and severe hepatic reactions have been observed with trastuzumab emtansine, but not with trastuzumab deruxtecan or with the monoclonal antibody without a conjugate.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies

Other Monoclonal Antibody Conjugates: Benlantamab Mafodotin, Brentuximab Vedotin, Enfortumab Vedotin, Gemtuzumab Ozogamicin, Inotuzumab Ozogamicin, Polatuzumab Vedotin, Sacituzumab Govitecan, Tisotumab Vedotin, Trastuzumab Deruxtecan



Trastuzumab Emtansine – Kadcyla®


Antineoplastic Agents

COMPLETE LABELING (Trastuzumab Emtansine)

Product labeling at DailyMed, National Library of Medicine, NIH






References updated: 30 January 2024

Abbreviations: CT, computerized tomography; FAERS, Food and Drug Administration Adverse Event Reporting System; HER-2, human epidermal growth factor receptor 2; MR, magnetic resonance; NRH, nodular regenerative hyperplasia; TNF, tumor necrosis factor.

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    (Among 835 patients with breast cancer receiving targeted therapy, rates of ALT elevations were slightly higher in the 52 with HBsAg [35%] and the 21 with anti-HCV [43%] than controls [28%] as were rates of chemotherapy disruption for liver test abnormalities [9.6% and 9.5% vs 5%], but no patient developed viral reactivation, although the proportion of those with HBsAg who were receiving antiviral prophylaxis was not provided).
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    (39 year old woman with HER2-positive breast cancer received a 1-year course of trastuzumab at the end of which she had normal ALT levels and CT appearance of the liver, but 18 months later she presented with abnormalities of both suggestive of pseudocirrhosis).
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    (48 year old woman with HER2-negative breast cancer in 2008 had recurrence in 2012 that was HER2-positive and after 12 months of trastuzumab emtansine therapy presented with mild ALT and AST elevations and MRI showing splenomegaly and dystrophic liver, a biopsy of which showed NRH, liver abnormalities improving, but cancer progressing when chemotherapy was stopped).
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  • Fujii Y, Doi M, Tsukiyama N, Hattori Y, Ohya K, Shiroma N, Morio K, et al. Sinusoidal obstruction syndrome post-treatment with trastuzumab emtansine (T-DM1) in advanced breast cancer. Int Cancer Conf J 2019; 9: 18-23. [PMC free article: PMC6942611] [PubMed: 31950012]
    (Two women with metastatic HER2-positive breast cancer developed noncirrhotic portal hypertension after 2.5 and 4.5 years of trastuzumab emtansine therapy, and liver biopsy showed sinusoidal obstruction syndrome and disordered hepatic plates in both).
  • Milam P, Berger M, Ramaswamy B, Reinbolt R, Wesolowski R, Kaffenberger BH. Spider telangiectases and palmar erythema as harbingers of structural liver changes in three breast cancer patients on ado-trastuzumab emtansine. J Clin Aesthet Dermatol 2019; 12: 23-6. [PMC free article: PMC6715332] [PubMed: 31531159]
    (Three women [ages 53, 60 and 63 years] with advanced breast cancer developed cutaneous stigmata of cirrhosis after 17 to 34 cycles of trastuzumab emtansine with spider angiomata and palmar erythema, minimal ALT and AST elevations, decreased platelet counts [43,000-123,000/µL], and usually with splenomegaly and nodular liver on CT or MR imaging).
  • Duret-Aupy N, Lagarce L, Blouet A, Kettani S, Conte C, Bourneau-Martin D, Drablier G, et al. Liver sinusoidal obstruction syndrome associated with trastuzumab emtansine treatment for breast cancer. Therapie 2019; 74: 675-7. [PubMed: 31023619]
    (87 year old woman on trastuzumab emtansine for two years developed variceal hemorrhage, ascites and edema, with normal ALT, and CT showing no evidence of cirrhosis, but liver biopsy showing sinusoidal obstruction syndrome).
  • Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, et al.; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. [PMC free article: PMC7458671] [PubMed: 31825192]
    (Among 184 patients with unresectable or metastatic refractory HER2 positive breast cancer treated with trastuzumab deruxtecan the objective response rate was 61% and overall adverse event rate was 99.5%, most commonly with nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, and 14% of patients developed interstitial lung disease, 5% a prolonged QT interval, 2.7% infusion reactions, and ALT elevations in 12% which were above 5 times ULN in 2%; no mention of clinically apparent liver injury).
  • Battisti NML, Rogerson F, Lee K, Shepherd S, Mohammed K, Turner N, McGrath S, et al. Safety and efficacy of T-DM1 in patients with advanced HER2-positive breast cancer The Royal Marsden experience. Cancer Treat Res Commun. 2020;24:100188. [PubMed: 32619830]
    (Among 128 patients with advanced, refractory HER2-positive breast cancer who were treated with trastuzumab emtansine at a single UK referral center from 2014 to 2019, the median overall survival rate was 20.4 months and adverse events were frequent including “deranged liver function” in 69%, “liver toxicity” in 20%, resulting in dose modification in 6%, and discontinuation in 2%).
  • Emens LA, Esteva FJ, Beresford M, Saura C, De Laurentiis M, Kim SB, Im SA, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020;21:1283-1295. [PubMed: 33002436]
    (Among 202 patients with advance, refractory HER2-positive breast cancer treated with trastuzumab emtansine with or without atezolizumab [anti-PD-L1], the median progression free survival was similar in the two groups [8.2 vs 6.8 months], while serious adverse events were more frequent with atezolizumab [33% vs 9%] including ALT elevations above 5 times ULN [5% vs 3%]).
  • Garrido I, Magalhães A, Lopes J, Macedo G. Trastuzumab Emtansine-Induced Nodular Regenerative Hyperplasia: Is Dose Reduction Enough as a Preventable Measure? Dig Dis. 2022;40:787-792. [PubMed: 35078201]
    (52 year old woman with HER2-positive, metastatic lung cancer was treated with trastuzumab emtansine and had an objective clinical response, but rapidly developed persistently abnormal liver tests which worsened [peak ALT 110 U/L, Alk P 474 U/L, bilirubin 1.7 mg/dL] with fall of platelet count to 74,000/mcL, with liver biopsy showing NRH, but a decrease in dose [3.6 to 1.8 mg/kg every 3 weeks] was followed by fall of liver tests and stabilization of platelet count with maintained clinical response).
  • Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, et al.; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022; 386: 1143-1154. [PubMed: 35320644]
    (Among 524 patients with refractory, advanced or metastatic HER2-positive breast cancer treated with trastuzumab deruxtecan or trastuzumab emtansine, progression free survival at 1 year was 76% vs 34% and adverse event rates 98% vs 87%, with deruxtecan having higher rates of neutropenia and anemia but lower rates of ALT elevations [19.5% vs 27%] which were above 5 times ULN in 1.6% vs 4.6%).
  • Ma P, Tian H, Shi Q, Liu R, Zhang Y, Qi X, Chen Y. High risks adverse events associated with trastuzumab emtansine and trastuzumab deruxtecan for the treatment of HER2-positive/mutated malignancies: a pharmacovigilance study based on the FAERS database. Expert Opin Drug Saf. 2023;22:685-696. [PubMed: 37068935]
    (Analysis of the FDA Adverse Event Reporting System [FARES] from 2004 to 2022 identified 2113 reports for trastuzumab emtansine [Tm] and 1269 for trastuzumab deruxtecan [Td], and while liver test abnormalities were reported with both, Tm had high report rates of hepatic cirrhosis [n=35], portal hypertension [24], and nodular regenerative hyperplasia [17], while Td had none for these diagnoses).
  • Sun C, Yang X, Tang L, Chen J. A pharmacovigilance study on drug-induced liver injury associated with antibody-drug conjugates (ADCs) based on the Food and Drug Administration Adverse Event Reporting System. Expert Opin Drug Saf. 2023:1-12. [PubMed: 37898875]
    (Analysis of the FDA reporting system [FAERS] for cases of drug induced liver injury submitted between 2004 and 2022, found 17,784 reports, 504 [3%] attributed to antibody-drug conjugates, 202 from the US, the implicated agents being gemtuzumab ozogamicin [n=98], brentuximab vedotin [n=37], trastuzumab emtansine [n=25], enfortumab vedotin [n=16], inotuzumab ozogamicin [n=15], trastuzumab deruxtecan [n=8], and polatuzumab vedotin [3]).