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 and above (n=1590), across multiple tumor types in clinical studies. The median duration of treatment in this pool was 7.8 months (range: 0.2 to 41.0).
Metastatic Breast Cancer: DESTINY-Breast03: The safety of ENHERTU was evaluated in DESTINY-Breast03 in 257 patients with unresectable or metastatic HER2-positive breast cancer (see Pharmacology: Pharmacodynamics under Actions). The median duration of treatment was 14.3 months (range: 0.7 to 29.8) in the ENHERTU group and 6.9 months (range: 0.7 to 25.1) in the trastuzumab emtansine group.
In DESTINY-Breast03 (N=257), the most common adverse reactions (frequency ≥20%) were nausea (75.9%), fatigue (49.4%), vomiting (49.0%), neutropenia (42.8%), alopecia (37.0%), constipation (34.2%), anemia (32.7%), transaminases increased (31.5%), musculoskeletal pain (31.1%), leukopenia (30.4%), decreased appetite (29.2%), diarrhea (29.2%), thrombocytopenia (25.7%), headache (21.8%), and abdominal pain (21.0 %). The most common serious adverse reactions (frequency >1%) were interstitial lung disease (2.3%) and vomiting (1.9%).
In DESTINY-Breast03, dose interruptions due to adverse reactions occurred in 34.2% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia (16.7%), leukopenia (5.1%), thrombocytopenia (4.3%), fatigue (4.3%), anemia (3.5%), nausea (3.1%), and interstitial lung disease (2.7%). Dose reductions occurred in 19.8% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea (6.2%), neutropenia (3.5%), and fatigue (3.1%). Discontinuation of therapy due to an adverse reaction occurred in 10.5% of patients treated with ENHERTU. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD (8.2%).
Tabulated List of Adverse Reactions: The adverse reactions in patients with unresectable or metastatic HER2-positive breast cancer in DESTINY-Breast03 are presented in Table 7. The adverse reactions are listed by Medical Dictionary for Regulatory Activities (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 in the ENHERTU arm. (See Table 7.)

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DESTINY-Breast01 and Study DS8201-A-J101: The safety of ENHERTU has been evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 9.8 months (range: 0.7 to 37.1).
In ENHERTU-treated patients (N=234), the median age was 56 years (range 28 to 96); 99.6% were female; 50.9% were White, 41.5% were Asian, 3.0% were Black or African American; and 57.7% had an Eastern Cooperative Oncology Group (ECOG) performance status 0 and 41.9% had an ECOG performance status of 1. The studies excluded patients with a history of treated ILD or ILD at screening and patients with a history of clinically significant cardiac disease.
The most common adverse reactions (frequency ≥20%) were nausea (79.9%), fatigue (60.3%), vomiting (48.7%), alopecia (46.2%), constipation (35.9%), decreased appetite (34.6%), anemia (33.8%), neutropenia (32.5%), diarrhea (30.8%), thrombocytopenia (23.1%), cough (21.4%), leukopenia (20.5%), and headache (20.1%). The most common National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.5.0) Grade ≥3 adverse reactions (frequency >1%) were neutropenia (18.8%), anemia (9.0%), nausea (6.8%), fatigue (6.4%), leukopenia (5.6%), lymphopenia (5.1%), vomiting (4.3%), thrombocytopenia (4.3%), hypokalemia (3.4%), ILD (3.0%), diarrhea (2.6%), febrile neutropenia (1.7%), dyspnea (1.7%), abdominal pain (1.3%), decreased appetite (1.3%), and alanine aminotransferase increased (1.3%). In six patients (2.6%) ILD led to death.
Dose interruptions due to adverse reactions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia (14.5%), anemia (3.4%), upper respiratory tract infection (3.0%), leukopenia (3.0%), ILD (2.6%), thrombocytopenia (2.6%), and fatigue (2.1%). Dose reductions occurred in 15% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue (3.8%), nausea (3.4%), and neutropenia (3.4%). Discontinuation of therapy due to an adverse reaction occurred in 11% of patients treated with ENHERTU. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD (9.4%).
Tabulated List of Adverse Reactions: The adverse reactions in 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg are presented in Table 8. 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 8.)

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DESTINY-Breast04: The safety of ENHERTU was evaluated in DESTINY-Breast04 in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer (see Pharmacology: Pharmacodynamics under Actions). The median duration of treatment was 8.2 months (range: 0.2 to 33.3) in the ENHERTU group and 3.5 months (range: 0.3 to 17.6) in the chemotherapy group.
In patients treated with ENHERTU in DESTINY-Breast04 (N=371), the most common adverse reactions (frequency ≥20%) were nausea (76.0%), fatigue (53.6%), vomiting (40.4%), alopecia (39.6%), anemia (38.5%), constipation (34.0%), neutropenia (34.0%), transaminases increased (32.3%), decreased appetite (31.8%), diarrhea (27.0%), musculoskeletal pain (26.7%), thrombocytopenia (25.6%), and leukopenia (24.0%). The most common serious adverse reactions (frequency >1%) were ILD/pneumonitis (4.3%), dyspnea (1.3%), musculoskeletal pain (1.3%), anemia (1.1%), febrile neutropenia (1.1%), nausea (1.1%), pyrexia (1.1%), and vomiting (1.1%). There were 5 (1.3%) patients with adverse reactions leading to death, 3 attributed to ILD (0.8%) and 1 (0.3%) each for dyspnea and febrile neutropenia.
Dose interruptions due to adverse reactions occurred in 25.9% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia (9.2%), fatigue (5.1%), anemia (4.6%), leukopenia (3.5%), ILD/pneumonitis (3.0%), transaminases increased (3.0%), and blood bilirubin increased (2.2%). Dose reductions occurred in 19.9% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue (4.6%), nausea (4.6%), thrombocytopenia (3.5%), and neutropenia (3.0%). Discontinuation of therapy due to an adverse reaction occurred in 11.1% of patients treated with ENHERTU. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD/pneumonitis (8.4%).
Tabulated List of Adverse Reactions: The adverse reactions in patients with unresectable or metastatic HER2-low breast cancer in DESTINY-Breast04 are presented in Table 9. The adverse reactions are listed by Medical Dictionary for Regulatory Activities (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 in the ENHERTU arm. (See Table 9.)

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Locally Advanced or Metastatic Gastric Cancer: The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. patients received intravenously at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or physician's choice of chemotherapy: either irinotecan (N=55) 150 mg/m² biweekly or paclitaxel (N=7) 80 mg/m² weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in ENHERTU-treated patients and 2.8 months (range: 0.5 to 13.1) in physician's choice-treated patients: 2.8 months (range: 0.5 to 7.4) in the irinotecan group and 4.6 months (range: 0.9 to 13.1) in the paclitaxel group.
The study population characteristics in the ENHERTU group and the physician's choice group were similar. The median age was 66 years (range 28 to 82), 76% were male, 100% were Asian, and 49% had an ECOG performance status 0 and 51% had an ECOG performance status of 1. The study excluded patients with a history of treated ILD and/or ILD at screening, and patients with a history of clinically significant cardiac disease.
The most common adverse reactions in patients treated with ENHERTU 6.4 mg/kg (frequency ≥20%) were neutropenia (63.2%), nausea (63.2%), decreased appetite (60.0%), anemia (57.6%), fatigue (55.2%), thrombocytopenia (39.2%), leukopenia (37.6%), diarrhea (32.0%), vomiting (26.4%), constipation (24.0%), pyrexia (24.0%), alopecia (22.4%), and lymphopenia (21.6%). The most common NCI CTCAE v.5.0 Grade ≥3 adverse reactions (frequency >2%) were neutropenia (51.2%), anemia (37.6%), leukopenia (20.8%), decreased appetite (16.8%), thrombocytopenia (11.2%), lymphopenia (11.2%), fatigue (8.8%), febrile neutropenia (4.8%), nausea (4.8%), hypokalemia (4.0%), hepatic function abnormal (3.2%), blood alkaline phosphatase increased (3.2%), diarrhea (2.4%), dehydration (2.4%), aspartate aminotransferase increased (2.4%), and ILD (2.4%).
Dose interruptions due to adverse reactions occurred in 55.2% of patients treated with 6.4 mg/kg of ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia (28.0%), anemia (11.2%), decreased appetite (8.8%), leukopenia (8.0%), fatigue (7.2%), thrombocytopenia (4.0%), ILD (3.2%), lymphopenia (3.2%), pneumonia (3.2%), upper respiratory tract infection (3.2%), diarrhea (2.4%), and hypokalemia (2.4%). Dose reductions occurred in 30.4% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia (12.8%), decreased appetite (9.6%), fatigue (8.0%), nausea (4.8%), and febrile neutropenia (2.4%). Discontinuation of therapy due to an adverse reaction occurred in 11.2% of patients treated with ENHERTU. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD (5.6%).
Tabulated List of Adverse Reactions: The adverse reactions in 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who received at least one dose of ENHERTU 6.4 mg/kg are presented in Table 10. 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 10.)

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Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. Across all doses evaluated in clinical studies, 2.0% (34/1668) of evaluable patients developed antibodies against trastuzumab deruxtecan following treatment with ENHERTU. The incidence of treatment-emergent neutralizing antibodies against trastuzumab deruxtecan was 0.1% (1/1668). There was no association between development of antibodies and allergic-type reactions.