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

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.

Table 1. Dosage regimen for JEMPERLI in combination with chemotherapy

^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.

^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.

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.

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

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 rash

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. Exfoliative dermatologic conditions should be managed as recommended in section 4.2. Events of Stevens-Johnson Syndrome or toxic epidermal necrolysis have been reported in patients treated with PD-1 inhibitors.

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.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 500 mg dose, i.e. essentially 'sodium-free'.

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.

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).

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

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 (22.8 %), rash maculopapular (14.1%), hypothyroidism (14.1 %), alanine aminotransferase increased (12.9 %), aspartate aminotransferase increased (12.0 %), pyrexia (12.0 %) and dry skin (10.4 %). 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; 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 RUBY study (N=52) was not different from that of the overall combination therapy population presented in Table 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. 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 to 151 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

^* 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 Reported from ongoing blinded trial of dostarlimab in combination; estimated frequency category

^g Includes uveitis and iridocyclitis

^h Includes myocarditis (combination with chemotherapy) and immune-mediated myocarditis from ongoing blinded trial of dostarlimab in combination; estimated frequency category

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 (combination with chemotherapy) and enteritis reported from ongoing trial of dostarlimab in combination

^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 Reported in ongoing trial of dostarlimab in combination^q Includes nephritis and tubulointerstitial nephritis

^r Includes transaminases increased, alanine aminotransferases increased, aspartate aminotransferases increased and hypertransaminasaemia

^s 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 28 (11.6%) 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 5 (17.9%) 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 5 (62.5%) 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 37 (15.4%) patients who received dostarlimab in combination with carboplatin-paclitaxel, including grade 2 (9.1%) and grade 3 (6.2%). Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in 7 (18.9%) patients experiencing rash. Rash led to discontinuation in 3 (1.2%) patients and resolved in 36 (97.3%) 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.

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.

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

Pharmacotherapeutic group: Anti-neoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FF07

Mechanism of action

Dostarlimab is a humanised mAb of the IgG4 isotype that binds to PD-1 receptors and blocks the interactions of binding with its ligands PD-L1 and PD-L2. The inhibition of PD-1 pathway-mediated immune response results in inhibition of T-cell function such as proliferation, cytokine production, and cytotoxic activity. Dostarlimab potentiates T-cell responses, including anti-tumour immuno responses through blockade of PD-1 binding to PD-L1 and PD-L2. In syngeneic mouse tumour models, blocking PD-1 activity resulted in decreased tumour growth.

Clinical efficacy and safety

RUBY: Randomised controlled study of combination therapy in treatment of adult patients with primary advanced or recurrent EC

The efficacy and safety of dostarlimab in combination with carboplatin-paclitaxel were investigated in a multicentre, randomised, double blinded, placebo-controlled Phase 3 study conducted in patients with primary advanced or recurrent EC.

Patients were randomised (1:1) to receive dostarlimab 500 mg plus carboplatin AUC 5 mg/mL/min and paclitaxel 175 mg/m² every 3 weeks for 6 cycles followed by dostarlimab 1000 mg every 6 weeks (n = 245) or placebo plus carboplatin AUC 5 mg/mL/min and paclitaxel 175 mg/m² every 3 weeks for 6 cycles followed by placebo every 6 weeks (n = 249). Randomisation was stratified by MMR/MSI status, prior external pelvic radiotherapy, and disease status (recurrent, primary Stage III, or primary Stage IV).

The key eligibility criteria for the study were International Federation of Gynaecology and Obstetrics (FIGO) primary Stage III or Stage IV disease, including Stage IIIA to IIIC1 disease with presence of evaluable or measurable disease per RECIST v.1.1, Stage IIIC1 patients with carcinosarcoma, clear cell, serous, or mixed histology (containing ≥ 10% carcinosarcoma, clear cell, or serous histology) regardless of presence of evaluable or measurable disease on imaging, Stage IIIC2 or Stage IV disease regardless of presence of evaluable or measurable disease. The study also included patients with first recurrent EC with a low potential for cure by radiation therapy or surgery alone or in combination, including patients who had first recurrent disease and were naï ve to systemic anticancer therapy or who had received prior neo-adjuvant/adjuvant systemic anticancer therapy and had a recurrence or progressive disease ≥ 6 months after completing treatment (first recurrence). Treatment continued for up to 3 years or until unacceptable toxicity, disease progression or investigator decision. Treatment could continue beyond 3 years or beyond disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed every 6 weeks through week 25, every 9 weeks through week 52 and every 12 weeks thereafter.

The primary efficacy outcome measures were progression-free survival (PFS) assessed by the investigator according to RECIST v1.1 in subjects with dMMR/MSI-H primary advanced or recurrent EC and in all subjects (overall ITT population) with primary advanced or recurrent EC, and overall survival (OS) in all subjects (overall ITT population) with primary advanced or recurrent EC. Secondary endpoints included objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central radiologists' (BICR) review and investigator assessment according to RECIST v1.1, and PFS2, defined as the time from treatment randomisation to the date of assessment of progression on the first subsequent anticancer therapy following study treatment or death by any cause, whichever was earlier.

A total of 118 patients with dMMR/MSI-H EC were evaluated for efficacy in the RUBY study. Baseline demographics and characteristics of the overall study population were: median age 64 years (49% age 65 years or older); 85% White, 9% Black, 2% Asian; and Eastern Cooperative Oncology Group (ECOG) PS 0 (57%) or 1 (43%); and primary stage III 20%; primary stage IV 30%; recurrent EC 50%.

The identification of dMMR/MSI-H tumour status was prospectively determined based on local testing assays (IHC, PCR or NGS), or central testing (IHC) when no local result was available.

Efficacy results in patients with dMMR/MSI-H EC are shown in Table 5 and Figure 1. The overall median treatment duration in weeks was 43 (range 3 to 153). The RUBY study demonstrated a statistically significant improvement in PFS in patients randomised to dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel.

Table 5: Efficacy results in RUBY for patients with EC

CI: Confidence interval; NA = not applicable; NE = not estimable

^a Efficacy data with a median follow-up of 25 months (cut-off date 28 Sept 2022).

^b One-sided p-value based on stratified log-rank test.

^c Based on stratified Cox regression model.

^d By Kaplan-Meier method.

^e Assessed by investigator according to RECIST v1.1.

^f For patients with a partial or complete response.

^g By Brookmeyer and Crowley method.

Figure 1: Kaplan-Meier curve of progression-free survival per investigator assessment in patients with dMMR/MSI-H EC (RUBY study)

GARNET: patients with recurrent or advanced dMMR/MSI-H EC who have progressed on or after treatment with a platinum-containing regimen

The efficacy and safety of JEMPERLI monotherapy were investigated in the GARNET study, a multicentre, uncontrolled, multiple parallel cohort, open-label study. The GARNET study included expansion cohorts in subjects with recurrent or advanced solid tumours who have limited available treatment options. Cohort A1 enrolled patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) EC who have progressed on or after a platinum-containing regimen.

Patients received 500 mg dostarlimab every 3 weeks for 4 cycles followed by 1000 mg dostarlimab every 6 weeks. Treatment continued until unacceptable toxicity or disease progression for up to two years.

The major efficacy outcome measures were ORR and DOR as assessed by BICR review according to response evaluation criteria in solid tumours (RECIST) v 1.1. The efficacy population was defined as patients who had measurable disease by BICR at baseline and had minimum of 24 weeks follow-up or had less than 24 weeks of follow-up and discontinued due to adverse events or disease progression.

A total of 143 patients with dMMR/MSI-H EC were evaluated for efficacy in the GARNET study. Among these 143 patients, the baseline characteristics were: median age of 65 years (52 % aged 65 years or older); 77 % white, 3.5 % Asian, 2.8 % black; and ECOG PS 0 (39 %) or 1 (61 %). At the time of diagnosis, 21 % of the patients with dMMR/MSI-H EC were FIGO Stage IV. At study entry (the most recent FIGO stage), 67 % of the patients were FIGO Stage IV. The median number of prior lines of therapy was one: 63 % of patients had one prior line, 37 % had two or more prior lines. Forty-nine patients (34 %) received treatment only in the neoadjuvant or adjuvant setting before participating in the study.

The identification of dMMR/MSI-H tumour status was prospectively determined based on local testing. Local diagnostic assays (IHC, PCR or NGS) available at the sites were used for the detection of the dMMR/MSI-H expression in tumour material. Most of the sites used IHC as it was the most common assay available.

Table 6 includes the efficacy data for the 143 patients. The overall median treatment duration in weeks was 34 (range 2 to 220). Twenty four percent of subjects who received any amount of dostarlimab received treatment >102 weeks (2 years).

Table 6: Efficacy results in GARNET for patients with dMMR/MSI-H EC

CI: Confidence interval

^a Efficacy data with a median follow-up of 27.6 months (cut-off date 01 Nov 2021)

^b For patients with a partial or complete response.

^c Includes patient with complete response, partial response and stable disease for at least 12 weeks.

Efficacy and PD-L1 status

Clinical activity was observed regardless of tumour PD-L1 combined positive score (CPS) by IHC. The relationship between PD-L1 status and efficacy was analysed post-hoc in patients with available tissue samples (N = 81) among the efficacy population from Cohort A1 of the GARNET study using a data cut-off date of 01 March 2020. Among 23 patients with PD-L1 CPS < 1 %, ORR was 30.4 % (7/23, 95 % CI 13.2, 52.9) and among 58 patients with PD-L1 CPS ≥ 1 %, ORR was 55.2 % (32/58, 95 % CI 41.5, 68.3).

Elderly patients

Of the 108 patients treated with dostarlimab in the GARNET study efficacy population, 50.0 % were older than 65 years.

Consistent results were observed in the elderly population, where the ORR by BICR (95 % CI) was 42.6 % (29.2 %, 56.8 %) in patients ≥ 65 years.

Of the 53 patients treated with dostarlimab in combination with platinum-containing chemotherapy in the RUBY study efficacy population, 43.4 % were older than 65 years.

Consistent results were observed in the elderly population, where an improvement in PFS by investigator according to RECIST v1.1 was demonstrated in patients ≥ 65 years randomised to dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel, HR of 0.25 (95% CI 0.11, 0.56).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with dostarlimab in all subsets of the paediatric population in the treatment of all conditions included in the category of malignant neoplasms, except haematopoietic and lymphoid tissue (see section 4.2 for information on paediatric use).

The pharmacokinetics (PK) of dostarlimab were assessed as a monotherapy and when administered in combination with chemotherapy.

Dostarlimab monotherapy or in combination with chemotherapy was characterised using population PK analysis from 869 patients with various solid tumours, including 546 patients with EC. When dosed at the recommended therapeutic dose for monotherapy (500 mg administered intravenously every 3 weeks for 4 doses, followed by 1000 mg every 6 weeks), or at the recommended therapeutic dose for combination with chemotherapy (500 mg administered intravenously every 3 weeks for 6 doses, followed by 1000 mg every 6 weeks), dostarlimab shows an approximate two-fold accumulation (C_min), consistent with the terminal half-life (t_1/2). The exposure of dostarlimab as monotherapy and/or in combination with chemotherapy was similar.

Absorption

Dostarlimab is administered via the intravenous route and therefore estimates of absorption are not applicable.

Distribution

The mean volume of distribution of dostarlimab at steady state is approximately 5.8 L (CV % of 14.9 %).

Biotransformation

Dostarlimab is a therapeutic mAb IgG4 that is expected to be catabolised into small peptides, amino acids, and small carbohydrates by lysosome through fluid-phase or receptor-mediated endocytosis. The degradation products are eliminated by renal excretion or returned to the nutrient pool without biological effects.

Elimination

The mean clearance is 0.007 L/h (CV % of 30.2 %) at steady state. The t_1/2 at steady state is 23.2 days (CV % of 20.8 %).

Dostarlimab clearance was estimated to be 7.8% lower when dostarlimab was given in combination with chemotherapy. There was no meaningful impact on dostarlimab exposure.

Linearity/non-linearity

Exposure (both maximum concentration [C_max] and the area under the concentration-time curve, [AUC_0-tau] and [AUC_0-inf]) was approximately dose proportional.

Pharmacokinetic/pharmacodynamic relationship

Based on exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety when doubling the exposure of dostarlimab. Full receptor occupancy as measured by both the direct PD-1 binding and interleukin 2 (IL-2) production functional assay was maintained throughout the dosing interval at the recommended therapeutic dosing regimen.

Special populations

A population PK analysis of the patient data indicates that there are no clinically important effects of age (range: 24 to 86 years), gender or race, ethnicity, or tumour type on the clearance of dostarlimab.

Renal impairment

Renal impairment was evaluated based on the estimated creatinine clearance [CL_CR mL/min] (normal: CL_CR ≥ 90 mL/min, n = 305; mild: CL_CR = 60-89 mL/min, n = 397; moderate: CL_CR = 30-59 mL/min, n = 164; severe: CL_CR = 15-29 mL/min, n = 3 and ESRD: CL_CR < 15 mL/min, n = 1). The effect of renal impairment on the clearance of dostarlimab was evaluated by population pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of dostarlimab were found between patients with mild or moderate renal impairment and patients with normal renal function. There are limited data in patients with severe renal impairment.

Hepatic impairment

Hepatic impairment was evaluated as defined using the US National Cancer Institute criteria of hepatic dysfunction by total bilirubin and AST (Normal: total bilirubin (TB) & AST < = upper limit of normal (ULN), n = 772; mild: TB > ULN to 1.5 ULN or AST > ULN, n = 92; and moderate: TB > 1.5-3 ULN, any AST, n = 5). The effect of hepatic impairment on the clearance of dostarlimab was evaluated by population pharmacokinetic analyses in patients with mild hepatic impairment compared to patients with normal hepatic function. No clinically important differences in the clearance of dostarlimab were found between patients with mild hepatic impairment and normal hepatic function. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment.

Nonclinical data reveal no special hazard for humans based on repeat-dose toxicity studies of duration up to 3 months in the cynomolgus monkey. No studies have been performed to assess the potential of dostarlimab for carcinogenicity or genotoxicity. Animal reproduction and development toxicity studies have not been conducted with dostarlimab. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss. These results indicate a potential risk that administration of dostarlimab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.

No notable effects on the male and female reproductive organs were observed in monkeys in the 1-month and 3-month repeat-dose toxicology studies; however, these results may not be representative at all of the potential clinical risk because of the immaturity of the reproductive system of animals used in the studies. Therefore, fertility toxicity remains unknown.

Trisodium citrate dihydrate

Citric acid monohydrate

L-arginine hydrochloride

Sodium chloride

Polysorbate 80

Water for injection

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial

3 years.

After dilution

If not used immediately, chemical and physical in-use stability has been demonstrated for 24 hours at 2 ° C – 8 ° C and 6 hours at room temperature (up to 25 ° C) from the time of preparation/dilution until the end of administration.

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 type I borosilicate clear glass vial, with a grey chlorobutyl elastomer stopper laminated with fluoropolymer, sealed with an aluminium flip-off cap containing 500 mg dostarlimab.

Each carton contains one vial.

Preparation/dilution

Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. JEMPERLI is a slightly opalescent colourless to yellow solution. Discard the vial if visible particles are observed.

JEMPERLI is compatible with an IV bag made of polyvinyl chloride (PVC) with or without di(2-ethylhexyl) phthalate (DEHP), ethylene vinyl acetate, polyethylene (PE), polypropylene (PP) or polyolefin blend (PP+PE), and a syringe made from PP.

For the 500 mg dose, withdraw 10 mL of JEMPERLI from a vial and transfer into an intravenous bag containing sodium chloride 9 mg/mL (0.9 %) solution for injection, or glucose 50 mg/mL (5 %) solution for injection. The final concentration of the diluted solution should be between 2 mg/mL and 10 mg/mL. This may require withdrawing a volume of diluent from the intravenous bag prior to adding a volume of JEMPERLI into the IV bag.

- For example, if preparing a 500 mg dose in a 250 mL diluent intravenous bag, to achieve a 2 mg/mL concentration would require withdrawing 10 mL of diluent from the 250 mL intravenous bag. Then, 10 mL of JEMPERLI would be withdrawn from the vial and transferred into the intravenous bag.

For the 1000 mg dose, withdraw 10 mL of JEMPERLI from each of two vials (withdraw 20 mL total) and transfer into an intravenous bag containing sodium chloride 9 mg/mL (0.9 %) solution for injection, or glucose 50 mg/mL (5 %) solution for injection. The final concentration of the diluted solution should be between 2 mg/mL and 10 mg/mL. This may require withdrawing a volume of diluent from the IV bag prior to adding a volume of JEMPERLI into the intravenous bag.

- For example, if preparing a 1000 mg dose in a 500 mL diluent intravenous bag, to achieve a 2 mg/mL concentration would require withdrawing 20 mL of diluent from the 500 mL intravenous bag. Then, 10 mL of JEMPERLI would be withdrawn from each of two vials, totaling 20 mL, and transferred into the intravenous bag.

Mix diluted solution by gentle inversion. Do not shake the final infusion bag. Discard any unused portion left in the vial.

Storage

Store in the original carton until time of preparation in order to protect from light. The prepared dose may be stored either:

- At room temperature up to 25 ° C for no more than 6 hours from the time of dilution until the end of infusion.

- Under refrigeration at 2 ° C to 8 ° C for no more than 24 hours from time of dilution until end of infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Administration

JEMPERLI should be administered by intravenous infusion using an intravenous infusion pump over 30 minutes by a health care practitioner. Tubing should be made of PVC, platinum cured silicon or PP; fittings made from PVC or polycarbonate and needles made from stainless steel. A 0.2 or 0.22 micron in-line polyethersulfone (PES) filter must be used during administration of JEMPERLI.

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

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

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