How Kadcyla works and who it is for
Kadcyla (ado-trastuzumab emtansine) is a HER2-targeted antibody and microtubule inhibitor conjugate: the trastuzumab antibody linked to DM1, a microtubule inhibitor. Section 1 of the FDA label gives two indications, both as a single agent and both for HER2-positive disease. For metastatic breast cancer (MBC), Kadcyla is for patients who previously received trastuzumab and a taxane, separately or in combination, and who either received prior therapy for metastatic disease or developed recurrence during or within six months of completing adjuvant therapy. For early breast cancer (EBC), Kadcyla is the adjuvant treatment of patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. Before the first dose, section 2.1 requires selecting patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens, using FDA-authorized tests specific for breast cancers in laboratories with demonstrated proficiency. One safety point from section 2.2 is printed on the calculator because it prevents a real dispensing error: do not substitute trastuzumab for or with Kadcyla. They are different products, and section 2.4 repeats that the vial labels must be checked so the drug prepared is Kadcyla and not trastuzumab.
The labelled dose, the cap, and the treatment duration (label section 2.2)
The recommended dose of Kadcyla is 3.6 mg/kg given as an intravenous infusion every 3 weeks (a 21-day cycle), and the label states the ceiling in the same breath: do not administer Kadcyla at doses greater than 3.6 mg/kg. This calculator therefore has no free mg/kg input; the only dose levels it can produce are the three in the label's reduction schedule, and the highest of them is the 3.6 mg/kg starting dose. The duration differs by indication. Patients with MBC receive treatment until disease progression or unmanageable toxicity. Patients with EBC receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity; the calculator shows the matching duration line for the indication selected. The infusion itself is monitored: the first infusion is given over 90 minutes, with observation during the infusion and for at least 90 minutes afterwards for fever, chills or other infusion-related reactions; subsequent infusions are given over 30 minutes if prior infusions were well tolerated, with observation during and for at least 30 minutes after. The infusion site is closely monitored for possible subcutaneous infiltration during administration.
Worked example: the 70 kg patient at all three dose levels
At 70 kg the starting dose is 3.6 x 70 = 252 mg. Kadcyla vials are reconstituted to 20 mg/mL, so the volume to withdraw is 252 divided by 20 = 12.6 mL. The vial sizes are 160 mg and 100 mg, and 252 mg is covered by one 160 mg vial plus one 100 mg vial (260 mg supplied). Because the reconstituted product is single-dose with no preservative, the calculated volume is drawn across the vials opened for that dose and the unused remainder is not saved for another patient. At the first reduction level (3.0 mg/kg) the same patient receives 210 mg, which is 10.5 mL, and at the second reduction level (2.4 mg/kg) she receives 168 mg, which is 8.4 mL, covered by two 100 mg vials. The table below uses the same fewest-vials rule as the calculator:
| Weight | Starting 3.6 mg/kg | First reduction 3 mg/kg | Second reduction 2.4 mg/kg |
|---|---|---|---|
| 60 kg | 216 mg (10.8 mL), 1 x 160 mg + 1 x 100 mg | 180 mg (9.0 mL), 2 x 100 mg | 144 mg (7.2 mL), 1 x 160 mg |
| 70 kg | 252 mg (12.6 mL), 1 x 160 mg + 1 x 100 mg | 210 mg (10.5 mL), 1 x 160 mg + 1 x 100 mg | 168 mg (8.4 mL), 2 x 100 mg |
| 100 kg | 360 mg (18.0 mL), 1 x 160 mg + 2 x 100 mg | 300 mg (15.0 mL), 2 x 160 mg | 240 mg (12.0 mL), 1 x 160 mg + 1 x 100 mg |
The 100 kg starting row shows why the calculator searches combinations rather than rounding up the largest vial: 360 mg could be supplied by three 160 mg vials (480 mg) but is covered exactly, with nothing over, by one 160 mg vial plus two 100 mg vials. Where two combinations use the same number of vials, the calculator picks the one supplying the fewest extra milligrams.
Dose modifications: the reduction schedule and the rules that surround it (label section 2.3)
Three rules in section 2.3 govern every change. Do not re-escalate the Kadcyla dose after a dose reduction is made. If a planned dose is delayed or missed, administer it as soon as possible; do not wait until the next planned cycle, adjust the schedule to maintain a 3-week interval between doses, and infuse at the dose and rate tolerated in the most recent infusion. And if the patient develops an infusion-related reaction, slow or interrupt the infusion rate; Kadcyla is permanently discontinued for life-threatening infusion-related reactions. Table 1 is the reduction schedule itself:
| Dose reduction schedule | Dose level |
|---|---|
| Starting dose | 3.6 mg/kg |
| First dose reduction | 3 mg/kg |
| Second dose reduction | 2.4 mg/kg |
| Requirement for further dose reduction | Discontinue treatment |
Table 2 then gives the modification guidelines separately for the two indications. For metastatic breast cancer:
| Adverse reaction | Severity | Treatment modification |
|---|---|---|
| Increased transaminases (AST/ALT) | Grade 2 (more than 2.5 to 5 x ULN) | Treat at the same dose level |
| Increased transaminases (AST/ALT) | Grade 3 (more than 5 to 20 x ULN) | Do not administer until AST/ALT recovers to Grade 2 or less, and then reduce one dose level |
| Increased transaminases (AST/ALT) | Grade 4 (more than 20 x ULN) | Discontinue Kadcyla |
| Hyperbilirubinemia | Grade 2 (more than 1.5 to 3 x ULN) | Do not administer until total bilirubin recovers to Grade 1 or less, and then treat at the same dose level |
| Hyperbilirubinemia | Grade 3 (more than 3 to 10 x ULN) | Do not administer until total bilirubin recovers to Grade 1 or less, and then reduce one dose level |
| Hyperbilirubinemia | Grade 4 (more than 10 x ULN) | Discontinue Kadcyla |
| Drug-induced liver injury | Serum transaminases more than 3 x ULN and concomitant total bilirubin more than 2 x ULN | Permanently discontinue, in the absence of another likely cause such as liver metastases or concomitant medication |
| Nodular regenerative hyperplasia | All grades | Permanently discontinue Kadcyla |
| Thrombocytopenia | Grade 3 (25,000 to less than 50,000 per mm3) | Do not administer until platelet count recovers to Grade 1 or less (75,000 per mm3 or more), and then treat at the same dose level |
| Thrombocytopenia | Grade 4 (less than 25,000 per mm3) | Do not administer until platelet count recovers to Grade 1 or less, and then reduce one dose level |
| Left ventricular dysfunction | Symptomatic CHF | Discontinue Kadcyla |
| Left ventricular dysfunction | LVEF less than 40% | Do not administer; repeat LVEF assessment within 3 weeks; if LVEF less than 40% is confirmed, discontinue Kadcyla |
| Left ventricular dysfunction | LVEF 40% to 45% and decrease is 10% points or more from baseline | Do not administer; repeat LVEF assessment within 3 weeks; if the LVEF has not recovered to within 10% points from baseline, discontinue Kadcyla |
| Left ventricular dysfunction | LVEF 40% to 45% and decrease is less than 10% points from baseline | Continue treatment; repeat LVEF assessment within 3 weeks |
| Left ventricular dysfunction | LVEF more than 45% | Continue treatment |
| Pulmonary toxicity | Interstitial lung disease (ILD) or pneumonitis | Permanently discontinue Kadcyla |
| Peripheral neuropathy | Grade 3 to 4 | Do not administer until resolution to Grade 2 or less |
For early breast cancer, the thresholds differ in places, most importantly for liver enzymes and LVEF:
| Adverse reaction | Severity | Treatment modification |
|---|---|---|
| Increased ALT | Grade 2 to 3 (more than 3.0 to 20 x ULN on the day of scheduled treatment) | Do not administer until ALT recovers to Grade 1 or less, and then reduce one dose level |
| Increased ALT | Grade 4 (more than 20 x ULN at any time) | Discontinue Kadcyla |
| Increased AST | Grade 2 (more than 3.0 to 5 x ULN on the day of scheduled treatment) | Do not administer until AST recovers to Grade 1 or less, and then treat at the same dose level |
| Increased AST | Grade 3 (more than 5 to 20 x ULN on the day of scheduled treatment) | Do not administer until AST recovers to Grade 1 or less, and then reduce one dose level |
| Increased AST | Grade 4 (more than 20 x ULN at any time) | Discontinue Kadcyla |
| Hyperbilirubinemia | Total bilirubin more than 1.0 to 2.0 x ULN on the day of scheduled treatment | Do not administer until total bilirubin recovers to 1.0 x ULN or less, and then reduce one dose level |
| Hyperbilirubinemia | Total bilirubin more than 2 x ULN at any time | Discontinue Kadcyla |
| Nodular regenerative hyperplasia | All grades | Permanently discontinue Kadcyla |
| Thrombocytopenia | Grade 2 to 3 on the day of scheduled treatment (25,000 to less than 75,000 per mm3) | Do not administer until platelet count recovers to Grade 1 or less (75,000 per mm3 or more), and then treat at the same dose level; if a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level |
| Thrombocytopenia | Grade 4 at any time (less than 25,000 per mm3) | Do not administer until platelet count recovers to Grade 1 or less, and then reduce one dose level |
| Left ventricular dysfunction | LVEF less than 45% | Do not administer; repeat LVEF assessment within 3 weeks; if LVEF less than 45% is confirmed, discontinue Kadcyla |
| Left ventricular dysfunction | LVEF 45% to less than 50% and decrease is 10% points or more from baseline | Do not administer; repeat LVEF assessment within 3 weeks; if the LVEF remains less than 50% and has not recovered to less than 10% points from baseline, discontinue Kadcyla |
| Left ventricular dysfunction | LVEF 45% to less than 50% and decrease is less than 10% points from baseline | Continue treatment; repeat LVEF assessment within 3 weeks |
| Left ventricular dysfunction | LVEF 50% or more | Continue treatment |
| Heart failure | Symptomatic CHF, Grade 3 to 4 LV systolic dysfunction or Grade 3 to 4 heart failure, or Grade 2 heart failure accompanied by LVEF less than 45% | Discontinue Kadcyla |
| Peripheral neuropathy | Grade 3 to 4 | Do not administer until resolution to Grade 2 or less |
| Pulmonary toxicity | Interstitial lung disease (ILD) or pneumonitis | Permanently discontinue Kadcyla |
| Radiotherapy-related pneumonitis | Grade 2 | Discontinue Kadcyla if not resolving with standard treatment |
| Radiotherapy-related pneumonitis | Grade 3 to 4 | Discontinue Kadcyla |
Monitoring that travels with the dose (label sections 5.1, 5.2, 5.3 and 5.7)
The dose calculation is only one part of each cycle. Section 5.1 requires serum transaminases and bilirubin to be monitored prior to initiation and prior to each dose, with dose reduction or discontinuation for increases, and permanent discontinuation when serum transaminases are more than 3 x ULN with concomitant total bilirubin more than 2 x ULN. Kadcyla has not been studied in patients with serum transaminases more than 2.5 x ULN or bilirubin more than 1.5 x ULN before starting treatment. Section 5.2 requires LVEF assessment before initiation and at regular intervals (for example every three months) during treatment; Kadcyla has not been studied in an adequately controlled study in patients with LVEF below 50%. Section 5.7 requires platelet counts before initiation and before each dose: thrombocytopenia was reported in the trials with the nadir generally by day 8, and Kadcyla has not been studied in patients with platelet counts below 100,000 per mm3 before starting; if the platelet count falls to Grade 3 or worse (below 50,000 per mm3), Kadcyla is not administered until recovery to Grade 1 (75,000 per mm3 or more). Section 5.3 covers embryo-fetal toxicity: pregnancy status of females of reproductive potential is verified before initiation, and effective contraception is used during treatment and for 7 months following the last dose.
Reconstitution and dilution in full (label section 2.4)
Kadcyla is supplied as a lyophilized powder in single-dose vials of 100 mg and 160 mg. Using aseptic technique, slowly inject 5 mL of Sterile Water for Injection or 0.45% Sodium Chloride Injection into the 100 mg vial, or 8 mL into the 160 mg vial, to yield a solution containing 20 mg/mL. Swirl the vial gently until completely dissolved; do not shake. The reconstituted solution should be clear to slightly opalescent, colorless to pale brown, and free of visible particulates. Reconstituted vials should be used immediately; if not, they may be stored refrigerated at 2 to 8 degrees C for up to 120 hours (5 days), and unused Kadcyla is discarded after that; do not freeze. The product contains no preservative and is single-dose only. For dilution, calculate the volume of the 20 mg/mL solution needed, withdraw it, and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection; do not use Dextrose (5%) solution. Gently invert the bag to mix and avoid foaming. The diluted solution should be used immediately, or stored refrigerated at 2 to 8 degrees C for up to 24 hours; do not freeze or shake. Administration is intravenous infusion only, with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter; Kadcyla is never given as an intravenous push or bolus and is not mixed with other medicinal products.
Sources
KADCYLA (ado-trastuzumab emtansine) injection, for intravenous use. FDA-approved prescribing information, Genentech, Inc. (DailyMed, setid 23f3c1f4-0fc8-4804-a9e3-04cf25dd302e): boxed warnings on hepatotoxicity, cardiac toxicity and embryo-fetal toxicity; section 1.1 metastatic breast cancer (prior trastuzumab and a taxane) and section 1.2 early breast cancer (adjuvant treatment with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment); section 2.1 patient selection by HER2 protein overexpression or gene amplification with FDA-authorized tests; section 2.2 recommended dose and schedules (3.6 mg/kg intravenously every 3 weeks; do not administer doses greater than 3.6 mg/kg; MBC until disease progression or unmanageable toxicity; EBC for a total of 14 cycles; first infusion over 90 minutes, subsequent infusions over 30 minutes if well tolerated); section 2.3 dose modifications (never re-escalate after a reduction; delayed or missed dose given as soon as possible with a maintained 3-week interval; Table 1 dose reduction schedule 3.6 to 3 to 2.4 mg/kg then discontinue; Table 2 dose modification guidelines for MBC and for EBC); section 2.4 preparation (reconstitute the 100 mg vial with 5 mL or the 160 mg vial with 8 mL of Sterile Water for Injection or 0.45% Sodium Chloride Injection to 20 mg/mL; dilute in 250 mL of 0.9% Sodium Chloride Injection; do not use dextrose (5%) solution; 0.2 or 0.22 micron PES in-line filter; no intravenous push or bolus); section 3 dosage forms (100 mg and 160 mg single-dose vials); sections 5.1 to 5.8 on hepatotoxicity monitoring, LVEF assessment, embryo-fetal toxicity and contraception for 7 months after the last dose, pulmonary toxicity, hemorrhage, thrombocytopenia monitoring and neurotoxicity.