Enhertu Adverse Reactions

Summary of the safety profile: The pooled safety population has been evaluated for patients who received at least one dose of Enhertu 5.4 mg/kg (n = 1449) across multiple tumour types in clinical studies. The median duration of treatment in this pool was 9.6 months (range: 0.2 to 45.1 months).
The most common adverse reactions were nausea (74.6%), fatigue (56.5%), vomiting (41.6%), alopecia (37.5%), neutropenia (34.6%), constipation (34.6%), anaemia (34.2%), decreased appetite (32.4%), diarrhoea (28.5%), transaminases increased (26.1%), musculoskeletal pain (25.7%), thrombocytopenia (24.0%) and leukopenia (23.5%).
The most common National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5.0) Grade 3 or 4 adverse reactions were neutropenia (16.5%), anaemia (9.4%), fatigue (8.1%), leukopenia (6.3%), nausea (5.8%), thrombocytopenia (5.0%), lymphopenia (4.8%), transaminases increased (3.6%), hypokalaemia (3.5%), vomiting (2.6%), diarrhoea (2.0%), decreased appetite (1.7%), pneumonia (1.4%) and ejection fraction decreased (1.1%). Grade 5 adverse reactions occurred in 1.3% of patients, including ILD (1.0%).
Dose interruptions due to adverse reactions occurred in 33.4% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (13.0%), fatigue (4.8%), anaemia (4.6%), leukopenia (3.7%), thrombocytopenia (3.0%), upper respiratory tract infection (2.6%) and ILD (2.4%). Dose reductions occurred in 20.1% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were nausea (4.8%), fatigue (4.8%), neutropenia (3.2%) and thrombocytopenia (2.1%). Discontinuation of therapy due to an adverse reaction occurred in 12.6% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (8.8%).
Tabulated list of adverse reactions: The adverse reactions in patients who received at least one dose of Enhertu in clinical studies are presented in Table 6. The adverse reactions are listed by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. (See Table 6.)

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Description of selected adverse reactions: Interstitial lung disease/pneumonitis: In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 1449), ILD occurred in 12.0% of patients. Most ILD cases were Grade 1 (3.2%) and Grade 2 (7.0%). Grade 3 cases occurred in 0.8% and no Grade 4 cases occurred. Grade 5 (fatal) events occurred in 1.0% of patients. Median time to first onset was 5.5 months (range: 26 days to 31.5 months) (see Dosage & Administration and Precautions).
Neutropenia: In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 1449) across multiple tumour types, neutropenia was reported in 34.6% of patients and 16.5% had Grade 3 or 4 events. Median time of onset was 43 days (range: 1 day to 31.9 months), and median duration of the first event was 22 days (range: 1 day to 17.0 months). Febrile neutropenia was reported in 0.9% of patients and 0.1% were Grade 5 (see Dosage & Administration).
Left ventricular ejection fraction decrease: In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 1449), LVEF decrease was reported in 57 patients (3.9%), of which 10 (0.7%) were Grade 1, 40 (2.8%) were Grade 2, and 7 (0.5%) were Grade 3. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 198/1321 (15.0%) for Grade 2, and 12/1321 (0.9%) for Grade 3. Treatment with Enhertu has not been studied in patients with LVEF less than 50% prior to initiation of treatment (see Dosage & Administration).
Infusion-related reactions: In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 1449) across multiple tumour types, infusion-related reactions were reported in 18 patients (1.2%), all of which were Grade 1 or Grade 2 severity. No Grade 3 events were reported. Three events (0.2%) of infusion-related reactions led to dose interruptions, and no events led to discontinuation.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. Across all doses evaluated in clinical studies, 2.1% (47/2213) of evaluable patients developed antibodies against trastuzumab deruxtecan following treatment with Enhertu. The incidence of treatment-emergent neutralising antibodies against trastuzumab deruxtecan was 0.1% (2/2213). There was no association between development of antibodies and allergic-type reactions.
Paediatric population: Safety has not been established in this population.
Elderly: In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 1449), 24.2% were 65 years or older and 4.3% were 75 years or older. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (48.9%) as compared to patients younger than 65 years old (42.3%), leading to more discontinuations due to adverse reactions.