JEMPERLI Concentrate for solution for infusion Ref.[27949] Active ingredients: Dostarlimab

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: Eastern Cooperative Oncology Group (ECOG) baseline performance score (PS) ≥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.

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 carboplatin and paclitaxel

The safety of dostarlimab has been evaluated in 241 patients with primary advanced or recurrent EC who received dostarlimab in combination with carboplatin and paclitaxel 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).

In the RUBY study the safety profile for patients with dMMR/MSI-H EC (N=52) was not different from that of the overall population (N=241) 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 carboplatin and paclitaxel for a median duration of treatment of 43 weeks (range: 3 to 151 weeks). For additional safety information when dostarlimab is administered in combination with carboplatin and paclitaxel, refer to the respective Prescribing Information for the combination products.

Adverse reactions known to occur with dostarlimab as monotherapy, or with carboplatin or paclitaxel given alone, may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with dostarlimab in combination with carboplatin and paclitaxel. 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
° 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. 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.

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.

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 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 4.5 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 carboplatin and paclitaxel did not affect dostarlimab immunogenicity. In the RUBY study, of the 225 patients who were treated with dostarlimab in combination with carboplatin and paclitaxel 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, 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).

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 the national reporting system listed in Appendix V.

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