Datopotamab deruxtecan

In patients with moderate renal impairment at baseline who received datopotamab deruxtecan 6 mg/kg, a higher incidence of serious adverse reactions was observed compared to those with normal renal function.

The recommended dosage of datopotamab deruxtecan has not been established in patients with severe renal impairment. Patients with severe renal impairment should be monitored carefully.

There are limited data to make a recommendation on dose adjustment in patients with moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. Insufficient data are available in patients with severe (total bilirubin >3 times ULN and any AST) hepatic impairment. Therefore, patients with moderate and severe hepatic impairment should be monitored carefully.

No human data on the effect of datopotamab deruxtecan on fertility are available. Based on results from animal toxicity studies, datopotamab deruxtecan may impair male and female reproductive function and fertility.

Both men and women should seek advice on fertility preservation before treatment. It is not known whether datopotamab deruxtecan or its metabolites are found in seminal fluid. Male patients must not freeze or donate sperm throughout the treatment period, and for at least 4 months after the final dose of datopotamab deruxtecan. Females must not donate, or retrieve for their own use, ova throughout the treatment period and for at least 7 months after the final dose of datopotamab deruxtecan.

Patients with clinically significant corneal disease were excluded from the study. Patients with pre-existing keratitis should be carefully monitored.

There are no available data on the use of datopotamab deruxtecan in pregnant women. However, based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component, DXd, can be expected to cause embryo-foetal harm when administered to pregnant women.

Datopotamab deruxtecan is not recommended during pregnancy and in women of childbearing potential not using contraception. Patients should be informed of the potential risks to the foetus before they become pregnant and to contact their doctor immediately if they become pregnant.

It is not known if datopotamab deruxtecan is excreted in human milk. Human IgG is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed children, women should discontinue breast-feeding prior to initiating treatment with datopotamab deruxtecan. Women may begin breast-feeding 1 month after concluding treatment.

Women of childbearing potential/Contraception in females and males

The pregnancy status of women of childbearing potential should be verified prior to initiation of datopotamab deruxtecan.

Women of childbearing potential should use effective contraception during treatment with datopotamab deruxtecan and for at least 7 months following the last dose.

Men with female partners of childbearing potential should use effective contraception during treatment with datopotamab deruxtecan and for at least 4 months following the last dose.

Fertility

No human data on the effect of datopotamab deruxtecan on fertility are available. Based on results from animal toxicity studies, datopotamab deruxtecan may impair male and female reproductive function and fertility.

Both men and women should seek advice on fertility preservation before treatment. It is not known whether datopotamab deruxtecan or its metabolites are found in seminal fluid. Male patients must not freeze or donate sperm throughout the treatment period, and for at least 4 months after the final dose of datopotamab deruxtecan. Females must not donate, or retrieve for their own use, ova throughout the treatment period and for at least 7 months after the final dose of datopotamab deruxtecan.

Datopotamab deruxtecan may influence the ability to drive and use machines. Patients should be advised to use caution when driving or operating machines in case they experience fatigue or vision changes during treatment with datopotamab deruxtecan.

Summary of safety profile

The pooled safety profile has been assessed from two clinical studies involving 443 patients who received datopotamab deruxtecan 6 mg/kg body weight for the treatment of breast cancer. The median exposure to datopotamab deruxtecan in this data set was 6.2 months (range 0.7 to 28.5 months).

The most common adverse reactions were stomatitis (64.8%), nausea (57.6%), fatigue (42.7%), alopecia (37.2%), constipation (33.0%), vomiting (26.0%), dry eye (25.5%), COVID-19 (17.8%), keratitis (17.8%), anaemia (17.2%), decreased appetite (16.3%), AST increased (16.0%), rash (15.3%), diarrhoea (12.9%), neutropenia (12.0%) and alanine aminotransferase (ALT) increased (10.4%).

The most common Grade ¾ adverse reactions were stomatitis (7.9%), fatigue (4.3%), anaemia (3.2%), AST increased (2.7%), vomiting (1.6%), ALT increased (1.6%), nausea (1.4%), urinary tract infection (1.4%), COVID-19 (1.1%), decreased appetite (1.1%), neutropenia (1.1%) and pneumonia (1.1%). Grade 5 adverse reactions occurred in 0.7% of patients and were due to ILD/pneumonitis, dyspnoea and sepsis.

The most common serious adverse reactions were COVID-19 (1.4%), urinary tract infection (1.1%), ILD/pneumonitis (1.1%) and sepsis (1.1%).

The frequency of treatment discontinuation due to adverse reactions was 3.6%. The most common adverse reaction leading to treatment discontinuation was ILD/pneumonitis (2.0%). The frequency of dose reductions due to adverse reactions was 21.0%. The most common adverse reactions leading to dose reduction were stomatitis (12.9%), fatigue (3.2%), nausea (1.8%) and keratitis (1.4%). The frequency of dose interruptions due to adverse reactions was 19.6%. The most common adverse reactions leading to dose interruption were stomatitis (5.2%), COVID-19 (4.1%), fatigue (2.3%), ILD/pneumonitis (1.6%), pneumonia (1.6%), keratitis (1.4%) and infusion-related reaction (1.1%).

Tabulated list of adverse reactions

The table below presents adverse reactions reported with datopotamab deruxtecan. Adverse reactions are listed by System Organ Class and frequency category. The adverse reaction frequencies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than datopotamab deruxtecan, such as the disease, other medicinal products or unrelated causes. The severity of adverse drug reactions was assessed based on the Common Terminology Criteria for Adverse Events (CTCAE), defining Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening, and Grade 5 = death.

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.

Adverse reactions in patients treated with datopotamab deruxtecan 6 mg/kg:

^a Including COVID-19, COVID-19 pneumonia, SARS-CoV-2 test positive.
^b Including pneumonia, lower respiratory tract infection and lower respiratory tract infection fungal.
^c Including neutropenia and neutrophil count decreased.
^d Including keratitis, punctate keratitis and ulcerative keratitis.
^e Including conjunctivitis, conjunctival disorder, conjunctival hyperaemia and conjunctival irritation.
^f Including interstitial lung disease and pneumonitis.
^g Including stomatitis, aphthous ulcer, glossitis, mouth ulceration, odynophagia, oral pain, oropharyngeal pain
and pharyngeal inflammation.
^h Including rash, erythematous rash, maculo-papular rash and pruritic rash.
ⁱ Including skin hyperpigmentation and skin discolouration.
^j Including fatigue and asthenia.
^k Infusion-related reaction includes as any reaction (infusion-related reaction, pruritus and rash) occurring within the same day as datopotamab deruxtecan infusion.

Description of selected adverse reactions

Interstitial lung disease/pneumonitis

ILD/pneumonitis occurred in 4.7% of the pool of patients with breast cancer treated with datopotamab deruxtecan 6 mg/kg, of which 3.6% were adjudicated as drug-related ILD/pneumonitis by independent review. Most ILD/pneumonitis cases were Grade 1 (2.9%). Grade 2 events occurred in 0.9% of patients. Grade 3 events occurred in 0.9% of patients. Adjudicated drug-related Grade 5 events occurred in 0.2% of patients. Median time to first onset was 5.8 months (range: 1.1 to 10.8).

Ocular surface undesirable effects

Ocular surface undesirable effects occurred in 49.0% of the pool of patients treated with datopotamab deruxtecan, of which 35.0% were Grade 1, 12.2% were Grade 2 and 1.8% were Grade 3. Keratitis occurred in 17.8% of the pool of patients treated with datopotamab deruxtecan, of which 13.3% were Grade 1, 3.6% were Grade 2 and 0.9% were Grade 3. The median time to onset was 4.1 months (range: 0 to 23.2). Discontinuation due to keratitis occurred in 0.5% of patients.

Stomatitis

Stomatitis occurred in 64.8% of the pool of patients treated with datopotamab deruxtecan, of which 29.3% were Grade 1, 27.5% were Grade 2 and 7.9% were Grade 3. Median time to first onset was 0.6 months (range: 0.03 to 12.2). Discontinuation due to stomatitis occurred in 0.5% of patients.

Haematological events

In study TROPION-Breast01 neutropenia occurred in 11.7% of patients treated with datopotamab deruxtecan (1.1% were Grade ≥3). Leukopenia occurred in 3.6% of patients treated with datopotamab deruxtecan (none were Grade ≥3). Colony stimulating factor was used by 2.7% of patients treated with datopotamab deruxtecan.

Elderly

Of the 443 patients with breast cancer treated with datopotamab deruxtecan 6 mg/kg, 23.3% were 65 years or older and 4.7% were 75 years or older. Data are limited to establish the safety in patients 85 years or older.

There was a numerically lower proportion of Grade ¾ adverse reactions (24.3% vs 25.0%) and a numerically higher proportion of serious adverse reactions (9.7% vs 6.8%) and adverse reactions leading to discontinuation (3.9% vs 3.5%) observed in patients aged 65 years or older compared to patients younger than 65 years old.