Leaflet HETRONIFLY 10mg / ml concentrate for solution for infusion

HETRONIFLY 10 mg/ml concentrate for solution for infusion.

Each ml of concentrate for solution for infusion contains 10 mg of serplulimab.

One vial of 10 ml of concentrate contains 100 mg of serplulimab.

Serplulimab is a humanised antibody (IgG4/kappa isotype with a stabilising sequence alteration in thehinge region) produced in Chinese hamster ovary cells by recombinant DNA technology.

Each 10 ml vial contains 0.98 mmol (22.5 mg) sodium and 2.0 mg polysorbate 80 (E 433).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Colourless to slightly yellow, clear to slightly opalescent solution, pH 5.2-5.8, osmolality ofapproximately 280-340 mOsm/kg.

Small cell lung cancer (SCLC)

HETRONIFLY in combination with carboplatin and etoposide is indicated for the first-line treatmentof adult patients with extensive-stage small cell lung cancer (ES-SCLC).

HETRONIFLY in combination with carboplatin and pemetrexed is indicated for the first-linetreatment of adult non-squamous NSCLC patients with no EGFR, ALK or ROS1 positive mutationsand who have: locally advanced NSCLC who are not candidates for surgery or radiotherapy, or metastatic NSCLC.

Oesophageal squamous cell carcinoma (OSCC)

HETRONIFLY in combination with fluoropyrimidine- and platinum-based chemotherapy is indicatedfor the first-line treatment of adult patients with unresectable, locally advanced, recurrent or metastaticoesophageal squamous cell carcinoma whose tumours express PD-L1 with a CPS ≥ 5.

Treatment must be initiated and supervised by a physician experienced in the treatment of cancer.

If specified in the indication, patient selection for treatment with HETRONIFLY based on the tumourexpression of PD-L1 should be assessed by a CE-marked IVD with the corresponding intendedpurpose. If the CE-marked IVD is not available, an alternative validated test should be used (seesections 4.1, pct. 4.4, and 5.1).

Small cell lung cancer (SCLC)

The recommended dose in both the induction and maintenance phases is 4.5 mg/kg bodyweightserplulimab every 3 weeks until disease progression or unacceptable toxicity. During the inductionphase (4 cycles), carboplatin is administered on day 1, and etoposide on days 1, 2 and 3 of each 3-week cycle.

The recommended dose in both the induction and maintenance phases is 4.5 mg/kg bodyweightserplulimab every 3 weeks until disease progression or unacceptable toxicity. During the inductionphase (4 cycles), carboplatin and pemetrexed are administered on day 1 of each 3-week cycle. Duringthe maintenance phase, the administration of pemetrexed is continued at the discretion of thephysician.

Oesophageal squamous cell carcinoma (OSCC)

The recommended dose in both the induction and maintenance phases is 3.0 mg/kg bodyweightserplulimab every 2 weeks until disease progression or unacceptable toxicity. During the inductionphase, cisplatin is administered on day 1 of each 2-week cycle for up to 8 cycles, and 5-fluorouracil onday 1 of each 2-week cycle for up to 12 cycles.

For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitanttherapies.

Dose escalation or reduction of HETRONIFLY is not recommended. Dose withholding ordiscontinuation may be required based on individual safety and tolerability. Dose withholding for upto 12 weeks for tolerability is acceptable (see section 4.4).

Recommended management of immune-mediated adverse reactions are described in Table 1.

Table 1. Recommended treatment modifications

Adverse reactions Severity Treatment modification#

Immune-mediated Grade 2 Withhold until adverselung disease reactions recover or improve to

Grade 1

Grade 3 or 4 or recurrent Grade 2 Permanently discontinue

Immune-mediated Grade 2 or 3 Withhold until adversecolitis reactions recover or improve to

Grade 1

Grade 4 or recurrent Grade 3 Permanently discontinue

Immune-mediated Grade 2 with AST or ALT > 3 to 5 times Withhold until adversehepatitis ULN, or total bilirubin > 1.5 to 3 times reactions recover or improve to

ULN Grade 1

Adverse reactions Severity Treatment modification#

Grade 3 or 4 with AST or ALT > 5 times Permanently discontinue

ULN, or total bilirubin > 3 times ULN

Immune-mediated Grade 2 elevation of serum creatinine Withhold until adversenephritis and renal reactions recover or improve toinsufficiency Grade 1

Grade 3 or 4 elevation of serum creatinine Permanently discontinue

Immune-mediated Symptomatic Withhold until symptomsendocrinopathies Grade 2 or 3 hypothyroidism, resolve and management with

Grade 2 or 3 hyperthyroidism, corticosteroids is complete.

Grade 2 or 3 hypophysitis, Treatment should be continued

Grade 2 adrenal insufficiency, in the presence of hormone

Grade 3 hyperglycaemia or type 1 diabetes replacement therapy as long asmellitus no symptoms are present

Grade 4 hypothyroidism Permanently discontinue

Grade 4 hyperthyroidism

Grade 4 hypophysitis

Grade 3 or 4 adrenal insufficiency

Grade 4 hyperglycaemia

Immune-mediated Grade 3 Withhold until adverseskin reactions reactions recover or improve to

Grade 1

Grade 4 Stevens Johnson Syndrome (SJS) Permanently discontinueor toxic epidermal necrolysis (TEN)

Other immune- Grade 2 myasthenia gravis/myasthenic Withhold until adversemediated adverse syndrome* reactions recover or improve toreactions Grade 3 or 4 elevation of serum amylase or Grade 1lipase

Grade 2 or 3 pancreatitis

Grade 2 myocarditis*

Grade 2 or 3 other immune-mediatedadverse reactions occurred for the firsttime

Grade 3 decreased platelet count(thrombocytopenia) or white blood cellcount

Grades 3 or 4 myasthenia gravis/Permanently discontinuemyasthenic syndrome

Grade 4 pancreatitis or recurrentpancreatitis of any grade

Grade 3 or 4 myocarditis

Grade 3 or 4 encephalitis

Grade 4 other immune-mediated adversereactions occurred for the first time

Grade 4 or recurrent Grade 3 decreasedplatelet count (thrombocytopenia) or whiteblood cell count

Infusion-related Grade 2 Reduce infusion rate to halfreactions rate or interrupt. Treatmentmay be resumed when theevent is resolved

Grade 3 or 4 Permanently discontinue

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteriafor Adverse Events Version 5.0 (NCI-CTCAE v5.0).

#: Serplulimab must be permanently discontinued for any Grade 3 immune-mediated adversereaction that recurs and for any Grade 4 immunemediated adverse reactions, except forendocrinopathies that are controlled with replacement hormones (see sections 4.4 and 4.8).†: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

*: The safety of retreatment with serplulimab in patients who experienced immune-mediatedmyasthenia gravis/myasthenic syndrome or myocarditis is not clear.

No dose adjustment is needed for elderly patients (≥ 65 years) (see section 5.1 and section 5.2).

No dose adjustment is needed for patients with mild (CRCL=60-89 ml/min) or moderate(CRCL=30-59 ml/min) renal impairment. There are insufficient data and no dose recommendation canbe made in patients with severe (CRCL=15-29 ml/min) renal impairment (see section 5.2).

No dose adjustment is needed for patients with mild (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 × ULN and any AST) hepatic impairment. There are insufficient data in patients withmoderate (bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairments and no data are available insevere (bilirubin > 3 × ULN and any AST) hepatic impairments. No dose recommendation can bemade for patients with moderate or severe hepatic impairment (see section 5.2).

There is no relevant use of serplulimab in the paediatric population.

HETRONIFLY is for intravenous use.

The initial infusion rate should be set up to 100 ml per hour. If the first infusion is well tolerated, allsubsequent infusions may be shortened to 30 minutes (± 10 minutes).

When administered in combination with chemotherapy, HETRONIFLY should be given first followedby chemotherapy on the same day. Use separate infusion bags for each infusion.

HETRONIFLY must not be administered as an intravenous push or bolus injection.

The total dose of HETRONIFLY required should be diluted with sodium chloride 9 mg/ml (0.9%)solution for injection (see section 6.6).

For instructions on dilution and handling of the medicinal product before administration, see section6.6.

Hypersensitivity to active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

When assessing the PD-L1 status of the tumour, it is important that a well validated methodology ischosen to minimise false negative or false positive determinations.

Immune-mediated adverse reactions

Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patientsreceiving serplulimab (see section 4.8). Most immune-mediated adverse reactions occurring duringtreatment were reversible and managed by withholding treatment, administration of corticosteroids,and/or supportive care (see section 4.2). Immune-mediated adverse reactions have also occurred up to3.6 months after the last dose. Immune-mediated adverse reactions affecting more than one bodysystem can occur simultaneously.

For suspected immune-mediated adverse reactions, adequate evaluation to confirm aetiology orexclude other causes should be ensured. Based on the severity of the adverse reaction, treatmentshould be withheld, and corticosteroid administered. For most Grade 2 and some specific Grade 3 or 4immune-mediated adverse reactions, administration should be withheld until recover or improve to

Grade 1. Serplulimab must be permanently discontinued for any Grade 4 and some specific Grade 3immune-mediated adverse reactions. For Grade 3, 4 and some specific Grade 2 immune-mediatedadverse reactions (e.g., immune-mediated pneumonitis, immune-mediated myocarditis), corticosteroid(1-2 mg/kg/day prednisone or equivalent) and other symptomatic treatments should be givenaccording to the clinical symptoms until recover or improve to Grade 1. Upon improvement to Grade≤ 1, corticosteroid taper should be initiated and continued over at least 1 month. Rapid tapering maylead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressivetherapy (e.g., infliximab) should be added if there is worsening or no improvement despitecorticosteroid use.

Immune-mediated lung disease

Immune-mediated pneumonitis, including fatal cases, has been reported in patients receiving

HETRONIFLY (see section 4.8). Patients should be monitored for signs and symptoms ofimmune-mediated pneumonitis such as radiographic changes (e.g., focal ground glass opacities,patchy filtrates), dyspnoea, and hypoxia. Suspected immune-mediated pneumonitis should beconfirmed with radiographic imaging, and other causes excluded. For treatment modification, seesection 4.2.

Immune-mediated colitis

Immune-mediated colitis, including fatal cases, has been reported in patients receiving serplulimab(see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated colitis,such as abdominal pain, diarrhoea, mucus, or blood in stool. Infection and other disease-mediatedaetiologies should be ruled out. For treatment modification, see section 4.2. The potential risk ofgastrointestinal perforation should be taken into consideration and confirmed by radiographic imagingand/or endoscopy if necessary.

Immune-mediated hepatitis

Immune-mediated hepatitis, including fatal cases, has been reported in patients receiving serplulimab(see section 4.8). Patients should be monitored for changes in liver function and clinical signs andsymptoms of immune-mediated hepatitis such as transaminase and total bilirubin elevationsperiodically (every month). Infection and diseases-related aetiologies should be ruled out. Thefrequency of liver function test should be increased, if immune-mediated hepatitis occurs. Fortreatment modification, see section 4.2.

Immune-mediated nephritis and renal insufficiency

Immune-mediated nephritis and renal insufficiency has been reported in patients receiving serplulimab(see section 4.8). Patients should be monitored for changes in renal function and clinical signs andsymptoms of immune-mediated nephritis and renal insufficiency periodically (every month). Thefrequency of renal function test should be increased, if immune-mediated nephritis occurs. Mostpatients present with asymptomatic increases in serum creatinine. Disease-related aetiologies shouldbe ruled out. For treatment modification, see section 4.2.

Immune-mediated endocrinopathies

Thyroid diseases

Thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis, have been reported inpatients receiving serplulimab (see section 4.8). Patients should be monitored for changes in thyroidfunction and clinical signs and symptoms of thyroid disorders. For Grade 2 or 3 symptomatichypothyroidism, serplulimab should be withheld and thyroid hormone replacement should be initiatedas needed. For Grade 2 or 3 symptomatic hyperthyroidism, serplulimab should be withheld andanti-thyroid medicinal product should be initiated as needed. If acute inflammation of the thyroid issuspected, serplulimab should be withheld and initiate hormone therapy. Treatment may be resumedwhen symptoms of hypothyroidism or hyperthyroidism are controlled, and thyroid function isimproved. For life-threatening hyperthyroidism or hypothyroidism, serplulimab must be permanentlydiscontinued. Thyroid function should be monitored continuously to ensure appropriate hormonereplacement (see section 4.2).

Hypophysitis has been reported in patients receiving serplulimab (see section 4.8). Patients should bemonitored for signs and symptoms of hypophysitis, and other causes should be ruled out. For Grade 2or 3 symptomatic hypophysitis, serplulimab should be withheld, and hormone replacement should beinitiated as needed. If acute hypophysitis is suspected, corticosteroids should be initiated. Forlife-threatening Grade 4 hypophysitis, serplulimab must be permanently discontinued (see section 4.2).

Adrenal insufficiency has been reported in patients receiving serplulimab (see section 4.8). Patientsshould be monitored for signs and symptoms, and other causes should be ruled out. For Grade 2adrenal insufficiency, serplulimab should be withheld and hormone replacement should be initiated asneeded. For life-threatening Grade 3 or 4 adrenal insufficiency, serplulimab must be permanentlydiscontinued. Adrenal gland function and hormone levels should be monitored continuously to ensureappropriate hormone replacement (see section 4.2).

Hyperglycaemia or type 1 diabetes mellitus has been reported in patients receiving serplulimab (seesection 4.8). Patients should be monitored for blood glucose level and related clinical signs andsymptoms. Insulin replacement therapy should be initiated as needed. For type 1 diabetes mellitus withpoor blood glucose control, serplulimab should be withheld, and insulin replacement therapy shouldbe initiated until the symptoms are improved. For life-threatening Grade 4 type 1 diabetes mellitus,serplulimab must be permanently discontinued. Blood glucose levels should be monitoredcontinuously to ensure appropriate insulin replacement (see section 4.2).

Immune-mediated skin reactions

Immune-mediated skin reactions have been reported in patients receiving serplulimab (see section4.8). For Grade 1 or 2 rash, serplulimab can be continued, and symptomatic treatment or localcorticosteroids treatment can be given. For Grade 3 rash, serplulimab should be withheld, andsymptomatic treatment or local corticosteroids treatment should be given. For Grade 4 rash,

Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN), serplulimab should bepermanently discontinued (see section 4.2).

Immune-mediated pancreatitis

Immune-mediated pancreatitis, including increases in serum amylase and lipase levels and fatal cases,has been reported in patients receiving serplulimab (see section 4.8). Patients should be monitored forchanges in serum lipase and amylase (at the beginning of treatment, periodically during treatment, andas indicated based on clinical evaluation), and clinical signs and symptoms of pancreatitis.

Serplulimab should be withheld for Grade 3 or 4 increase in serum amylase or lipase levels, and Grade2 or 3 pancreatitis. For Grade 4 pancreatitis or recurrent pancreatitis of any grade, serplulimab shouldbe permanently discontinued (see section 4.2).

Immune-mediated myocarditis

Immune-mediated myocarditis, including fatal cases, has been reported in patients receivingserplulimab (see section 4.8). Patients should be monitored for clinical signs and symptoms ofmyocarditis. Suspected immune-mediated myocarditis should be confirmed with myocardial enzymeexaminations, and other causes excluded. For Grade 2 myocarditis, serplulimab should be withheld,and corticosteroid treatment should be given. The safety of restarting serplulimab treatment in patientspreviously experiencing immune-mediated myocarditis is unclear. A multidisciplinary discussion isrecommended before restarting serplulimab in patients with previous Grade 2 myocarditis, and thedecision should be based on various clinical factors, including the degree of cardiac recovery,oncological response to the treatment, availability of alternative oncology treatments and prognosis.

For Grade 3 or 4 myocarditis, serplulimab must be permanently discontinued and corticosteroidstherapy should be initiated. Once a diagnosis of myocarditis is established, serplulimab should bewithheld or permanently discontinued. Myocardial enzymes and cardiac function should be monitoredclosely for any grade myocarditis (see section 4.2).

Immune-mediated uveitis

If uveitis and other immune-mediated adverse reactions occur at the same time, such as

Vogt-Koyanagi-Harada syndrome, systemic corticosteroids should be given to prevent permanentblindness.

Other immune-mediated adverse reactions

Given the mechanism of action of serplulimab, other potential immune-mediated adverse reactionsmay occur. Other fatal and life-threatening immune-mediated adverse reactions have been observed inpatients treated with serplulimab in clinical trials across doses and tumour types: thrombocytopenia,acute coronary syndrome, myocardial infarction, immune-mediated encephalitis, myasthenia gravisand myasthenic syndrome (see section 4.8). Patients should be made aware of the symptoms ofmyasthenia gravis and myasthenic syndromes (e.g. muscle weakness and tiring easily) and be advisedto immediately seek medical attention if symptoms occur.

For other suspected immune-mediated adverse reactions, adequate evaluation should be performed toconfirm aetiology and exclude other causes. Based on the severity of adverse reactions, serplulimabshould be withheld for Grade 2 or 3 immune-mediated adverse reactions which occur for the first time.

For recurrent Grade 3 immune-mediated adverse reactions (except endocrinopathies) and Grade 4immune-mediated adverse reactions, serplulimab must be permanently discontinued. Corticosteroidscan be initiated as clinically indicated (see section 4.2).

Infusion-related reactions have been reported in patients receiving serplulimab. Patients should bemonitored for clinical signs and symptoms of infusion-related reactions. Patients with Grade 1infusion-related reactions may continue administration under close monitoring. The rate of infusionshould be reduced, or treatment should be interrupted in patients with Grade 2 infusion-relatedreactions. Antipyretic and antihistamines may be considered. Treatment with serplulimab may beresumed under close monitoring when Grade 2 infusion-related reactions are controlled. For Grade ≥ 3infusion-related reactions, infusion should be stopped immediately, treatment should be permanentlydiscontinued, and appropriate treatment should be given (see section 4.2).

Patients with the following conditions were excluded from clinical trials: active or prior documentedautoimmune disease, patients with active tuberculosis or hepatitis B or C or HIV infection or patientsreceiving live attenuated vaccine within 28 days prior to serplulimab administration, patients with anyactive infection requiring systemic anti-infective therapy within 14 days prior to the first dose, historyof pneumonitis or interstitial lung disease, patients with active brain metastases, history of significantcardiovascular disease (e.g. myocardial infarction within half a year), a history of hypersensitivity toanother monoclonal antibody, systemic immunosuppressive medicinal products within 2 weeks priorto receiving serplulimab.

This medicinal product contains 0.98 mmol (or 22.5 mg) sodium per 10 ml vial, equivalent to 1.1% ofthe WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicine contains 2.0 mg of polysorbate 80 (E 433) in each 10 ml vial. Polysorbates may causeallergic reactions.

For instructions on dilution and handling of the medicinal product before administration, see section6.6.

The prescriber must discuss the risks of serplulimab therapy with the patient. The patient will beprovided with the patient card with each prescription.

Drug-drug interaction studies have not been conducted. As monoclonal antibodies are not metabolisedby cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition, or induction ofthese enzymes by co-administered medicinal products is not anticipated to affect the pharmacokineticsof HETRONIFLY.

The use of systemic corticosteroids or immunosuppressants before starting serplulimab should beavoided because of their potential interference with the pharmacodynamic activity and efficacy.

However, systemic corticosteroids or other immunosuppressants can be used to treat immune-mediated adverse reactions after starting serplulimab (see section 4.4).

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

There is no data on the use of serplulimab in pregnant women. Animal studies have demonstrated thatinhibition of the PD-1 pathway causes embryofoetal toxicity (see section 5.3). Human IgG is known tocross the placental barrier and serplulimab is an IgG4; therefore, it has the potential to be transmittedfrom the mother to the developing foetus. Serplulimab is not recommended during pregnancy and inwomen of childbearing potential not using contraception.

It is unknown whether serplulimab is excreted in human milk. Human IgGs are known to be excretedin 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.

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

Serplulimab has minor influence on the ability to drive and use machines. Because of potential adversereactions such as fatigue (see section 4.8), patients should be advised to use caution when driving oroperating machinery until they are certain that serplulimab does not adversely affect them.

The safety of serplulimab in combination with chemotherapy is based on pooled data in 985 patients.

The most common adverse reactions were anaemia (78.6%), neutropenia (72.9%), leukopenia(69.9%), thrombocytopenia (50.7%), nausea (48.5%), decreased appetite (36.5%), hypoproteinaemia(33.4%), vomiting (31.2%), constipation (29.0%), and asthenia (29.0%).

The most common Grade ≥ 3 adverse reactions were neutropenia (42.7%), leukopenia (22.5%),anaemia (21.5%), thrombocytopenia (13.7%), hyponatraemia (7.4%), and hypokalaemia (5.2%).

The most common serious adverse reactions were thrombocytopenia (8.3%), leukopenia (5.6%),neutropenia (5.6%), pneumonia (4.7%), anaemia (4.1%), and pneumonitis (3.4%).

The most common immune-mediated adverse reactions were hypothyroidism (12.6%),hyperthyroidism (8.7%), immune-mediated skin adverse reactions (6.8%), immune-mediated lungdisease (4.9%), abnormal liver function (3.1%), immune-mediated nephritis and renal dysfunction(3.1%), and immune-mediated colitis (1.5%).

Serplulimab was discontinued due to adverse reactions in 6.6% of patients. The most common adversereaction leading to treatment discontinuation was pneumonitis (1.3%).

Adverse reactions reported in clinical trial and in post-marketing experience are listed by system organclass and frequency (see Table 2). Unless otherwise stated, the frequencies of adverse reactions arebased on all-cause adverse event frequencies identified in trials in which 985 patients were exposed toserplulimab in combination with chemotherapy. See section 5.1 for information about the maincharacteristics of patients in the pivotal clinical trials.

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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inthe order of decreasing seriousness.

Table 2. Adverse reactions in patients treated with serplulimab*

Serplulimab in combination with chemotherapy

Very common pneumonia a

Common urinary tract infection b, respiratory tract infection c, skin infection

Uncommon septic shock, gastrointestinal infection, meningoencephalitis herpetic

Very common neutropenia, leukopenia, anaemia, thrombocytopenia, lymphopenia

Common coagulation function test abnormal d, granulocytopenia, febrile neutropenia

Uncommon lymphadenitis

Uncommon infusion-related reaction e, anaphylactic reaction

Very common hypothyroidism f, hyperthyroidism g, hyperglycaemia or type 1 diabetesmellitus h

Common thyroiditis i, adrenal insufficiency j

Uncommon other thyroid disorder k, hyperadrenocorticism, hypophysitis, thyroid functiontest abnormal l, hypoparathyroidism

Very common hyperlipidaemia, decreased appetite, hypoproteinaemia, hyperuricaemia,electrolyte imbalance m, weight decreased

Common hypoglycaemia, lipoprotein abnormal

Very common insomnia

Common paraesthesia, headache, dizziness, neuropathy peripheral n, vertigo

Uncommon immune-mediated encephalitis o, neurotoxicity, motor dysfunction, cerebralinfarction, taste disorder, memory impairment

Rare myasthenia gravis, myasthenic syndrome

Uncommon vision blurred, keratitis, conjunctivitis

Very common arrhythmia p

Common sinus tachycardia, conduction defects q, sinus bradycardia, cardiac failure r,troponin increased, myocardial injury

Uncommon cardiomyopathy, myocardial ischaemia, pericardial effusion, myocarditis

Common hypertension, vasculitis, hypotension

Uncommon venous thrombosis

Very common cough, chest pain

Common pneumonitis s, dyspnoea, dysphonia, pulmonary embolism

Uncommon respiratory failure

Very common nausea, constipation, diarrhoea, vomiting

Common dysphagia, abdominal pain, flatulence, gastrointestinal disorder t, stomatitis,dyspepsia, dry mouth

Uncommon enteritis u, gastritis, immune-mediated pancreatitis, gingival bleeding,oesophagitis, gastric ulcer

Very common alanine aminotransferase increased, aspartate aminotransferase increased,gamma-glutamyltransferase increased

Common hyperbilirubinaemia, liver injury v

Very common rash w, alopecia

Common pruritus, dermatitis x, pigmentation disorder

Uncommon psoriasis, dry skin, hyperhidrosis

Very common musculoskeletal pain

Uncommon myositis y, arthritis

Very common protein urine present, blood creatinine increased

Common blood urea increased, haematuria, renal injury z

Uncommon dysuria, pollakiuria

Very common pyrexia, asthenia

Common malaise, oedema

Uncommon chills

Common blood alkaline phosphatase increased, myoglobin blood increased, bloodcreatine phosphokinase increased, amylase increased, lipase increased

* Adverse reaction frequencies presented in Table 2 may not be fully attributable to serplulimab alonebut may contain contributions from the underlying disease or from other medicinal products used in acombination.

The following terms represent a group of related events that describe a medical condition rather than asingle event:

a. Includes pneumonia, lung abscess.

b. Includes urinary tract infection, asymptomatic bacteriuria, white blood cells urine positive.

c. Includes upper respiratory tract infection, pharyngotonsillitis, tonsillitis, influenza-like illness,lower respiratory tract infection.

d. Includes activated partial thromboplastin time prolonged, activated partial thromboplastin time,activated partial thromboplastin time shortened, international normalised ratio decreased,prothrombin level increased, coagulopathy, hypercoagulation.

e. Includes drug hypersensitivity, infusion-related reaction.

f. Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroxine freedecreased, thyroxine decreased, central hypothyroidism, tri-iodothyronine decreased, tri-iodothyronine free decreased.

g. Includes hyperthyroidism, blood thyroid stimulating hormone decreased, thyroxine increased,tri-iodothyronine increased, tri-iodothyronine free increased, thyroxine free increased.

h. Includes hyperglycaemia, type 1 diabetes mellitus, blood glucose increased, impaired fastingglucose, diabetic ketoacidosis, blood ketone body increased, glucose tolerance impaired,ketoacidosis, glycosuria.

i. Includes thyroid disorder, thyroiditis.j. Includes adrenal insufficiency, cortisol decreased.k. Includes euthyroid sick syndrome, ultrasound thyroid abnormal.l. Includes anti-thyroid antibody positive, thyroglobulin increased.m. Includes hyponatraemia, hypocalcaemia, hypokalaemia, hypomagnesaemia,hypophosphataemia, hypochloraemia, hyperphosphataemia, hyperkalaemia,hypermagnesaemia, hypercalcaemia.

n. Includes neuropathy peripheral, peripheral sensorimotor neuropathy, immune-mediatedneuropathy.

o. Includes immune-mediated encephalitis, encephalitis autoimmune.p. Includes supraventricular extrasystoles, supraventricular tachycardia, arrhythmia, ventricularextrasystoles, arrhythmia supraventricular, atrial fibrillation, atrial tachycardia,bradyarrhythmia, early repolarisation syndrome, ventricular arrhythmia, palpitations,electrocardiogram abnormal.

q. Includes atrioventricular block first degree, bundle branch block right, atrial conduction timeprolongation, bundle branch block left, defect conduction intraventricular.

r. Includes cardiac failure, cardiac failure acute, left ventricular failure, N terminal prohormonebrain natriuretic peptide increased.

s. Includes immune-mediated lung disease, pneumonitis, interstitial lung disease.t. Includes acquired trachea-oesophageal fistula, gastrointestinal haemorrhage, gastrointestinaldisorder, intestinal obstruction.u. Includes enteritis, enteritis infectious, immune-mediated enterocolitis **.v. Includes hepatic function abnormal, drug-induced liver injury, liver injury, immune-mediatedhepatitis, immune-mediated hepatic disorder **, hepatic failure **.w. Includes rash, rash maculo-papular, eczema, drug eruption, erythema, skin toxicity, palmar-plantar erythrodysaesthesia syndrome.x. Includes autoimmune dermatitis, dermatitis, dermatitis allergic, dermatitis bullous, seborrhoeicdermatitis.y. Includes myositis **, immune-mediated myositis.z. Includes acute kidney injury, renal failure, renal impairment, renal injury, chronic kidneydisease, creatinine renal clearance decreased, immune-mediated nephritis.

** Post-marketing event.

Serplulimab is associated with immune-mediated adverse reactions. The data for the followingimmune-mediated adverse reactions are based on 2 086 patients who received serplulimabmonotherapy (n=292) or in combination with other medicinal products (n=1 794) across nine doses(0.3, 1, 3, 10 mg/kg every 2 weeks, 4.5 mg/kg every 3 weeks, 200 mg every 2 weeks, 300 mg every 3weeks, 400 mg every 4 weeks, or 600 mg every 6 weeks) in ten clinical trials. The managementguidelines for these adverse reactions are described in sections 4.2 and 4.4.

Immune-mediated lung disease

Immune-mediated lung disease occurred in 4.9% of patients, including Grade 3, 4 or 5 in 1.2%, 0.2%,and 0.3% of patients, respectively. The median time to onset was 4.40 months (range: 0.03-34.53months). The median duration was 1.76 months (range: 0.10-13.34 months). 2.5% of patients receivedhigh-dose corticosteroid treatment. Immune-mediated lung disease led to discontinuation in 1.3% ofpatients.

Immune-mediated colitis

Immune-mediated colitis occurred in 2.0% of patients, including Grade 3 in 0.6% of patients and

Grade 5 in < 0.1% of patients. The median time to onset was 3.35 months (range: 0.03-30.55 months).

The median duration was 0.43 months (range: 0.03-8.94 months). 0.7% of patients received high-dosecorticosteroid treatment. Immune-mediated colitis led to discontinuation in 0.2% of patients.

Immune-mediated hepatitis

Hepatitis occurred in 0.8% of patients, including Grade 3 in 0.3% of patients, Grade 4 in 0.1% ofpatients, and Grade 5 in 0.1% of patients. The median time to onset was 2.48 months (range:0.36-26.78 months). The median duration was 0.95 months (range: 0.10-8.48 months). 0.4% ofpatients received high-dose corticosteroid treatment. Hepatitis led to discontinuation in 0.3% ofpatients. Abnormal liver function occurred in 3.7% of patients, including Grade 3 in 0.8% of patients,and Grade 4 in 0.1% of patients. The median time to onset was 2.30 months (range: 0.07-45.31months). The median duration was 1.31 months (range: 0.26-17.54 months). 0.5% of patients receivedhigh-dose corticosteroid treatment. Abnormal liver function led to discontinuation in 0.2% of patients.

Immune-mediated nephritis and renal insufficiency

Immune-mediated nephritis and renal insufficiency occurred in 3.0% of patients, including Grade 3 in0.3% of patients and Grade 4 in < 0.1% of patients. The median time to onset was 2.83 months (range:0.23-17.77 months). The median duration was 1.48 months (range: 0.13-17.94 months). 0.4% ofpatients received high-dose corticosteroid treatment. Immune-mediated nephritis and renalinsufficiency led to discontinuation in 0.2% of patients.

Immune-mediated endocrinopathies

Hypothyroidism occurred in 11.7% of patients, including Grade 3 in 0.2% of patients. The mediantime to onset was 3.83 months (range: 0.46-34.10 months). The median duration was 2.73 months(range: 0.13-29.08 months). 6.7% of patients received thyroid hormone replacement therapy. < 0.1%patients discontinued serplulimab due to hypothyroidism.

Hyperthyroidism occurred in 6.7% of patients, and there were no Grade ≥ 3 hyperthyroidism. Themedian time to onset was 2.73 months (range: 0.62-31.18 months). The median duration was 1.45months (range: 0.07-17.77 months). No patients discontinued serplulimab due to hyperthyroidism.

Thyroiditis occurred in 0.7% of patients, and there were no Grade ≥ 3 thyroiditis. The median time toonset was 6.64 months (range: 0.99-13.50 months). The median duration was 1.30 months (range:0.56-11.30 months). 0.2% of patients received thyroid hormone replacement therapy. No patientsdiscontinued serplulimab due to thyroiditis.

Adrenal gland disorders occurred in 0.5% of patients, including Grade 3 in 0.1% of patients. Themedian time to onset was 6.24 months (range: 3.55-21.45 months). The median duration was 4.60months. < 0.1% of patients received high dose corticosteroid treatment. No patients discontinuedserplulimab due to adrenal gland disorders.

Pituitary disorders occurred in 0.8% of patients, including Grade 3 in 0.1% of patients. The mediantime to onset was 6.72 months (range: 1.41-20.53 months). The median duration was 3.25 months.0.2% of patients received high-dose corticosteroid treatment. Pituitary disorders led to discontinuationin 0.1% of patients.

Type 1 diabetes mellitus/hyperglycaemia

Type 1 diabetes mellitus/hyperglycaemia occurred in 0.9% of patients, including Grade 3 in 0.4% ofpatients and Grade 4 in 0.1% of patients. The median time to onset was 4.34 months (range:0.69-40.28 months). The median duration was 3.48 months (range: 0.53-10.68). 0.5% of patientsreceived insulin replacement therapy. Type 1 diabetes mellitus/hyperglycaemia led to discontinuationin < 0.1% of patients.

Immune-mediated skin reactions

Immune-mediated skin reactions occurred in 7.8% of patients, including Grade 3 in 0.8% of patients,

Grade 4 in < 0.1% of patients, and Grade 5 in < 0.1% of patients. The median time to onset was 2.96months (range: 0.03-30.52 months). The median duration was 1.56 months (range: 0.07-19.06months). 1.2% of patients received high-dose corticosteroid treatment. Immunemediated skin reactionsled to discontinuation in 0.5% of patients.

Immune-mediated pancreatitis

Immune-mediated pancreatitis occurred in 1.0% of patients, including Grade 3 in 0.3% of patients,

Grade 4 in 0.1% of patients and Grade 5 in < 0.1% of patients. The median time to onset was 2.86months (range: 0.23-13.67 months). The median duration was 0.76 months (range: 0.16-10.12months). 0.1% of patients received high-dose corticosteroid treatment. Immune-mediated pancreatitisled to discontinuation in 0.2% of patients.

Immune-mediated myocarditis

Immune-mediated myocarditis occurred in 0.7% of patients, including Grade 3 in 0.1% of patients,

Grade 4 in < 0.1% of patients and Grade 5 in 0.2% of patients. The median time to onset was 1.71months (range: 0.26-20.70 months). The median duration was 0.79 months (range: 0.30-5.72 months).0.5% of patients received high-dose corticosteroid treatment. Immune-mediated myocarditis led todiscontinuation in 0.3% of patients.

Immune-mediated uveitis

Immune-mediated uveitis occurred in < 0.1% of patients, which was Grade 1. The time to onset was6.90 months. The duration of immune-mediated uveitis was 1.35 months. The event resolved for thepatient.

Other immune-mediated adverse reactions

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

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

Nervous system: immune-mediated encephalitis, neuropathy peripheral, epilepsy, encephalopathy,peripheral sensorimotor neuropathy.

Eye disorders: vision blurred.

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

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

Gastrointestinal: mouth ulceration, vomiting, proctitis, upper gastrointestinal haemorrhage.

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

Other: panic disorder, abnormal behaviour, cholangitis acute, sepsis, peritonitis, blood alkalinephosphatase increased, blood creatine phosphokinase increased, blood lactate dehydrogenaseincreased, n-terminal prohormone brain natriuretic peptide increased, blood cholesterol increased,electrolyte imbalance, chronic kidney disease, urinary tract inflammation.

Infusion-related reactions occurred in 1.7% of patients, including Grade 3 in 0.1% of patients and

Grade 4 in 0.1% of patients. The median time to onset was 1.74 months (range: 0.03-34.04 months).

The median duration was 0.07 months (range: 0.03-6.70 months). No patients discontinuedserplulimab due to infusion-related reactions.

The proportions of patients who experienced a shift from baseline to a Grade ≥ 3 laboratoryabnormality were as follows: 0.5% for platelet count decreased, 0.3% for neutrophil count decreased,0.2% for blood creatine phosphokinase increased, 0.1% for white blood cell count decreased, 0.1% fortroponin I increased.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions,and appropriate symptomatic treatment instituted immediately.

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drugconjugates, PD-1/PD-L1 (Programmed cell death-1/death ligand 1) inhibitors

ATC code: L01FF12.

Serplulimab (HLX10) is a humanised monoclonal IgG4 antibody, which binds to the programmed celldeath-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptoris a negative regulator of T-cell activity that has been shown to be involved in the control of T-cellimmune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed inantigen presenting cells and may be expressed by tumours or other cells in the tumourmicroenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Serplulimabpotentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to

PD-L1 and PD-L2 ligands.

The PD-1 receptor occupation of peripheral T cells and interleukin-2 (IL-2) release ability in vitrowere studied in the phase 1 trial involving 29 Chinese patients with advanced solid tumour that wereinjected with single and multiple doses (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg) of serplulimab. Theresult showed that serplulimab could stably maintain the saturation state of receptor occupation andsustained functional blockage at the dosage from 0.3 mg/kg to 10 mg/kg every 2 weeks interval.

Small cell lung cancer (SCLC)

ASTRUM-005: Randomised phase III trial in patients with chemotherapy-naïve extensive-stage SCLC,in combination with carboplatin and etoposide

The efficacy of serplulimab in combination with chemotherapy (carboplatin plus etoposide) for thefirst-line treatment of ES-SCLC was evaluated in ASTRUM-005 trial (NCT04063163), a phase 3,randomised, double-blind, multiregional clinical trial. The primary efficacy endpoint was overallsurvival (OS). Secondary efficacy endpoints were progression free survival (PFS), objective responserate (ORR) and duration of response (DOR) as assessed by independent radiology review committee(IRRC) and investigator based on RECIST 1.1. Analysis for the primary endpoint was performed at 25and 33 months since the start of the clinical trial. The study treatment regimens were unblinded afterthe primary analysis.

The trial included adult patients (18 years or older) with ES-SCLC (according to the Veterans

Administration Lung Study Group [VALG] staging system) who had not been treated with systemictherapy and with an ECOG performance-status score of 0 or 1. Patients were excluded if they hadactive or untreated central nervous system metastases; active autoimmune disease; administration ofsystemic immunosuppressive medicinal products within 14 days prior to the first dose.

A total of 585 patients were enrolled and randomised (2:1) to receive one of the treatment regimensdescribed in Table 3. Randomisation was stratified by PD-L1 expression level (negative: tumourproportion scores [TPS] < 1%, positive: TPS ≥ 1%, or not evaluable/not available, measured by PD-L1

IHC 22C3 pharmDx kit), brain metastasis (yes versus no), and age (≥ 65 years versus < 65 years).

Table 3. Intravenous treatment regimens

Treatment Induction Maintenanceregimen (Four 21-Day Cycles) (21-Day Cycles)

A Serplulimab (4.5 mg/kg) a + carboplatin (AUC=5, aup to 750 mg) b + etoposide (100 mg/m2) b,c Serplulimab (4.5 mg/kg)

B Placebo + carboplatin (AUC=5, up to 750 mg) b +etoposide (100 mg/m2) b,c Placebo

a. Serplulimab was administered until disease progression or unacceptable toxicity.

b. Carboplatin and etoposide were administered until completion of 4 cycles, or progressive disease orunacceptable toxicity, whichever occurred first.

c. Etoposide was administered on day 1, 2 and 3 of each cycle.

Baseline characteristics were balanced between the treatment arms. Among the patients enrolled,68.5% were Asian (401 patients), and 31.5% were non-Asian (184 patients), all of which were White.

The median age was 62 years (range: 28-83) with 39.3% of patients ≥ 65 years of age, and 1.9% ofpatients ≥ 75 years of age. 82.2% of patients were men. Baseline ECOG performance-status score was0 (17.6%) or 1 (82.4%). 16.9% of patients were PD-L1 positive (TPS ≥ 1%). 13.3% of patients had ahistory of brain metastases.

At the time of the interim analysis cut-off on 22 October 2021 when 66% of predefined OS eventswere observed (defined approximately 226, actual 246 OS events), patients had a median survivalfollow-up time of 12.3 months. OS, PFS and ORR results from the interim analysis are summarised in

Table 4.

Table 4. Efficacy data at the primary analysis (data cut-off date: 22 October 2021)

Arm A Arm B(Serplulimab + carboplatin + (Placebo + carboplatin +etoposide) etoposide)

Number of patients 389 196

Primary endpoint

Number of patientswith events, n (%) 146 (37.5%) 100 (51.0%)

Median OS (months) 15.4 10.9

OS Hazard ratio (95%

CI) 0.63 (0.49-0.82)p-value < 0.001

Secondary endpoints

PFS Median PFS

- IRRC per (months) 5.7 4.3

RECIST Hazard ratio (95%1.1 CI) 0.48 (0.38-0.59)

Confirmed

ORR (%) 67.4% 58.7%

Median

DOR Months (95% CI) 5.8 (5.2-7.5) 4.1 (3.0-4.2)

Updated analysis after unblinding with longer follow-up duration (median: 19.7 months) wasconducted by the cut-off date 13 June 2022 when 100% of predefined OS events were observed(defined approximately 342, actual 363 OS events). The median OS was 15.8 months in theserplulimab group and 11.1 months in the placebo group. The stratified HR (95% CI) was 0.62 (0.50,0.76). The median PFS by IRRC assessment per RECIST 1.1 was 5.7 months and 4.3 months,respectively, with a stratified HR (95% CI) of 0.47 (0.38, 0.58). The efficacy results of final analysiswere consistent with the primary analysis. Kaplan-Meier curves for OS and PFS of final analysis arepresented in Figures 1 and 2.

Figure 1. Kaplan-Meier curve of OS in overall population at the updated analysis (ITT) (datacut-off date: 13 June 2022)

Figure 2. Kaplan-Meier curve of PFS (RECIST 1.1) by IRRC in overall population at theupdated analysis (ITT) (data cut-off date: 13 June 2022)

ASTRUM-002: Randomised phase III trial in chemotherapy-naïve patients with locally advanced ormetastatic non-squamous NSCLC, in combination with carboplatin and pemetrexed

ASTRUM-002 consisted of two stages. Stage I was a single-arm safety run-in designed to evaluate thesafety, tolerability, and preliminary efficacy of serplulimab combined with bevacizumab andchemotherapy (carboplatin + pemetrexed) as first-line treatment for advanced non-squamous NSCLC.

Stage II was a three-arm, randomised, double-blind, multicentre, Phase III clinical trial. The primaryefficacy endpoint was progression free survival (PFS) as assessed by independent radiology reviewcommittee (IRRC), the key secondary efficacy endpoint was overall survival (OS). Other secondaryefficacy endpoints were PFS as assessed by investigator, objective response rate (ORR) and durationof response (DOR) as assessed by IRRC and investigator based on RECIST 1.1.

The trial included adult (≥ 18 years and ≤ 75 years) patients with histologically or cytologicallyconfirmed unresectable or radiographically ineligible stage IIIB, IIIC, or IV non-squamous NSCLC,without EGFR sensitizing mutations or ALK/ROS1 rearrangements, and no prior systemic therapy foradvanced disease. Patients were required to have ≥1 measurable lesion per RECIST 1.1 assessed by

IRRC and ECOG PS 0-1.

Patients with active/suspected autoimmune diseases, active CNS metastases and/or carcinomatousmeningitis, or prior treatment with immune checkpoint inhibitors (e.g., PD-1, PD-L1, CTLA-4antibodies) were excluded.

Six subjects were enrolled in Stage I of the study. A total of 636 patients were enrolled in Stage II andwere randomised (1:1:1). In Arm A, patients received serplulimab 4.5 mg/kg, bevacizumab 15 mg/kg,carboplatin (AUC=5, up to 800 mg, for up to four cycles), and pemetrexed (500 mg/m²) every threeweeks until disease progression or unacceptable toxicity. Patients randomized to Arm B and Arm Creceived treatments as shown in Table 5. Randomisation was stratified by PD-L1 expression measuredby PD-L1 IHC 22C3 pharmDx kit (negative [CPS<1] versus positive [CPS≥1] versus indeterminate),smoking history (yes versus no), and brain metastasis (yes versus no).

Table 5. Intravenous treatment regimens

Treatment regimen Induction Maintenance(Four 21-Day Cycles) (21-Day Cycles)

Serplulimab (4.5 mg/kg) a + a

B placebo (15 mg/kg) a + carboplatin Serplulimab (4.5 mg/kg) +(AUC=5, up to 800 mg) b + placebo (15 mg/kg) a +pemetrexed (500 mg/m2) a pemetrexed (500 mg/m2) a

Placebo (4.5 mg/kg) a + placebo Placebo (4.5 mg/kg) a +

C (15 mg/kg) a + carboplatin placebo (15 mg/kg) a +(AUC=5, up to 800 mg) b + pemetrexed (500 mg/m2) a,cpemetrexed (500 mg/m2) a

a. Serplulimab and pemetrexed were administered until disease progression or unacceptable toxicity.

b. Carboplatin was administered until completion of 4 cycles, or progressive disease or unacceptabletoxicity, whichever occurred first.

c. Crossover was allowed from arm C to receive serplulimab 4.5 mg/kg every 3 weeks andbevacizumab treatment 15 mg/kg every 3 weeks.

Baseline characteristics were balanced between treatment arms. Among the patients enrolled, 100%were Asian (636 patients). The median age was 61 years (range: 27 to 75), and 73.1% of patients weremale, and most patients were current or previous smokers (66.8%). Baseline ECOG performancestatus was 0 (26.9%) or 1 (73.0%). Thirty-nine percent had tumour PD-L1 expression TPS < 1%[negative], 31% had TPS 1-49%, 28% had TPS ≥ 50%. A total of 78.0% of patients’ tumours had PD-

L1 expression positive (CPS ≥ 1) and 18.7% had brain metastasis at baseline. 79 subjects (37.6%) in

Arm C received treatment with serplulimab combined with bevacizumab after confirmed diseaseprogression.

The median survival follow-up was 23.1 months at the primary analysis (data cut-off: 15 June 2023)and 45.4 months at the updated analysis (data cut-off: 07 August 2025). PFS, ORR and DOR resultsfrom the primary analysis, and OS results from the updated analysis are summarised in Table 6.

Kaplan-Meier curves for PFS of primary analysis and OS of updated analysis are presented in Figure 3and Figure 4.

Table 6. Efficacy data in ASTRUM-002

Arm B Arm C(Serplulimab + carboplatin + (Placebo + carboplatin +pemetrexed) pemetrexed)

Number of patients 214 210

Primary endpoint

Number of patientswith events, n (%) 130 (60.7%) 156 (74.3%)

PFS 1 Median PFS (months,

- IRRC per 95% CI) 11.0 (8.4, 12.7) 5.6 (4.8, 6.8)

RECIST1.1 Hazard ratio (95%

CI) 0.55 (0.43-0.69)p-value < 0.0001

Secondary endpoints

Number of patientswith events, n (%) 132 (61.7%) 162 (77.1%)

OS 2 Median OS (months,95% CI) 26.8 (21.2, 30.9) 20.3 (16.2, 24.6)

Hazard ratio (95%

CI) 0.66 (0.52-0.83)

Confirmed

ORR 1 (%, 95% CI) 52.8% (45.9%-59.7%) 27.6% (21.7%-34.2%)1PFS and ORR results are based on the pre-specified interim analysis with data cutoff of 15 June 2023.2OS results are based on the final analysis with a data cutoff of 07 August 2025.

Figure 3. Kaplan-Meier curve of PFS (RECIST 1.1) by IRRC in overall population at theprimary analysis (data cut-off date: 15 June 2023)

Figure 4. Kaplan-Meier curve of OS in overall population at the updated analysis (data cut-offdate: 07 August 2025)

Table 7 summarises efficacy results of PFS for PD-L1 subgroups (TPS < 1%, 1% ≤ TPS < 50%, and

TPS ≥ 50%) from the updated analysis.

Table 7. IRRC assessed PFS by PD-L1 expression (data cut-off date: 07 August 2025)

Arm B Arm C(Serplulimab + carboplatin + (Placebo + carboplatin +pemetrexed) pemetrexed)

PD-L1 Events /N Median (months, Events /N Median (months, Stratified hazard ratioexpression (%) 95% CI) (%) 95% CI) (95% CI)

TPS < 1% 59/84 8.5 (5.6, 13.9) 51/68(70.2%) (75.0%) 6.8 (4.6, 9.8) 0.83 (0.55, 1.26)1% ≤ TPS < 45/64 62/7350% (70.3%) 10.3 (8.1, 15.5) (84.9%) 6.9 (5.1, 8.4) 0.63 (0.43, 0.94)

TPS ≥ 50% 37/62 12.1 (9.5, 45.4) 51/62(59.7%) (82.3%) 4.4 (4.0, 5.8) 0.36 (0.23, 0.57)

Oesophageal squamous cell carcinoma (OSCC)

ASTRUM-007: Randomised phase III trial of combination therapy in oesophageal squamous cellcarcinoma patients

The efficacy of serplulimab in combination with chemotherapy was investigated in ASTRUM-007(NCT03958890), a multicentre, randomised, double-blind, placebo-controlled study in patients withunresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma. Thedual primary endpoints were progression-free survival (PFS) assessed by an Independent Radiology

Review Committee (IRRC) based on RECIST v1.1, and overall survival (OS) in the intent-to-treat(ITT) population. The secondary endpoints included PFS assessed by the investigator, objectiveresponse rate (ORR) and duration of response (DOR) assessed by IRRC and by the investigator. Thestudy treatment regimens were unblinded after the primary analysis.

The trial included adult (≥ 18 years and ≤ 75 years) patients with histologically diagnosed local-advanced, recurrent or distantly metastatic oesophageal (including gastro-oesophageal junction)squamous cell carcinoma, and no prior systemic therapy for recurrence or metastasis. Patients withrecurrent OSCC who had received neoadjuvant/adjuvant treatment or curative concurrentchemoradiotherapy or radiotherapy could be included if the last treatment was more than 6 monthsfrom relapse or disease progression. Patients were required to have ≥ 1 measurable lesion per RECIST1.1 assessed by IRRC, positive PD-L1 expression with CPS ≥ 1 based on the PD-L1 IHC 22C3pharmDx Kit and ECOG PS 0 or 1. Patients with history of gastrointestinal perforation and/or fistulaewithin 6 months prior to the first dose of study product, active autoimmune diseases, CNS metastases,or prior treatment with anti-PD-1 or anti-PD-L1 antibodies were excluded.

A total of 551 patients were enrolled and randomised (2:1) to receive one of the treatment regimensdescribed in Table 8. Randomisation was stratified by PD-L1 expression level (1 ≤ CPS < 10 versus

CPS ≥ 10), age (≥ 65 years versus < 65 years), and tumour state (locally advanced versus distantmetastasis).

Table 8. Intravenous treatment regimens

Treatment Induction Maintenanceregimen (14-Day Cycles) (14-Day Cycles)

A Serplulimab (3.0 mg/kg) a + cisplatin (50 mg/m2) b+ 5-fluorouracil (5-FU, 2400 mg/m2) c Serplulimab (3.0 mg/kg) a

B Placebo + cisplatin (50 mg/m2) b + 5-FU(2400 mg/m2) c Placebo

a. Serplulimab was administered until disease progression, unacceptable toxicity, or up to 2 years.

b. Cisplatin was administered until completion of 8 cycles, or progressive disease, or unacceptabletoxicity, whichever occurred first.

c. 5-FU was administered by continuous intravenous drip for 44-48 hours in each cycle untilcompletion of 12 cycles or progressive disease or unacceptable toxicity, whichever occurred first.

Of the 551 patients enrolled, 343 (62.3%) had tumours that expressed PD-L1 with a CPS ≥ 5. Amongthese 343 patients, all were Asian. The median age was 64 years (range: 34-75) with 48.4% of patients≥ 65 years of age. 85.7% of patients were men. Baseline ECOG performance-status score was 0(26.2%) or 1 (73.8%). 70.3% of patients were CPS ≥ 10. 14.0% of patients had locally advanceddiseases. 34.7% of patients received prior anti-cancer treatment including surgery, radiotherapy andsystemic anti-cancer therapy before enrolment in this study.

At the time of the interim analysis cut-off on 15 April 2022 patients had a median survival follow-uptime of 14.9 months. For all patients enrolled in this study, the median PFS by IRRC assessment per

RECIST 1.1 was 5.8 (95% CI: 5.7, 6.9) months in the serplulimab group and 5.3 (95% CI: pct. 4.3, 5.6)months in the placebo group, respectively, with a stratified HR (95% CI) of 0.60 (0.48, 0.75). Themedian OS was 15.3 (95% CI: 14.0, 18.6) months in the serplulimab group and 11.8 (95% CI: 9.7,14.0) months in the placebo group. The stratified HR (95% CI) was 0.68 (0.53, 0.87).

An updated analysis after unblinding with longer follow-up duration (median: 24.3 months) wasconducted with cut-off date 09 January 2023 and showed consistent efficacy results with the interimanalysis. Efficacy results from the updated analysis (data cut-off date 09 January 2023) for patientswith a CPS ≥ 5 are summarised in Table 9. Kaplan-Meier curves for PFS and OS of updated analysisin patients with a CPS ≥ 5 are presented in Figure 5 and Figure 6.

Table 9. Efficacy data at the updated analysis for patients with CPS ≥ 5 (data cut-off date: 09

January 2023)

Arm A Arm B(Serplulimab + cisplatin + 5-FU) (Placebo + cisplatin + 5-FU)

Number of patients 230 113

Dual primary endpoints

PFS Number of patients

- IRRC per with events, n (%) 154 (67.0%) 84 (74.3%)

RECIST Median PFS (95%1.1 CI) (months) 6.9 (5.7, 8.1) 5.3 (4.1, 5.8)

Arm A Arm B(Serplulimab + cisplatin + 5-FU) (Placebo + cisplatin + 5-FU)

Hazard ratio (95%

CI) 0.57 (0.43, 0.75)

Number of patientswith events, n (%) 144 (62.6%) 89 (78.8%)

OS Median OS (95%

CI) (months) 16.5 (13.8, 19.5) 10.7 (8.7, 13.9)

Hazard ratio (95%

CI) 0.60 (0.46, 0.79)

Secondary endpoints

Confirmed

ORR % (95% CI) 65.2% (58.7%, 71.4%) 39.8% (30.7%, 49.5%)

Figure 5. Kaplan-Meier curve of PFS (RECIST 1.1) by IRRC in patients with a CPS score ≥ 5 atthe updated analysis (data cut-off date: 09 January 2023)

Figure 6. Kaplan-Meier curve of OS in patients with a CPS ≥ 5 at the updated analysis (datacut-off date: 09 January 2023)

The immunogenicity of serplulimab was evaluated in 389 patients treated with serplulimab at4.5 mg/kg Q3W in the ASTRUM-005 trial. Seven patients (1.8%) were ADA positive at any visit, ofwhom 6 patients (1.5%) were treatment-emergent ADA positive, defined as at least one post-baseline

ADA positive. All the positive ADA samples were tested as negative NAbs.

The immunogenicity of serplulimab was evaluated in 503 patients (6 patients in Stage I safety run-inphase and 497 patients in Stage II phase III study) treated with serplulimab at 4.5 mg/kg Q3W in the

ASTRUM-002 trial. 22 patients (4.4%) were ADA positive at any visit, of whom 17 patients (3.4%)were treatment-emergent ADA positive, defined as at least one post-baseline ADA positive. 2 (0.4%)

ADA positive samples were tested as positive NAbs.

The immunogenicity of serplulimab was evaluated in 382 patients treated with serplulimab at 3 mg/kg

Q2W in the ASTRUM-007 trial, including 374 that received serplulimab + chemotherapy and 8 thatreceived alternated therapy. A total of 24 patients (6.3%) were ADA positive at any visit, of whom 22patients (5.8%) were treatment-emergent ADA positive, defined as at least one post-baseline ADApositive. 19 (5.1%) subjects that received serplulimab + chemotherapy throughout the study weredetected positive for ADA at least once at visits after administration, and 1 (0.3%) subject wasdetected positive for Nab at least once; 3 (37.5%) subjects with alternated medication were detectedpositive for ADA at least once at visits after administration, with negative NAb detected in the furthertest.

In dose escalation and dose expansion study HLX10-001, the overall percentage of treatment-emergent ADA for dose finding cohorts and dose expansion cohorts were 3.4% (1/29) and 18.9%(7/37) respectively. All the ADA positive samples were detected with negative NAbs.

No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed. However, data arestill limited.

In the ASTRUM-005, ASTRUM-002 and ASTRUM-007 trials, of the 985 patients in the serplulimabgroup in the overall population, 410 (41.6%) were ≥ 65 years. No overall differences in efficacy wereobserved between elderly patients and younger patients. Data for patients ≥ 75 years of age are toolimited to draw conclusions on this population.

The European Medicines Agency has waived the obligation to submit the results of studies withserplulimab in all subsets of the paediatric population for malignant neoplasms (except haematopoieticand lymphoid tissue) (see section 4.2 for information on paediatric use).

Serplulimab pharmacokinetics has been investigated in a population pharmacokinetic (popPK)analysis that included 2 110 patients with cancer (including OSCC, SCLC, NSCLC) and other solidcancer types from 11 studies. The patients received serplulimab intravenously as monotherapy orcombination therapy in the dose range of 0.3 to 10 mg/kg Q2W, 4.5 mg/kg Q3W, 200 mg Q2W,300 mg Q3W and 400 mg Q4W. The PK was described by a two-compartment model withtime-dependent clearance (CL). Inter-individual variability (coefficient of variation, CV) ranges from16.3% to 54.3%. The mean (CV) observed trough concentration at steady state ranges from 44.2 (34.7)to 60.7 (30.3) across all tumour types.

Serplulimab is administered by intravenous infusion and is therefore immediately and completelybioavailable. Other routes of administration have not been investigated.

Based on a popPK analysis the volume of distribution of serplulimab is approximately in the rangefrom 6.17 L to 6.46 L.

The metabolic pathway of serplulimab has not been characterised. Serplulimab is expected to becatabolised into small peptides and amino acids by general protein degradation processes.

Based on a popPK analysis, serplulimab clearance (CL) after the first dose is in the range from0.171 L/day to 0.211 L/day. The clearance decreases over time by a maximum of 8.8% (CV 34.1%)with 221 days to reach half of the maximum effect. The half-life at steady state is in the range 25.0-31.2 days.

Serplulimab exhibited linear pharmacokinetics over the dose range of 0.3 to 10 mg/kg Q2W (includingflat doses of 200 mg Q2W, 300 mg Q3W and 400 mg Q4W) both after single and multiple doses.

No dedicated studies have been performed in special populations. A popPK analysis suggested nodifference in the total systemic clearance of serplulimab based on age (23-83 years), race (n=265

Whites and n=1 845 Asians), and ECOG performance-status score (0 or 1). Serplulimab clearanceincreased with increasing body weight.

No effect of creatinine or creatinine clearance (CRCL) (Cockcroft-Gault) was found on serplulimab

CL based on a popPK analysis in patients with mild (CRCL=60-89 ml/min; n=917), moderate(CRCL=30-59 ml/min; n=216), and severe (CRCL=15-29 ml/min; n=1) renal impairment, and normalrenal function (CRCL≥ 90 ml/min, n=973). There are insufficient data in patients with severe renalimpairment for dosing recommendations (see section 4.2).

No effect of ALT, AST or total bilirubin was found on serplulimab CL based on a popPK analysis inpatients with mild (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5 × ULN and any AST;n=279) and moderate (bilirubin > 1.5 to 3 × ULN and any AST; n=4) hepatic impairment, and normal(bilirubin ≤ ULN and AST ≤ ULN; n=1 819) hepatic function. There are insufficient data in patientswith moderate hepatic impairment for dosing recommendations. Serplulimab has not been studied inpatients with severe (bilirubin > 3 × ULN and any AST) hepatic impairment (see section 4.2).

In the repeat-dose toxicity study in cynomolgus monkeys dosed for up to 31 weeks, a high incidenceof pharmacology-related perivascular mononuclear cell infiltration in the brain choroid plexus wasobserved at 100 mg/kg. The no observed adverse effect level (NOAEL) in the 31-weeks toxicity studywas 50 mg/kg/week, which produced exposure 36 times (calculated by AUC0-t) the exposure inhumans at dose of 3 mg/kg every two weeks.

Reproductive toxicity studies have not been performed.

The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughoutpregnancy. Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupttolerance to the foetus and to result in an increase in foetal loss.

Two anti-PD-L1 monoclonal antibodies were evaluated in cynomolgus monkeys for reproductive anddevelopmental toxicity and were shown to cause premature delivery, foetal loss and prematureneonatal death when administrated to pregnant monkeys.

Therefore, potential risks of administering serplulimab during pregnancy include increased rates ofabortion or stillbirth. Based on its mechanism of action, foetal exposure to serplulimab may increasethe risk of developing immune-mediated disorders or altering the normal immune response andimmune-mediated disorders that have been reported in PD-1 knockout mice.

No studies have been performed to assess the genotoxic or carcinogenic potential of serplulimab.

Citric acid monohydrate (for pH-adjustment)

Sodium citrate (E331) (for pH-adjustment)

Sodium chloride

Mannitol (E421)

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts, except those mentioned in section 6.6. HETRONIFLY should not be infused concomitantlyin the same intravenous line with other medicinal products.

Unopened vial3 years.

From a microbiological point of view, the product, once diluted, should be used immediately. Thediluted solution must not be frozen. If not used immediately, in-use storage times and conditions priorto use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C. This24-hour hold may include up to 6 hours at room temperature (≤ 25°C). If refrigerated, the vials and/orintravenous bags must be allowed to come to room temperature prior to use.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

10 ml of concentrate in a 10 ml Type I clear glass vial with chlorobutyl rubber stopper andaluminium-plastic combination caps containing 100 mg of serplulimab.

Pack of 1 vial.

Preparation and administration

* Aseptic handling should be ensured during the preparation of infusion.

* Do not shake the vial.

* Equilibrate the vial to room temperature (at or below 25°C).

* The product should be inspected visually for the particulate matters and discoloration prior toadministration. The concentrate is a colourless to slightly yellow, clear to slightly opalescentsolution. Discard the vial if visible particles are observed.

* Confirm the dose of the product and calculate the required volume of HETRONIFLY.

* Withdraw a volume of sodium chloride 9 mg/ml (0.9%) solution for injection corresponding tothe volume of infused product from the target intravenous bag using a sterile syringe anddiscard.

* Use a syringe to withdraw the required volume of HETRONIFLY from the vial and inject it intothe sodium chloride 9 mg/ml (0.9%) solution for injection to prepare a diluted solution with afinal concentration range from 1.0 to 8.0 mg/ml. Mix the diluted solution by gentle inversion.

* Administer the infusion solution intravenously using a sterile, non-pyrogenic, low-proteinbinding 0.2 to 5.0 μm in-line or add-on filter.

* Set the initial infusion rate to 100 ml per hour (25 drops per minute is recommended). Theinfusion rate can be adjusted if infusion-related reactions occur (see section 4.2). If there is noinfusion-related adverse reaction in the first infusion, the duration of subsequent administrationcan be shortened to 30 minutes (± 10 minutes).

* From a microbiological point of view, the product, once diluted, should be used immediately.

The diluted solution must not be frozen. If not used immediately, the diluted solution can bestored for 24 hours at 2°C to 8°C. This 24- hour hold may include up to 6 hours at roomtemperature (≤ 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to cometo room temperature prior to use (see section 6.3).

* At the end of infusion, the infusion tube is flushed with sodium chloride 9 mg/ml (0.9%)solution according to the routine operation procedure of the hospital.

* Do not co-administer other medical products through the same infusion line.

* In order to improve the traceability of biological medicinal products, the name and the batchnumber of the administered product should be clearly recorded in the patient file.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est, 6a Planta08039 Barcelona

Spain

EU/1/24/1870/001

Date of first authorisation: 03 February 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu