Kadcyla

T-DM1 (kadcyla) instructions
Common name: T-DM1
Trade name: kadcyla
Full names: T-DM1, trastuzumab-metansin conjugate, kadcyla, Ado-trastuzumab emtansine, Hercelium, emtansine trastuzumab

Indications:
Applicable to patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane separately or in combination. Patients should have any of the following conditions:
(1) Previous treatment for metastatic disease. (2) Disease recurrence occurs within six months after completing adjuvant treatment.

Usage and dosage:
(1) Kadcyla can only be used as intravenous infusion. Intravenous injection or oral administration is prohibited, and dilution with glucose solution is prohibited.
(2) The recommended dose of Kayla is 3.6mg/kg, intravenous infusion, once every 3 weeks until disease progression or intolerable toxicity occurs. Dosage exceeding 3.6 mg/kg is prohibited, and Kadcyla and trastuzumab are prohibited from being used instead of each other.
(2) The dose of kadacyla should not be increased after lowering it. The starting dose is 3.6 mg/kg, the first dose is reduced to 3 mg/kg, and the second dose is reduced to 2.4 mg/kg. If further dose reduction is required, the medication needs to be stopped.

Adverse reactions:
> 10% (MBC all grades)
Nausea (40%)
Fatigue (36%)
Musculoskeletal pain (36%)
Bleeding (32%)
Thrombocytopenia (31%)
AST/ Increased ALT (29%)
Constipation (27%)
Headache (28%)
Diarrhea (24%)
Epistaxis (23%)
Peripheral neuropathy (21%)
Vomiting (19%)
Abdominal pain (19%)
Irritability (19%)
Arthralgia (19%) )
Weakness (18%)
Cough (18%)
Dry mouth (17%)
Myalgia (14%)
Anemia (14%)
Stomatitis (14%)
Insomnia (12%)
Difficulty breathing (12%)
Skin rash (12%)

> 10% (EBC all levels)
Fatigue (50%)
Nausea (42%)
AST / Increased ALT (32%)
Musculoskeletal pain (30%)
Thrombocytopenia (29%)
Bleeding (29%)
Headache (28%)
Peripheral neuropathy (28%)
Joint pain (26%)
Estistaxis (22%)
Poop Secret (17%)
Myalgia (15%)
Stomatitis (15%)
Vomiting (15%)
Dry mouth (14%)
Cough (14%)
Insomnia (14%)
Diarrhea (12%)
Abdominal pain (11%)

> 10% (MBC [Grade 3 or 4])
Thrombocytopenia (15%)

1-10% (all grades)
MBC
Hypokalemia (10%)
Dizziness (10%)
EBC< br>Anemia (10%)
Irritability (10%)
Dizziness (10%)
Urinary tract infection (10%)

1-10% (3rd or 4th grade)
MBC
AST / Increased ALT (8%)
Anemia (4.1%)
Hypokalemia (2.7%)
Fatigue (2.5%)
Peripheral neuropathy (2.2%)
Musculoskeletal pain (1.8%)
Bleeding (1.8%)
Diarrhea (1.6%)
EBC
Thrombocytopenia (6%)
Peripheral neuropathy (1.6%)
AST/ Increased ALT (1.5%)

<1% (3rd or 4th grade)
Nausea/vomiting (0.8%)
Headache (0.8%)
Trouble breathing (0.8%)
Arthralgia/myalgia (0.6%)
Nausea (0.5%)
Constipation (0.4%)
Weakness (0.4%)
Dizziness (0.4%)
Insomnia (0.4%)
Dry mouth (0.4%)
Stomatitis (0.2%)
Fever (0.2%)
Nasal discharge Blood (0.2%)
Cough (0.2%)

Contraindications:
None

Precautions:
Reported hepatotoxicity, mainly in the form of asymptomatic, transient increases in serum aminotransferase concentrations
Reported cases of liver nodule regeneration and hyperplasia; Treatment must be permanently discontinued when nodular regenerative hyperplasia of the liver is diagnosed
Risk of developing left ventricular dysfunction is increased
Treatment must be permanently discontinued if the patient is diagnosed with nodular regenerative hyperplasia
Known to cause fetal harm and death
Pulmonary toxicity may occur; Interstitial lung disease cases reporting pneumonitis, treatment should be permanently discontinued
For patients with radiation pneumonitis on adjuvant therapy, treatment should be permanently discontinued with grade greater than or equal to 3 or grade 2 not meeting standard of care
Patients with dyspnea due to advanced malignancy, complications and concurrent pulmonary radiation therapy may be at increased risk for pulmonary toxicity
Infusion-related reactions (IRR) and/or hypersensitivity reactions may occur; Temporarily interrupt infusion for severe IRR or permanently discontinue infusion if life-threatening IRR occurs
Report of thrombocytopenia or reduced platelet count
Bleeding events (including central nervous system, respiratory, and gastrointestinal bleeding) have been reported; although, in some cases, patients were also receiving anticoagulant therapy, antiplatelet therapy, or had thrombocytopenia, in other cases, no other risk factors were known; Use these agents with caution and consider additional monitoring when concurrent use is medically necessary
Peripheral neuropathy may occur
Extravasation has been observed during clinical trials; Monitor the infusion site carefully during the infusion and inform the patient to report any tenderness/redness

Storage:
Unused vials: Refrigerate at 2-8ºC (36-46°F)
Reconstituted vials or diluted solutions
Refrigerate at 2-8ºC (36-46°F)
Discard after 4 hours
Do not freeze

Mechanism of Action:
Ado-trastuzumab emtansine is an antibody-drug conjugate targeting HER2. The antibody was humanized anti-HER2 IgG1, trastuzumab. The small molecule cytotoxin, DM1, is a microtubule inhibitor. Binding to subregion IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in the intracellular release of DM1-containing cytotoxic degradation products. DM1 binds to tubulin and disrupts the intracellular microtubule network, resulting in cell cycle arrest and apoptotic cell death. Additionally, in vitro studies have demonstrated that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2.

Efficacy and Safety:
The efficacy of KADCYLA was evaluated in a randomized, multicenter, open-label trial in 991 patients with HER2-positive, unresectable locally advanced or metastatic breast cancer. Patients were required to have prior taxane- and trastuzumab-based therapy before inclusion in the trial. Only patients with prior adjuvant therapy were required to have disease relapse during or within 6 months of completing adjuvant therapy. Breast tumor samples were required to show HER2 overexpression as measured by a central laboratory, defined as a 3+ IHC or FISH amplification ratio ≥ 2.0. Patients were randomly assigned (1:1) to receive lapatinib plus capecitabine or KADCYLA. Randomization was stratified by world region (United States, Western Europe, Other), number of prior chemotherapy regimens for unresectable locally advanced or metastatic disease (0–1, >1), and visceral versus nonvisceral disease as determined by the investigator.
Randomized trial confirms statistically significant improvement in IRC-assessed progression-free survival compared with KADCYLA-treated lapatinib plus capecitabine-treated group [hazard ratio (HR) = 0.65, 95% CI: 0.55, 0.77, p< 0.0001], while median PFS increased by 3.2 months (median PFS was 9.6 months in the KADCYLA-treated group compared with 6.4 months in the lapatinib plus capecitabine group). See Table 8 and Figure 1. Investigator-assessed PFS results were similar to IRC-assessed PFS.
At the time of progression-free survival PFS analysis, 223 patients had died. Deaths occurred more frequently in the lapatinib plus capecitabine arm (26%) than in the KADCYLA arm (19%), but the interim OS analysis did not meet the prespecified stopping margin for statistical significance. At the time of the second interim OS analysis, 331 events had occurred. Overall survival OS met the co-primary endpoint; overall survival OS was significantly improved in patients receiving KADCYLA (HR =0.68, 95% CI: 0.55, 0.85, p = 0.0006).