Serplulimab

The use of systemic corticosteroids or immunosuppressants before starting serplulimab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy. However, systemic corticosteroids or other immunosuppressants can be used to treat immune-related adverse reactions after starting serplulimab.

There are insufficient data and no dose recommendation can be made in patients with severe (CRCL=15-29 ml/min) renal impairment.

There are insufficient data in patients with moderate (BIL > 1.5 to 3 × ULN and any AST) hepatic impairments and no data are available in severe (BIL > 3 × ULN and any AST) hepatic impairments. No dose recommendation can be made for patients with moderate or severe hepatic impairment.

There is no data on the use of serplulimab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1 pathway causes embryofoetal toxicity. Human IgG is known to cross the placental barrier and serplulimab is an IgG4; therefore, it has the potential to be transmitted from the mother to the developing foetus. Serplulimab is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether serplulimab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, serplulimab could be used during breast-feeding if clinically needed.

Women of childbearing potential/contraception

Women of childbearing potential should use effective contraception during treatment and for at least 6 months after the last dose of serplulimab.

Fertility

Studies to evaluate fertility have not been performed. Thus, the effect of serplulimab on male and female fertility is unknown.

Serplulimab has minor influence on the ability to drive and use machines. Because of potential adverse reactions such as fatigue, patients should be advised to use caution when driving or operating machinery until they are certain that serplulimab does not adversely affect them.

Summary of the safety profile

The safety of serplulimab in combination with chemotherapy is based on data in 389 patients with ES-SCLC. The most common adverse reactions were neutropenia (82.8%), leukopenia (74.0%), anaemia (72.8%), thrombocytopenia (56.0%), alopecia (54.2%), nausea (36.2%), hyperlipidaemia (32.1%), decreased appetite (28.3%), hypoproteinaemia (25.4%), and hyponatraemia (25.4%).

The most common Grade ≥ 3 adverse reactions were neutropenia (65.3%), leukopenia (33.7%), thrombocytopenia (23.1%), anaemia (19.8%), hyponatraemia (10.0%), and lymphopenia (5.1%).

The most common serious adverse reactions were thrombocytopenia (9.3%), neutropenia (7.7%), leukopenia (6.7%), pneumonia (3.3%), and hyperglycaemia or diabetes mellitus (2.3%).

The most common immune-related adverse reactions were hypothyroidism (13.1%), hyperthyroidism (10.8%), immune-related skin adverse reactions (7.5%), abnormal liver function (4.1%), immune-related lung disease (3.1%), anaemia (2.8%), malaise (2.1%), hyperglycaemia or diabetes mellitus (1.8%), immune-related colitis (1.8%), and platelet count decreased (1.5%).

Serplulimab was discontinued due to adverse reactions in 5.4% of patients.

Tabulated list of adverse reactions

Adverse reactions reported in clinical trial and in post-marketing experience are listed by system organ class and frequency (see table). Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in ASTRUM-005 trial, in which 389 patients were exposed to serplulimab in combination with chemotherapy for a median duration of 22 weeks.

Frequencies 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); 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 serplulimab* in ASTRUM-005:

^* Adverse reaction frequencies presented in Table 2 may not be fully attributable to serplulimab alone but may contain contributions from the underlying disease or from other medicinal products used in a combination.
The following terms represent a group of related events that describe a medical condition rather than a single event:
^a Includes pneumonia, pneumonia fungal.
^b Includes urinary tract infection, asymptomatic bacteriuria.
^c Includes upper respiratory tract infection, pharyngotonsillitis, tonsillitis.
^d Includes activated partial thromboplastin time prolonged, activated partial thromboplastin time, activated partial thromboplastin time shortened, international normalised ratio decreased, prothrombin level increased.
^e Includes drug hypersensitivity, infusion-related reaction.
^f Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroxine free decreased, central hypothyroidism, tri-iodothyronine decreased.
^g Includes hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, blood ketone body increased, glucose tolerance impaired, ketoacidosis.
^h Includes blood thyroid stimulating hormone decreased, tri-iodothyronine increased, anti-thyroid antibody positive, thyroglobulin increased, thyroxine increased.
ⁱ Includes thyroid disorder, thyroiditis.
^j Includes adrenal insufficiency, cortisol decreased.
^k Includes euthyroid sick syndrome, ultrasound thyroid abnormal.
^l Includes cortisol increased, hyperadrenocorticism.
^m Includes hyponatraemia, hypocalcaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia, hypochloraemia, hyperphosphataemia, hyperkalaemia, hypermagnesaemia, hypercalcaemia.
ⁿ Includes neuropathy peripheral, peripheral sensorimotor neuropathy, immune-mediated neuropathy**.
° Includes immune-mediated encephalitis, encephalitis autoimmune.
^p Includes supraventricular extrasystoles, supraventricular tachycardia, arrhythmia, ventricular extrasystoles, arrhythmia supraventricular, atrial fibrillation, atrial tachycardia, bradyarrhythmia, early repolarisation syndrome, ventricular arrhythmia, electrocardiogram QT prolonged, electrocardiogram repolarisation abnormality, electrocardiogram T wave abnormal.
^q Includes atrioventricular block first degree, bundle branch block right, atrial conduction time prolongation, bundle branch block left, defect conduction intraventricular.
^r Includes cardiac failure, cardiac failure acute, left ventricular failure.
^s Includes cardiomyopathy, metabolic cardiomyopathy.
^t Includes phlebitis, phlebitis superficial.
^u Includes immune-mediated lung disease, pneumonitis, interstitial lung disease.
^v Includes gastrointestinal haemorrhage, gastrointestinal disorder, lower gastrointestinal haemorrhage.
^w Includes enteritis, immune-mediated enterocolitis**.
^x Includes hepatic function abnormal, drug-induced liver injury, liver injury, immune-mediated hepatitis, immune-mediated hepatic disorder**, hepatic failure**.
^y Includes rash, rash maculo-papular, eczema, drug eruption, erythema, skin toxicity.
^z Includes autoimmune dermatitis, dermatitis, dermatitis allergic, dermatitis bullous, seborrhoeic dermatitis.
^aa Includes back pain, myalgia, musculoskeletal chest pain, spinal pain, neck pain.
^bb Includes muscular weakness, musculoskeletal discomfort.
^cc Includes myositis**, immune-mediated myositis**.
^dd Includes acute kidney injury, renal failure, renal impairment, renal injury.
^ee Includes face oedema, oedema peripheral, peripheral swelling, swelling, swelling face.
^** Post-marketing event.

Immune-related lung disease

Immune-related lung disease occurred in 3.5% of patients, including Grade 3, 4 or 5 in 0.9%, 0.1%, and 0.3% of patients, respectively. The median time to onset was 3.25 months (range: 0.03-34.53 months). The median duration was 1.91 months (range: 0.26-13.34 months). 1.6% of patients received high-dose corticosteroid treatment. Immune-related lung disease led to discontinuation in 1.0% of patients.

Immune-related colitis

Immune-related colitis occurred in 2.4% of patients, including Grade 3 in 0.6% of patients and Grade 5 in 0.1% of patients. The median time to onset was 3.01 months (range: 0.03-20.11 months). The median duration was 0.43 months (range: 0.03-4.40 months). 0.5% of patients received high-dose corticosteroid treatment. Immune-related colitis led to discontinuation in 0.3% of patients.

Immune-related hepatitis

Hepatitis occurred in 0.7% of patients, including Grade 3 in 0.3% of patients, Grade 4 in 0.2% of patients, and Grade 5 in 0.2% of patients. The median time to onset was 2.48 months (range: 0.43-6.60 months). The median duration was 0.95 months (range: 0.53-1.51 months). 0.2% of patients received high-dose corticosteroid treatment. Hepatitis led to discontinuation in 0.3% of patients. Abnormal liver function occurred in 4.5% of patients, including Grade 3 in 1.0% of patients. The median time to onset was 1.51 months (range: 0.07-29.73 months). The median duration was 1.41 months (range: 0.26-17.54 months). 0.3% of patients received high-dose corticosteroid treatment. Abnormal liver function led to discontinuation in 0.3% of patients.

Immune-related nephritis and renal dysfunction

Immune-related nephritis and renal dysfunction occurred in 2.4% of patients, including Grade 3 in 0.3% of patients and Grade 4 in 0.1% of patients. The median time to onset was 2.78 months (range: 0.23-17.28 months). The median duration was 1.12 months (range: 0.13-5.32 months). 0.2% of patients received high-dose corticosteroid treatment. Immune-related nephritis and renal dysfunction led to discontinuation in 0.2% of patients.

Immune-related endocrinopathies

Hypothyroidism

Hypothyroidism occurred in 11.2% of patients, including Grade 3 in 0.1% of patients. The median time to onset was 3.84 months (range: 0.62-34.10 months). The median duration was 2.76 months (range: 0.53-7.49 months). 5.9% of patients received thyroid hormone replacement therapy. No patients discontinued serplulimab due to hypothyroidism.

Hyperthyroidism

Hyperthyroidism occurred in 6.3% of patients, and there were no Grade ≥ 3 hyperthyroidism. The median time to onset was 1.79 months (range: 0.69-31.18 months). The median duration was 1.41 months (range: 0.07-4.21 months). No patients discontinued serplulimab due to hyperthyroidism.

Thyroiditis

Thyroiditis occurred in 0.7% of patients, and there were no Grade ≥ 3 thyroiditis. The median time to onset was 5.65 months (range: 1.94-13.50 months). The median duration was 5.93 months (range: 0.56-11.30 months). 0.2% of patients received thyroid hormone replacement therapy. No patients discontinued serplulimab due to thyroiditis.

Adrenal gland disorders

Adrenal gland disorders occurred in 0.3% of patients, all of which were Grade 2. The median time to onset was 5.78 months (range: 5.75-6.93 months). No patients discontinued serplulimab due to adrenal gland disorders.

Pituitary disorders

Pituitary disorders occurred in 0.9% of patients, including Grade 3 in 0.2% of patients. The median time to onset was 6.97 months (range: 1.41-20.53 months). The median duration was 2.43 months.

0.3% of patients received high-dose corticosteroid treatment. Pituitary disorders led to discontinuation in 0.2% of patients.

Diabetes mellitus/hyperglycaemia

Diabetes mellitus/hyperglycaemia occurred in 1.0% of patients, including Grade 3 in 0.5% of patients and Grade 4 in 0.1% of patients. The median time to onset was 4.09 months (range: 0.69-11.10 months). The median duration was 2.96 months. 0.6% of patients received insulin replacement therapy. Diabetes mellitus/hyperglycaemia led to discontinuation in 0.1% of patients.

Immune-related skin adverse reactions

Immune-related skin adverse reactions occurred in 8.7% of patients, including Grade 3 in 0.8% of patients. The median time to onset was 2.10 months (range: 0.03-30.52months). The median duration was 0.82 months (range: 0.07-12.39 months). 1.4% of patients received high-dose corticosteroid treatment. Immune-related skin adverse reactions led to discontinuation in 0.4% of patients.

Immune-related pancreatitis

Immune-related pancreatitis occurred in 1.1% of patients, including Grade 3 in 0.3% of patients, Grade 4 in 0.2% of patients and Grade 5 in 0.1% of patients. The median time to onset was 2.30 months (range: 0.23-12.42 months). The median duration was 0.76 months (range: 0.16-10.12 months). 0.2% of patients received high-dose corticosteroid treatment. Immune-related pancreatitis led to discontinuation in 0.2% of patients.

Immune-related myocarditis

Immune-related myocarditis occurred in 0.6% of patients, including Grade 3 in 0.2% of patients and Grade 5 in 0.1% of patients. The median time to onset was 1.87 months (range: 0.26-25.36 months). The median duration was 0.89 months (range: 0.72-4.57 months). 0.3% of patients received high-dose corticosteroid treatment. Immune-related myocarditis led to discontinuation in 0.2% of patients.

Immune-related uveitis

Immune-related uveitis occurred in 0.1% of patients, which was Grade 1. The time to onset was 6.90 months. The duration of immune-related uveitis was 1.35 months. The event resolved for the patient.

Other immune-related adverse reactions

Other clinically significant immune-related adverse reactions reported in patients who received serplulimab were as follows. Severe or fatal cases have been reported for some of these adverse reactions.

Blood and lymphatic system: anaemia, leukopenia, thrombocytopenia, neutropenia.

Nervous system: dizziness, immune-mediated encephalitis, neuropathy peripheral.

Eye disorders: vision blurred.

Cardiac/vascular: acute coronary syndrome, myocardial infarction, cardiac failure acute, cardiotoxicity, troponin increased.

Respiratory, thoracic and mediastinal: dyspnoea, chronic obstructive pulmonary disease, respiratory failure.

Gastrointestinal: mouth ulceration, vomiting, proctitis.

General disorders and administration site conditions: asthenia, fatigue, pyrexia.

Other: panic disorder, tinnitus, cholangitis acute, sepsis, cortisol decreased, blood alkaline phosphatase increased, electrolyte imbalance.

Infusion-related reactions

Infusion-related reactions occurred in 1.4% of patients, including Grade 3 in 0.2% of patients and Grade 4 in 0.1% of patients. The median time to onset was 1.02 months (range: 0.03-9.86 months). The median duration was 0.07 months (range: 0.03-0.53 months). No patients discontinued serplulimab due to infusion-related reactions.

Laboratory abnormalities

The proportions of patients who experienced a shift from baseline to a Grade ≥ 3 laboratory abnormality were as follows: 0.6% for platelet count decreased, 0.4% for neutrophil count decreased, 0.3% for blood creatine phosphokinase increased, 0.2% for white blood cell count decreased, 0.1% for blood lactate dehydrogenase increased, and 0.1% for blood cholesterol increased.

Elderly

No overall differences in safety were reported between elderly (≥65 years) and younger patients. Data for patients ≥75 years of age are too limited to draw conclusions on this population.