4.1. Therapeutic indications

JEMPERLI is indicated in combination with platinum-containing chemotherapy for the treatment of adult patients with primary advanced or recurrent endometrial cancer (EC) and who are candidates for systemic therapy.

JEMPERLI is indicated as monotherapy for the treatment of adult patients with mismatch repair deficient (dMMR)/ microsatellite instability-high (MSI‑H) recurrent or advanced EC that has progressed on or following prior treatment with a platinum‑containing regimen.

4.2. Posology and method of administration

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

The identification of dMMR/MSI-H tumour status should be determined using a validated testing method such as IHC, PCR or NGS* (see section 5.1 for information on assays used in the studies).

*IHC=immunohistochemistry; PCR=polymerase chain reaction; NGS=next-generation sequencing.

Posology

JEMPERLI in combination with chemotherapy

For the dosage or recommended dose modifications of concomitantly used chemotherapeutic agents, refer to the product information for these medicinal products (see also section 5.1).

The recommended dose as combination therapy is 500 mg dostarlimab every 3 weeks for 6 cycles followed by 1000 mg every 6 weeks for all cycles thereafter.

The dosage regimen in combination with chemotherapy is presented in Table 1.

a Administer dostarlimab prior to chemotherapy on the same day.

Administration of dostarlimab should continue according to the recommended schedule until disease progression or unacceptable toxicity, or for a duration of up to 3 years (see section 5.1).

JEMPERLI monotherapy

The recommended dose as monotherapy is 500 mg dostarlimab every 3 weeks for 4 cycles followed by 1000 mg every 6 weeks for all cycles thereafter.

The dosage regimen as monotherapy is presented in Table 2.

Table 2. Dosage regimen for JEMPERLI as monotherapy

Administration of dostarlimab should continue according to the recommended schedule until disease progression or unacceptable toxicity (see section 5.1).

Dose modifications

Dose reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Recommended modifications to manage adverse reactions are provided in Table 3.

Detailed guidelines for the management of immune‑related adverse reactions and infusion‑related reactions are described in section 4.4.

Table 3. Recommended dose modifications for JEMPERLI

Immune‑related adverse reactions

Severity gradea

Dose modification

Colitis

2 or 3

Withhold dose. Restart dosing when toxicity resolves to grade 0 or 1.

4

Permanently discontinue.

Hepatitis

Grade 2 with ASTb or ALTc > 3 and

up to 5 × ULNd

or

total bilirubin > 1.5 and up to 3 × ULN

Withhold dose. Restart dosing when toxicity resolves to grade 0 or 1.

Grade ≥ 3 with AST or ALT > 5 × ULN

or

total bilirubin > 3 × ULN

Permanently discontinue (see exception below)e.

Type 1 diabetes mellitus (T1DM)

3 or 4 (hyperglycaemia)

Withhold dose. Restart dosing in appropriately managed, clinically and metabolically stable patients.

Hypophysitis or adrenal insufficiency

2, 3 or 4

Withhold dose. Restart dosing when toxicity resolves to grade 0 or 1. Permanently discontinue for recurrence or worsening while on adequate hormonal therapy.

Hypothyroidism or hyperthyroidism

3 or 4

Withhold dose. Restart dosing when toxicity resolves to grade 0 or 1.

Pneumonitis

2

Withhold dose. Restart dosing when toxicity resolves to grade 0 or 1. If grade 2 recurs, permanently discontinue.

3 or 4

Permanently discontinue.

Nephritis

2

Withhold dose. Restart dosing when toxicity resolves to grade 0 or 1.

3 or 4

Permanently discontinue.

Exfoliative dermatologic conditions (e.g. SJSf, TENg, DRESSh)

Suspected

Withhold dose for any grade. Restart dosing if not confirmed and when toxicity resolves to grade 0 or 1.

Confirmed

Permanently discontinue.

Myocarditis

2, 3 or 4

Permanently discontinue.

Severe neurological toxicities (myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, encephalitis, transverse myelitis)

2, 3 or 4

Permanently discontinue.

Other immune‑related adverse reactions (including but not limited to myositis, sarcoidosis, autoimmune haemolytic anaemia, pancreatitis, iridocyclitis, uveitis, diabetic ketoacidosis, arthralgia, solid organ transplant rejection, graft-versus-host disease)

3

Withhold dose. Restart dosing when toxicity resolves to grade 0 or 1.

4

Permanently discontinue.

Recurrence of immune‑related adverse reactions after resolution to ≤ grade 1 (except for pneumonitis, see above)

3 or 4

Permanently discontinue.

Other adverse reactions

Severity gradea

Dose modification

Infusion‑related reactions

2

Withhold dose. If resolved within 1 hour of stopping, may be restarted at 50 % of the original infusion rate, or restart when symptoms resolve with pre‑medication. If grade 2 recurs with adequate premedication, permanently discontinue.

3 or 4

Permanently discontinue.

a Toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

b AST = aspartate aminotransferase

c ALT = alanine aminotransferase

d ULN = upper limit of normal

e For patients with liver metastases who begin treatment with grade 2 increase of AST or ALT, if AST or ALT increases by ≥ 50 % relative to baseline and lasts for at least 1 week, then treatment should be discontinued

f SJS = Stevens-Johnson syndrome

g TEN = toxic epidermal necrolysis

h DRESS = drug reaction with eosinophilia and systemic symptoms.

Patient Card

All prescribers of JEMPERLI should inform patients about the Patient Card, explaining what to do should they experience any symptom of immune‑related adverse reactions. The physician will provide the Patient Card to each patient.

Special populations

Elderly

No dose adjustment is recommended for patients who are aged 65 years or over.

There are limited clinical data with dostarlimab in patients aged 75 years or over (see section 5.1).

Renal impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment. There are limited data in patients with severe renal impairment or end‑stage renal disease undergoing dialysis (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of JEMPERLI in children and adolescents aged under 18 years have not been established. No data are available.

Method of administration

JEMPERLI is for intravenous infusion only. JEMPERLI should be administered by intravenous infusion using an intravenous infusion pump over 30 minutes.

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

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Traceability

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

Immune‑related adverse reactions

Immune‑related adverse reactions, which may be severe or fatal, can occur in patients treated with antibodies blocking the programmed cell death protein‑1 / programmed death‑ligand 1 (PD‑1/PD‑L1) pathway, including dostarlimab. While immune‑related adverse reactions usually occur during treatment with PD‑1/PD‑L1 blocking antibodies, symptoms can also manifest after discontinuation of treatment. Immune‑related adverse reactions may occur in any organ or tissue and may affect more than one body system simultaneously. Important immune‑related adverse reactions listed in this section are not inclusive of all possible severe and fatal immune‑related reactions.

Early identification and management of immune‑related adverse reactions are essential to ensure safe use of PD‑1/PD‑L1 blocking antibodies. Patients should be monitored for symptoms and signs of immune‑related adverse reactions. Haematological and clinical chemistries, including liver, kidney and thyroid function tests, should be evaluated at baseline and periodically during treatment. For suspected immune‑related adverse reactions, adequate evaluation including specialty consultation should be ensured.

Based on the severity of the adverse reaction, treatment with dostarlimab should be withheld or permanently discontinued and corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other appropriate therapy administered (see below and section 4.2). Upon improvement to grade ≤1, corticosteroid taper should be initiated and continued for 1 month or longer. Based on limited data from clinical studies in patients whose immune‑related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Hormone replacement therapy for endocrinopathies should be instituted as warranted.

Treatment with dostarlimab should be permanently discontinued for any grade 3 immune‑related adverse reaction that recurs and for any grade 4 immune‑related adverse reaction toxicity, except for endocrinopathies that are controlled with replacement hormones and unless otherwise specified in Table 3.

Immune‑related pneumonitis

Pneumonitis has been reported in patients receiving dostarlimab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Patients should be managed with dostarlimab treatment modifications and corticosteroids (see section 4.2).

Immune‑related colitis

Dostarlimab can cause immune‑related colitis (see section 4.8). Patients should be monitored for signs and symptoms of colitis and managed with dostarlimab treatment modifications, anti‑diarrhoeal agents and corticosteroids (see section 4.2).

Immune‑related hepatitis

Dostarlimab can cause immune‑related hepatitis (see section 4.8). Patients should be monitored for changes in liver function periodically as indicated, based on clinical evaluation and managed with dostarlimab treatment modifications and corticosteroids (see section 4.2).

Immune‑related endocrinopathies

Immune‑related endocrinopathies, including hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis and adrenal insufficiency, have been reported in patients receiving dostarlimab (see section 4.8).

Hypothyroidism and hyperthyroidism

Immune‑related hypothyroidism and hyperthyroidism (including thyroiditis) occurred in patients receiving dostarlimab, and hypothyroidism may follow hyperthyroidism. Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and as indicated based on clinical evaluation. Immune‑related hypothyroidism and hyperthyroidism (including thyroiditis) should be managed as recommended in section 4.2.

Adrenal insufficiency

Immune‑related adrenal insufficiency occurred in patients receiving dostarlimab. Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenal insufficiency, patients should be managed as recommended in section 4.2.

Immune‑related nephritis

Dostarlimab can cause immune‑related nephritis (see section 4.8). Patients should be monitored for changes in renal function and manage with dostarlimab treatment modifications and corticosteroids (see section 4.2).

Immune‑related skin adverse reactions

Immune-related rash has been reported in patients receiving dostarlimab, including pemphigoid (see section 4.8). Patients should be monitored for signs and symptoms of rash. Stevens-Johnson syndrome (SJS) which can be life-threatening or fatal, has been reported in association with dostarlimab treatment (see section 4.8). Events of toxic epidermal necrolysis have been reported in patients treated with PD-1 inhibitors. Patients should be advised of the signs and symptoms of severe cutaneous adverse reactions (SCARs) and monitored closely for skin reactions. Patients should be advised to seek medical advice from their physician immediately when observing any indicative signs or symptoms. For suspected SCARs, patients should be referred to a specialist for further assessment and treatment, and managed as recommended in section 4.2

Caution should be used when considering the use of dostarlimab in a patient who has previously experienced a severe or life‑threatening skin adverse reaction on prior treatment with other immune‑stimulatory anticancer agents.

Immune‑related arthralgia

Immune‑related arthralgia has been reported in patients receiving dostarlimab (see section 4.8). Patients should be monitored for signs and symptoms of arthralgia. Suspected immune‑related arthralgia should be confirmed and other causes excluded. Patients should be managed with dostarlimab treatment modifications and corticosteroids (see section 4.2).

Other immune‑related adverse reactions

Given the mechanism of action of dostarlimab other potential immune‑related adverse reactions may occur, including potentially serious events [e.g. myositis, myocarditis, encephalitis, demyelinating neuropathy (including Guillain Barré syndrome), sarcoidosis]. Clinically significant immune‑related adverse reactions reported in less than 1 % of patients treated with dostarlimab as monotherapy in clinical studies include encephalitis, autoimmune haemolytic anaemia, pancreatitis, iridocyclitis and uveitis. Patients should be monitored for signs and symptoms of immune‑related adverse reactions and managed as described in section 4.2. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with dostarlimab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with dostarlimab versus the risk of possible organ rejection should be considered in these patients.

Fatal and other serious complications can occur in patients who receive allogeneic haematopoietic stem cell transplantation (HSCT) before or after being treated with a PD‑1/PD-L1–blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GvHD), acute GvHD, chronic GvHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1–blocking antibody prior to or after an allogeneic HSCT.

Infusion‑related reactions

Dostarlimab can cause infusion‑related reactions, which can be severe (see section 4.8). For severe (grade 3) or life‑threatening (grade 4) infusion‑related reactions, the infusion should be stopped and treatment should be permanently discontinued (see section 4.2).

Patients excluded from clinical studies

Patients with the following status were excluded from the GARNET study: ECOG baseline performance score ≥ 2; uncontrolled central nervous system metastases or carcinomatous meningitis; other malignancies within the last 2 years; immunodeficiency or receiving immunosuppressive therapy within 7 days; active HIV, hepatitis B or hepatitis C infection; active autoimmune disease requiring systemic treatment in the past 2 years excluding replacement therapy; history of interstitial lung disease; or receiving live vaccine within 14 days.

Patients with the following status were excluded from the RUBY study: has a concomitant malignancy, or has a prior non-endometrial invasive malignancy who has been disease-free for <3 years or who received any active treatment in the last 3 years for that malignancy; uncontrolled central nervous system metastases or carcinomatous meningitis, or both; known history of HIV or active hepatitis B or hepatitis C; immunodeficiency or receiving immunosuppressive therapy within 7 days; considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection requiring systemic therapy; or receiving, a live vaccine within 30 days before first dose of study treatment, during study treatment, and for up to 180 days after receiving the last dose of study treatment.

Polysorbate 80 content

This medicinal product contains polysorbate 80 (see section 2), which may cause allergic reactions.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 500 mg dose, i.e. essentially 'sodium-free'. This medicinal product may be diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Monoclonal antibodies (mAb) such as dostarlimab are not substrates for cytochrome P450 or active substance transporters. Dostarlimab is not a cytokine and is unlikely to be a cytokine modulator. Additionally, pharmacokinetic (PK) interaction of dostarlimab with small molecule active substances is not expected. There is no evidence of interaction mediated by non‑specific clearance of lysosome degradation for antibodies.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

There is a risk associated with the administration of dostarlimab to women of childbearing potential. Women of childbearing potential must use effective contraception during treatment with dostarlimab and until 4 months after the last dose of dostarlimab.

Pregnancy

There are no or limited amount of data on the use of dostarlimab in pregnant women. Based on its mechanism of action, dostarlimab can cause foetal harmful pharmacological effects when administered during pregnancy.

Animal reproduction and development studies have not been conducted with dostarlimab; however, inhibition of the PD‑1/PD‑L1 pathway can lead to increased risk of immune‑mediated rejection of the developing foetus resulting in foetal death (see section 5.3). Human immunoglobulins (IgG4) are known to cross the placental barrier, and therefore, being an IgG4, dostarlimab has the potential to be transmitted from the mother to the developing foetus.

JEMPERLI is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

Breast‑feeding

It is unknown whether dostarlimab/metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

JEMPERLI should not be used during breast‑feeding and breast‑feeding should be avoided for at least 4 months after the last dose of dostarlimab.

Fertility

Fertility studies have not been conducted with dostarlimab (see section 5.3).

4.7. Effects on ability to drive and use machines

JEMPERLI has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

Dostarlimab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of dostarlimab (see “Description of selected adverse reactions” below).

Dostarlimab in monotherapy

The safety of dostarlimab has been evaluated in 605 patients with EC or other advanced solid tumours who received dostarlimab monotherapy in the GARNET study, including 153 patients with advanced or recurrent dMMR/MSI-H EC. Patients received doses of 500 mg every 3 weeks for 4 cycles followed by 1000 mg every 6 weeks for all cycles thereafter.

In patients with advanced or recurrent solid tumours (N = 605), the most common adverse reactions (> 10 %) were anaemia (28.6 %), diarrhoea (26.0 %), nausea (25.8 %), vomiting (19.0 %), arthralgia (17.0 %), pruritus (14.2 %), rash (13.2 %), pyrexia (12.4 %), aspartate aminotransferase increased (11.2 %) and hypothyroidism (11.2 %). JEMPERLI was permanently discontinued due to adverse reactions in 38 (6.3 %) patients; most of them were immune‑related events. Adverse reactions were serious in 11.2 % of patients; most serious adverse reactions were immune-related adverse reactions (see section 4.4).

The safety profile for patients with dMMR/MSI-H EC in the GARNET study (N=153) was not different from that of the overall monotherapy population presented in Table 4.

Dostarlimab in combination with chemotherapy

The safety of dostarlimab has been evaluated in 241 patients with primary advanced or recurrent EC who received dostarlimab in combination with paclitaxel and carboplatin in the RUBY study. Patients received doses of 500 mg dostarlimab every 3 weeks for 6 cycles followed by 1000 mg every 6 weeks for all cycles thereafter.

In patients with primary advanced or recurrent EC (N = 241), the most common adverse reactions (≥ 10 %) were rash (23.2 %), rash maculopapular (14.5 %), hypothyroidism (14.5 %), pyrexia (12.9 %), alanine aminotransferase increased (12.9 %), aspartate aminotransferase increased (12.0 %) and dry skin (10.0 %). JEMPERLI was permanently discontinued due to adverse reactions in 12 (5.0 %) patients; most were immune‑related events. Adverse reactions were serious in 5.8 % of patients; approximately one-half of serious adverse reactions were immune-related adverse reactions (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials of dostarlimab as a monotherapy or in combination with chemotherapy are listed in Table 4 by system organ class and by frequency. Unless otherwise stated, the frequencies of adverse reactions listed in the dostarlimab monotherapy column are based on all-cause adverse event frequency identified in 605 patients with advanced or recurrent solid tumours from the GARNET study exposed to dostarlimab monotherapy for a median duration of treatment of 24 weeks (range: 1 week to 229 weeks). Unless otherwise stated, the frequencies of adverse reactions listed in the dostarlimab in combination with chemotherapy column are based on all-cause adverse event frequency identified in 241 patients with primary advanced or recurrent EC from the RUBY study exposed to dostarlimab in combination with chemotherapy for a median duration of treatment of 43 weeks (range: 3.0 to 192.6 weeks). For additional safety information when dostarlimab is administered in combination, refer to the respective Prescribing Information for the combination products.

Adverse reactions known to occur with dostarlimab as monotherapy or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (cannot be estimated from the available data).

Table 4: Adverse reactions in patients treated with dostarlimab

System Organ Class

Dostarlimab monotherapy

Dostarlimab in combination therapy

Blood and lymphatic system disorders

Very common

Anaemiaa

Endocrine disorders

Very common

Hypothyroidism*b

Common

Hyperthyroidism*, adrenal insufficiency*

Uncommon

Thyroiditis*c, hypophysitisd

Very common

Hypothyroidisme

Common

Hyperthyroidism

Uncommon

Thyroiditis, adrenal insufficiency

Metabolism and nutrition disorders

Uncommon

Type 1 diabetes mellitus, diabetic ketoacidosis

Uncommon

Type 1 diabetes mellitus

Nervous system disorders

Uncommon

Encephalitis, myasthenia gravis

Uncommon

Myasthenic syndrome†, Guillain‑Barré syndrome†f

Eye disorders

Uncommon

Uveitisg

Uncommon

Uveitis

Cardiac disorders

Uncommon

Myocarditis†h

Respiratory, thoracic and mediastinal disorders

Common

Pneumonitis*i

Common

Pneumonitis

Gastrointestinal disorders

Very common

Diarrhoea, nausea, vomiting

Common

Colitis*j, pancreatitisk, gastritis

Uncommon

Oesophagitis

Common

Colitis†l , pancreatitis

Uncommon

Immune mediated gastritis†, vasculitis gastrointestinal†

Hepatobiliary disorders

Common

Hepatitis*m

Skin and subcutaneous tissue disorders

Very common

Rash*n, pruritus

Uncommon

Stevens-Johnson syndrome†

Very common

Rasho, dry skin

Musculoskeletal and connective tissue disorders

Very common

Arthralgia*

Common

Myalgia

Uncommon

Immune-mediated arthritis, polymyalgia rheumatica, immune-mediated myositis

Uncommon

Immune-mediated arthritis, myositis†

Renal and urinary disorders

Uncommon

Nephritis*p

General disorders and administration site conditions

Very common

Pyrexia

Common

Chills

Very common

Pyrexia

Uncommon

Systemic inflammatory response syndrome†

Investigations

Very common

Transaminases increasedq

Very common

Alanine aminotransferase increased, aspartate aminotransferase increased

Injury, poisoning and procedural complications

Common

Infusion-related reaction*r

† Includes events identified from other clinical trials in patients with solid tumours receiving dostarlimab monotherapy or dostarlimab in combination with various types of anticancer therapies.

* See section 'Description of selected adverse reactions.'

a Includes anaemia and autoimmune haemolytic anaemia

b Includes hypothyroidism and autoimmune hypothyroidism

c Includes thyroiditis and autoimmune thyroiditis

d Includes hypophysitis and lymphocytic hypophysitis

e Includes hypothyroidism and immune-mediated hypothyroidism

f Includes Guillain-Barré syndrome and demyelinating polyneuropathy

g Includes uveitis and iridocyclitis

h Includes myocarditis and immune-mediated myocarditis

i Includes pneumonitis, interstitial lung disease and immune-mediated lung disease

j Includes colitis, enterocolitis and immune-mediated enterocolitis

k Includes pancreatitis and pancreatitis acute

l Includes colitis and enteritis

m Includes hepatitis, autoimmune hepatitis and hepatic cytolysis

n Includes rash, rash maculo-papular, erythema, rash macular, rash pruritic, rash erythematous, rash papular, erythema multiforme, skin toxicity, drug eruption, toxic skin eruption, exfoliative rash and pemphigoid

o Includes rash and rash maculo-papular

p Includes nephritis and tubulointerstitial nephritis

q Includes transaminases increased, alanine aminotransferases increased, aspartate aminotransferases increased and hypertransaminasaemia

r Includes infusion-related reaction and hypersensitivity.

Description of selected adverse reactions

The selected adverse reactions described below are based on the safety of dostarlimab in a combined monotherapy safety database of 605 patients in the GARNET study in patients with EC or other advanced solid tumours. Immune‑related adverse reactions were defined as events of grade 2 and above; the frequencies below exclude grade 1 events. Details for immune-related adverse reactions for dostarlimab when given in combination are presented if clinically relevant differences were noted in comparison to dostarlimab monotherapy. The management guidelines for these adverse reactions are described in section 4.2.

Immune‑related adverse reactions (see section 4.4)

Immune‑related pneumonitis

Immune‑related pneumonitis occurred in 14 (2.3 %) patients, including grade 2 (1.3 %), grade 3 (0.8 %) and grade 4 (0.2 %) pneumonitis. Pneumonitis led to discontinuation of dostarlimab in 8 (1.3 %) patients.

Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 11 (78.6 %) patients experiencing pneumonitis. Pneumonitis resolved in 11 (78.6 %) patients.

Immune‑related colitis

Colitis occurred in 8 (1.3 %) patients, including grade 2 (0.7 %) and grade 3 (0.7 %) colitis. Colitis did not lead to discontinuation of dostarlimab in any patients.

Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 5 (62.5 %) patients. Colitis resolved in 5 (62.5 %) patients experiencing colitis.

Immune‑related hepatitis

Hepatitis occurred in 3 (0.5 %) patients, all of which were grade 3. Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 2 (66.7 %) patients. Hepatitis led to discontinuation of dostarlimab in 1 (0.2%) patient and resolved in 2 of the 3 patients.

Immune‑mediated endocrinopathies

Hypothyroidism occurred in 46 (7.6 %) patients, all of which were grade 2. Hypothyroidism did not lead to discontinuation of dostarlimab and resolved in 17 (37.0 %) patients.

Hypothyroidism occurred in 30 (12.4 %) patients who received dostarlimab in combination with carboplatin-paclitaxel, all of which were grade 2. Hypothyroidism led to discontinuation of dostarlimab in 1 (0.4%) patient and resolved in 7 (23.3 %) patients experiencing hypothyroidism.

Hyperthyroidism occurred in 14 (2.3 %) patients, including grade 2 (2.1 %) and grade 3 (0.2 %). Hyperthyroidism did not lead to discontinuation of dostarlimab and resolved in 10 (71.4 %) patients.

Hyperthyroidism occurred in 8 (3.3%) patients who received dostarlimab in combination with carboplatin-paclitaxel, including grade 2 (2.9%) and grade 3 (0.4%). Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 1 (12.5 %) patient experiencing hyperthyroidism. Hyperthyroidism did not lead to discontinuation of dostarlimab and resolved in 6 (75 %) patients experiencing hyperthyroidism.

Thyroiditis occurred in 3 (0.5 %) patients; all were grade 2. None of the events of thyroiditis resolved; there were no discontinuations of dostarlimab due to thyroiditis.

Adrenal insufficiency occurred in 7 (1.2 %) patients, including grade 2 (0.5 %), and grade 3 (0.7 %). Adrenal insufficiency resulted in discontinuation of dostarlimab in 1 (0.2 %) patient and resolved in 4 (57.1 %) patients.

Immune‑mediated nephritis

Nephritis, including tubulointerstitial nephritis, occurred in 3 (0.5 %) patients; all were grade 2. Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 2 (66.7 %) patients experiencing nephritis. Nephritis led to discontinuation of dostarlimab in 1 (0.2 %) patient and resolved in all 3 patients.

Immune‑related rash

Immune-related rash (rash, rash maculo-papular, rash macular, rash pruritic, pemphigoid, drug eruption, skin toxicity, toxic skin eruption) occurred in 31 (5.1 %) patients, including grade 3 in 9 (1.5 %) patients receiving dostarlimab. The median time to onset of rash was 57 days (range 2 days to 1485 days). Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 9 (29.0 %) patients experiencing rash. Rash led to discontinuation of dostarlimab in 1 (0.2 %) patient and resolved in 24 (77.4 %) patients.

Immune-related rash (rash, rash maculo-papular) occurred in 39 (16.2 %) patients who received dostarlimab in combination with carboplatin-paclitaxel, including grade 2 (9.1%) and grade 3 (7.1 %). Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 8 (20.5 %) patients experiencing rash. Rash led to discontinuation in 3 (1.2%) patients and resolved in 38 (97.4 %) patients experiencing rash.

Immune‑related arthralgia

Immune‑related arthralgia occurred in 34 (5.6 %) patients. Grade 3 immune‑related arthralgia was reported in 5 (0.8 %) patients receiving dostarlimab. The median time to onset of arthralgia was 94.5 days (range 1 day to 840 days). Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 3 (8.8 %) patients experiencing arthralgia. Arthralgia led to discontinuation of dostarlimab in 1 (0.2 %) patient and resolved in 19 (55.9 %) patients experiencing arthralgia.

Infusion‑related reactions

Infusion‑related reactions including hypersensitivity occurred in 6 (1.0 %) patients, including grade 2 (0.3 %) and grade 3 (0.2 %) infusion‑related reactions. All patients recovered from the infusion‑related reaction.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with dostarlimab: coeliac disease; pancreatic exocrine insufficiency.

Immunogenicity

In the GARNET study, anti‑drug antibodies (ADA) were tested in 315 patients who received dostarlimab and the incidence of dostarlimab treatment‑emergent ADAs was 2.5 %. Neutralising antibodies were detected in 1.3 % of patients. Co administration with chemotherapy did not affect dostarlimab immunogenicity. In the RUBY study, of the 225 patients who were treated with dostarlimab in combination with chemotherapy and evaluable for the presence of ADAs, there was no incidence of dostarlimab treatment-emergent ADA or treatment‑emergent neutralising antibodies.

In the patients who developed ADAs, there was no evidence of altered efficacy or safety of dostarlimab.

Elderly population

Of the 605 patients treated with dostarlimab monotherapy in the GARNET study, 51.6 % were under 65 years, 36.9 % were 65 to less than 75 years, and 11.5 % were 75 years or older. No overall differences in safety were reported between elderly (≥ 65 years) and younger patients (< 65 years).

Of the 241 patients treated with dostarlimab in RUBY, 52.3% were younger than 65 years, 36.5% were aged 65 to less than 75 years, and 11.2% were 75 years or older. No overall differences in safety were observed between elderly (≥ 65 years) and younger patients (< 65 years).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

If overdose is suspected, the patient should be monitored for any signs or symptoms of adverse reactions or effects, and appropriate symptomatic treatment instituted.