KATHERINE was a Phase 3, open-label, randomised, multicentre study that assessed adjuvant Kadcyla vs trastuzumab in patients with HER2+ eBC who had residual invasive disease in the breast and/or axilla, following trastuzumab-based neoadjuvant therapy.

Within 12 weeks of surgery, patients (N=1,486) were randomised 1:1 to receive Kadcyla (3.6 mg/kg) or trastuzumab (6 mg/kg) for 14 cycles.

Primary endpoint: IDFS, defined as the time as the time from randomisation until the date of the first occurrence of one of the following: recurrence of ipsilateral invasive breast tumour, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause.

Secondary endpoints: DFS including second primary non-breast cancer as per the STEEP definition, DFS, OS, distant recurrence-free survival, and safety.

Randomisation was stratified by clinical stage at presentation, hormone receptor status, neoadjuvant HER2-targeted therapy, and pathological nodal status evaluated after pre-operative therapy.¹³

†Dual neoadjuvant anti-HER2 therapy was also permitted.¹³ Within 12 weeks after surgery, patients were randomised.¹³

Patients received T-DM1 at a dose of 3.6 mg per kilogram of body weight or trastuzumab at a dose of 6 mg per kilogram intravenously every 3 weeks for 14 cycles.

IDFS

The final analysis for IDFS was exploratory as statistical significance was reached at the primary analysis.¹⁴

OS

^*Boundary for statistical significance, HR <0.739 or P<0.0263.^14,15

The second interim analysis for OS was pre-planned. The final analysis is expected 12 years after the first patient in.^13,14

The safety profile of adjuvant Kadcyla was consistent with previous studies.^13,16 There were more adverse events with Kadcyla than with trastuzumab.¹³
 
Among all adverse events, fatigue and nausea were the most common experienced by patients treated with Kadcyla.¹

Adverse events with an incidence of ≥15% in either treatment group in the safety population¹³

^*All listed adverse events are Grade 3 except for decreased platelet count, which includes 2.0% of patients in the Kadcyla group and 0.1% of patients in the trastuzumab group who had a Grade 4 decreased platelet count.

Serious adverse events occurred in 12.7% of patients treated with Kadcyla and 8.1% of patients treated with trastuzumab.¹⁵

There was one Grade 5 adverse event in a patient treated with Kadcyla. The patient had a platelet count of 55,000 mm³ and fell at home and died of an intracranial haemorrhage.¹⁵
 
From the patients who received Kadcyla, 71.4% completed the planned 14 cycles of treatment and 85.7% had no dose reductions.¹³

The safety of Kadcyla has been evaluated in 2,611 breast cancer patients in clinical studies. In this patient population:

• The most common adverse drug reactions (≥25% of patients) were nausea, fatigue, musculoskeletal pain, haemorrhage, headache, transaminases increased, thrombocytopenia, and peripheral neuropathy. The majority of these were of Grade 1 or 2
• The most common serious adverse drug reactions (>0.5% of patients) were haemorrhage, pyrexia, thrombocytopenia, dyspnoea, abdominal pain, musculoskeletal pain, and vomiting
• The most common NCI-CTCAE Grade ≥3 adverse drug reactions (>2%) were thrombocytopenia, increased transaminases, anaemia, neutropenia, fatigue, and hypokalaemia

Very common and common adverse drug reactions in patients treated with Kadcyla in clinical studies¹

Please see the SmPC for further details prior to initiating therapy.

Thrombocytopenia

• Commonly reported with Kadcyla and was the most common adverse reaction leading to treatment discontinuation, dose reduction, and dose interruption 
• It is recommended to monitor platelet counts prior to each Kadcyla dose 
• Close monitoring is recommended for patients with thrombocytopenia (≤100,000/mm³) and patients on anticoagulant treatment while on Kadcyla 

Haemorrhage

• Haemorrhagic events, (including CNS, respiratory and gastrointestinal), have been reported with Kadcyla
• Fatal outcomes have been observed in some cases the patients had thrombocytopenia or were also receiving anti-coagulant therapy or anti-platelet therapy. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary

Hepatotoxicity

• Hepatotoxicity, predominantly asymptomatic transaminase elevations (Grade 1–4 transaminitis), has been observed during treatment 
• Elevations were generally transient with peak elevation at day 8 after administration of therapy and subsequent recovery to Grade 1 or less prior to the next cycle. A cumulative effect on transaminases has also been observed 
• Patients with elevated transaminases improved to Grade 1 or normal within 30 days of the last dose of trastuzumab emtansine in the majority of the cases. 
• Serious hepatobiliary disorders, including NRH of the liver and some with a fatal outcome due to drug-induced liver injury have been observed in patients treated with Kadcyla 
• Liver function should be monitored prior to initiation of treatment and each dose 
  • Patients with baseline elevation of ALT may be predisposed to liver injury with a higher risk of a Grade 3–5 hepatic event or liver function test increase 
  • Dose reductions or discontinuation for increased serum transaminases and total bilirubin are specified in the SmPC 
• Kadcyla has not been studied in patients with serum transaminases >2.5 × ULN or total bilirubin >1.5 × ULN prior to initiation of treatment 
  • Treatment in patients with serum transaminases >3 × ULN and concomitant total bilirubin >2 × ULN should be permanently discontinued. Treatment of patients with hepatic impairment should be undertaken with caution

Neurotoxicity

• Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical studies with Kadcyla

Left ventricular dysfunction 

• Patients treated with Kadcyla are at increased risk of developing left ventricular dysfunction 
• LVEF <40% has been observed and therefore CHF is a potential risk
• Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning) should be performed prior to initiation of treatment and also at regular intervals (e.g. every three months) during treatment. The dosing should be delayed, or treatment discontinued as necessary in cases of left ventricular dysfunction

Pulmonary toxicity

• ILD, including pneumonitis, has been reported in with Kadcyla 
• It is recommended to permanently discontinue Kadcyla in patients who are diagnosed with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting, where Kadcyla should be permanently discontinued for ≥Grade 3 or for Grade 2 not responding to standard treatment

Infusion-related reactions

• Kadcyla has not been studied in patients who had trastuzumab permanently discontinued due to IRR; treatment is not recommended for these patients 
• Patients should be observed closely for IRRs, especially during the first infusion 

Hypersensitivity reactions

• Kadcyla has not been studied in patients who had trastuzumab permanently discontinued due to hypersensitivity; treatment with Kadcyla is not recommended for these patients 
• Patients should be observed closely for hypersensitivity/allergic reactions, which may have the same clinical presentation as an IRR. Serious, anaphylactic reactions have been observed in clinical studies with Kadcyla 
  • Medicinal products to treat such reactions, and emergency equipment, should be available for immediate
• Permanently discontinue Kadcyla in the event of a true hypersensitivity reaction 

Injection-site reactions 

• Extravasation of Kadcyla during IV injection may produce local pain 
• In exceptional cases, severe tissue lesions and epidermal necrosis may occur. If so, terminate the infusion immediately and regularly examine the patient for necrosis (days to weeks after) 

Kadcyla is not recommended in women who are pregnant (or who are trying to become pregnant), effective contraception is required. Kadycla is not recommended in women who are breast feeding. Please refer to the SmPC for full details

Kadcyla is for IV use. Kadcyla must be reconstituted and diluted by a healthcare professional and administered as an IV infusion. It must not be administered as an IV push or bolus.

The recommended dose of Kadcyla is 3.6 mg/kg bodyweight administered as an IV infusion every 3 weeks (21-day cycle).

Patients should be observed during infusions for fever, chills or other IRRs. The infusion site should be closely monitored for possible SC infiltration during administration. If the patient develops infusion-related symptoms, the infusion rate should be slowed or interrupted.

Kadcyla should be discontinued in case of life-threatening infusion reactions.

Management of symptomatic adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation.

Dose reduction guidelines for adverse reactions

Kadcyla dose should not be re-escalated after a dose reduction is made. Please see the SmPC for dose modifications recommendations for specific adverse reactions. There is no data in patients with altered hepatic and renal function.