Dostarlimab

Dostarlimab is a humanised IgG4 monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary cells. It acts on the PD-1 receptor, an immune checkpoint on T cells that tumours can use to damp down the immune attack, and blocking it lets T cells act against the cancer again. In the EU it is used in endometrial cancer, together with chemotherapy in primary advanced or recurrent disease and alone in tumours with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).

Mechanism of Action

• PD-1 blockade: dostarlimab binds the PD-1 receptor and prevents it from interacting with its two ligands, PD-L1 and PD-L2.
• Reactivation of T cells: engagement of PD-1 by these ligands restrains T-cell proliferation and cytokine production. Blocking the pathway restores T-cell functions such as proliferation, cytokine production and cytotoxic activity, and strengthens anti-tumour immune responses. In mouse tumour models with an intact immune system, blocking PD-1 reduced tumour growth.
• Mismatch repair deficiency: tumours with dMMR or MSI-H can raise their expression of PD-1 ligands, so the pathway is a particular target in these cancers. For the monotherapy indication the tumour status must be established with a validated test.
• Immune-related effects: the PD-1 pathway also helps to keep immune responses against normal tissue in check, so blocking it can cause immune-related adverse reactions in any organ (see Special Instructions).

Pharmacokinetics

• Absorption: not applicable, because dostarlimab is infused into a vein. Peak concentration and total exposure rise approximately in proportion to the dose. At the recommended regimens the trough level accumulates about two-fold, in line with the terminal half-life, and exposure is similar whether dostarlimab is given alone or with carboplatin and paclitaxel.
• Distribution: the mean volume of distribution at steady state is about 5.8 L.
• Metabolism: as an IgG4 antibody, dostarlimab is expected to be broken down in lysosomes into small peptides, amino acids and small carbohydrates, which are either excreted by the kidney or returned to the body’s nutrient pool. It is not a substrate of cytochrome P450 enzymes or of active transporters.
• Elimination: mean clearance at steady state is about 0.007 L/h and the half-life about 23.2 days. Clearance was about 7.8% lower with carboplatin and paclitaxel, without a meaningful effect on exposure.
• Exposure and response: doubling the exposure did not produce clinically significant differences in efficacy or safety, and full PD-1 receptor occupancy was maintained throughout the dosing interval at the recommended regimens.
• Special populations: no dose adjustment is recommended for age (65 years or over), mild or moderate renal impairment or mild hepatic impairment. Data are limited in patients aged 75 or over, in severe renal impairment or end-stage renal disease on dialysis and in moderate hepatic impairment, and absent in severe hepatic impairment.

• First-line treatment of primary advanced or recurrent endometrial cancer (EC): in combination with carboplatin and paclitaxel, in adults who are candidates for systemic therapy.
• dMMR/MSI-H endometrial cancer after platinum therapy: as monotherapy, in adults with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) recurrent or advanced EC that has progressed on or following prior treatment with a platinum-containing regimen.

Tumour dMMR/MSI-H status is determined with a validated method such as immunohistochemistry (IHC), polymerase chain reaction (PCR) or next-generation sequencing (NGS).

• Hypersensitivity to dostarlimab or to any of the excipients (trisodium citrate dihydrate, citric acid monohydrate, L-arginine hydrochloride, sodium chloride, polysorbate 80).

Dostarlimab is most commonly associated with immune-related adverse reactions. Most of them, including severe ones, resolved once appropriate medical treatment was started or dostarlimab was withdrawn. The frequencies below come from two groups: 605 patients with endometrial cancer or other advanced solid tumours who received dostarlimab alone in the GARNET study (median treatment 24 weeks), and 241 patients with primary advanced or recurrent endometrial cancer who received it with carboplatin and paclitaxel in the RUBY study (median treatment 43 weeks). They count all adverse events, whatever their cause.

On monotherapy the most common reactions (more than 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%), raised aspartate aminotransferase (11.2%) and hypothyroidism (11.2%). Treatment was stopped permanently because of adverse reactions in 6.3% of patients, and 11.2% had serious reactions, most of them immune-related. With carboplatin and paclitaxel the most common reactions (10% or more) were rash (23.2%), maculopapular rash (14.5%), hypothyroidism (14.5%), pyrexia (12.9%), raised alanine aminotransferase (12.9%), raised aspartate aminotransferase (12.0%) and dry skin (10.0%); 5.0% stopped permanently, 5.8% had serious reactions and the most frequent serious reaction (more than 1%) was pyrexia (2.9%).

Very common (≥1/10): with dostarlimab alone, anaemia (including autoimmune haemolytic anaemia), hypothyroidism, diarrhoea, nausea, vomiting, rash, pruritus, arthralgia, pyrexia and raised transaminases; with carboplatin and paclitaxel, hypothyroidism, rash (including maculopapular rash), dry skin, pyrexia and raised alanine and aspartate aminotransferase.

Common (≥1/100 to <1/10): with dostarlimab alone, hyperthyroidism, adrenal insufficiency, pneumonitis (including interstitial lung disease), colitis, pancreatitis, gastritis, hepatitis, myalgia, chills and infusion-related reactions (including hypersensitivity); with carboplatin and paclitaxel, hyperthyroidism, pneumonitis, colitis and pancreatitis.

Uncommon (≥1/1,000 to <1/100): with dostarlimab alone, thyroiditis, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, encephalitis, myasthenia gravis, uveitis, oesophagitis, Stevens-Johnson syndrome, immune-mediated arthritis, polymyalgia rheumatica, immune-mediated myositis and nephritis; with carboplatin and paclitaxel, thyroiditis, adrenal insufficiency, type 1 diabetes mellitus, myasthenic syndrome, Guillain-Barré syndrome, uveitis, myocarditis, immune-mediated gastritis, gastrointestinal vasculitis, immune-mediated arthritis, myositis and systemic inflammatory response syndrome.

Some of the combination entries, such as myocarditis, Guillain-Barré syndrome, myasthenic syndrome and systemic inflammatory response syndrome, include events identified in other clinical trials of dostarlimab in patients with solid tumours.

Immune-related reactions. In the pooled monotherapy data (605 patients), immune-related reactions were counted when they reached grade 2 or higher. They included hypothyroidism in 7.6% (all grade 2), arthralgia in 5.6%, rash in 5.1% (grade 3 in 1.5%), pneumonitis in 2.3% (grade 3 in 0.8%, grade 4 in 0.2%; permanent discontinuation in 1.3%), hyperthyroidism in 2.3%, colitis in 1.3%, adrenal insufficiency in 1.2%, infusion-related reactions including hypersensitivity in 1.0%, hepatitis in 0.5% (all grade 3), thyroiditis in 0.5% and nephritis in 0.5%. Anti-drug antibodies appeared during treatment in 2.5% of 315 evaluable patients in GARNET (neutralising antibodies in 1.3%) and in none of 225 evaluable patients in RUBY, with no evidence of an effect on efficacy or safety.

Safety did not differ overall between patients aged 65 or over and younger patients. Other immune checkpoint inhibitors have been associated with coeliac disease and exocrine pancreatic insufficiency, which could also occur with dostarlimab.

No interaction studies have been performed with dostarlimab, and the SmPC names no specific interacting medicine.

• Cytochrome P450 and transporters: monoclonal antibodies such as dostarlimab are not substrates of cytochrome P450 enzymes or of active substance transporters, so a pharmacokinetic interaction with small-molecule medicines is not expected.
• Cytokines: dostarlimab is not a cytokine and is unlikely to modulate cytokines.
• Antibody clearance: there is no evidence of an interaction mediated by the non-specific, lysosomal clearance of antibodies.
• Carboplatin and paclitaxel: given together, dostarlimab clearance was about 7.8% lower, with no meaningful effect on exposure.

Treatment must be started and supervised by specialist physicians experienced in the treatment of cancer. Dostarlimab is for intravenous infusion only: it is diluted before use and given with an infusion pump over 30 minutes. It must not be given as an intravenous push or bolus injection. Where the monotherapy indication applies, dMMR/MSI-H tumour status is established beforehand with a validated test.

Dose with Carboplatin and Paclitaxel

• 500 mg every 3 weeks together with carboplatin and paclitaxel every 3 weeks for 6 cycles, then 1,000 mg every 6 weeks as monotherapy for all later cycles. The first 1,000 mg dose follows 3 weeks after the sixth cycle.
• Dostarlimab is given before carboplatin and paclitaxel on the same day. The SmPCs of carboplatin and paclitaxel apply to their own dosing.
• Treatment continues until disease progression or unacceptable toxicity, or for up to 3 years.

Dose as Monotherapy

• 500 mg every 3 weeks for 4 cycles, then 1,000 mg every 6 weeks for all later cycles. The first 1,000 mg dose follows 3 weeks after the fourth cycle.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Modifications

• Dose reduction is not recommended. Dosing may be delayed or stopped according to individual safety and tolerability; the SmPC holds a table of recommended actions for specific immune-related reactions.
• Immune-related reactions are managed by withholding or permanently stopping dostarlimab and giving corticosteroids (see Special Instructions). Any recurrent grade 3 and any grade 4 immune-related reaction leads to permanent discontinuation, except endocrinopathies controlled with replacement hormones and unless the SmPC table states otherwise.
• For a severe (grade 3) or life-threatening (grade 4) infusion-related reaction, the infusion is stopped and treatment is permanently discontinued.

Special Populations

• Elderly: no dose adjustment for patients aged 65 or over; clinical data are limited in patients aged 75 or over.
• Renal impairment: no adjustment in mild or moderate impairment; limited data in severe impairment or end-stage renal disease on dialysis.
• Hepatic impairment: no adjustment in mild impairment; limited data in moderate and none in severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established. A study of dostarlimab with niraparib in children aged 5 to under 18 with recurrent or refractory solid tumours (outside the authorised indications) was too limited to show that the benefits outweigh the risks.

Traceability

The trade name and batch number of each administered dose should be clearly recorded.

Immune-Related Adverse Reactions

• Scope: immune-related reactions can be severe or fatal, can affect any organ or tissue and more than one body system at once, and usually occur during treatment but can also appear after it has stopped.
• Monitoring: patients are monitored for symptoms and signs. Blood counts and clinical chemistry, including liver, kidney and thyroid function, are checked at baseline and periodically. A suspected reaction needs adequate evaluation, including specialist consultation.
• Treatment: depending on severity, dostarlimab is withheld or permanently stopped and corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other suitable therapy are given. Once the reaction improves to grade 1 or less, the corticosteroid is tapered over 1 month or longer. If corticosteroids do not control the reaction, other systemic immunosuppressants can be considered. Hormone replacement is given for endocrinopathies as needed.
• Permanent discontinuation: any recurrent grade 3 and any grade 4 immune-related reaction, except endocrinopathies controlled with replacement hormones and unless the SmPC table states otherwise.

Organ-Specific Immune-Related Reactions

• Pneumonitis: patients are monitored for signs and symptoms; suspected pneumonitis is confirmed with imaging and other causes are excluded.
• Colitis: patients are monitored for signs and symptoms; management includes treatment modification, anti-diarrhoeal agents and corticosteroids.
• Hepatitis: liver function is monitored periodically as clinically indicated.
• Endocrinopathies: hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis, type 1 diabetes mellitus (including diabetic ketoacidosis) and adrenal insufficiency have been reported. Thyroid function is checked before and periodically during treatment, hypothyroidism may follow hyperthyroidism, and patients are watched for signs of adrenal insufficiency.
• Nephritis: renal function is monitored.
• Skin reactions: immune-related rash, including pemphigoid, has been reported. Stevens-Johnson syndrome, which can be life-threatening or fatal, has been reported with dostarlimab, and toxic epidermal necrolysis with PD-1 inhibitors. Patients should know the signs of severe cutaneous reactions and seek medical advice at once; suspected cases are referred to a specialist. Caution is advised in patients who had a severe or life-threatening skin reaction on other immune-stimulating anticancer agents.
• Arthralgia: patients are monitored, and other causes are excluded when immune-related arthralgia is suspected.
• Other reactions: myositis, myocarditis, encephalitis, demyelinating neuropathy (including Guillain-Barré syndrome) and sarcoidosis may occur. Encephalitis, autoimmune haemolytic anaemia, pancreatitis, iridocyclitis and uveitis were reported in fewer than 1% of patients on monotherapy.

Infusion-Related Reactions

Infusion-related reactions can occur and can be severe. For a severe (grade 3) or life-threatening (grade 4) reaction, the infusion is stopped and treatment is permanently discontinued.

Transplant Recipients and Stem Cell Transplantation

• Solid organ transplant: rejection has been reported after marketing in patients treated with PD-1 inhibitors, and dostarlimab may increase the risk. The benefit is weighed against the risk of organ rejection.
• Allogeneic haematopoietic stem cell transplantation: fatal and other serious complications can occur in patients transplanted before or after a PD-1/PD-L1 blocking antibody, including graft-versus-host disease (hyperacute, acute and chronic), hepatic veno-occlusive disease after reduced-intensity conditioning and steroid-requiring febrile syndrome without an identified infectious cause. Patients are followed closely and the benefit and risk of the antibody are weighed.

Patients Excluded from the Studies

The GARNET study excluded, among others, patients with an ECOG performance score of 2 or more, uncontrolled central nervous system metastases or carcinomatous meningitis, other malignancies within 2 years, immunodeficiency or immunosuppressive therapy within 7 days, active HIV, hepatitis B or hepatitis C infection, active autoimmune disease needing systemic treatment in the past 2 years, a history of interstitial lung disease, or a live vaccine within 14 days. The RUBY study excluded, among others, patients with a concomitant or recent other malignancy, uncontrolled central nervous system metastases, known HIV or active hepatitis B or C, immunodeficiency or immunosuppressive therapy within 7 days, a serious uncontrolled medical disorder or active infection needing systemic therapy, and a live vaccine from 30 days before the first dose until 180 days after the last. After careful consideration of the possible extra risk, dostarlimab may be used with appropriate medical management in such patients.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and until 4 months after the last dose.
• Pregnancy: there are no or limited data. Because of its mechanism, dostarlimab can cause foetal harm: inhibiting the PD-1/PD-L1 pathway can increase the risk of immune-mediated rejection of the developing foetus, resulting in foetal death, and IgG4 antibodies cross the placenta. It is not recommended in pregnancy or in women of childbearing potential who are not using effective contraception. Animal reproduction studies have not been conducted.
• Breastfeeding: it is unknown whether dostarlimab is excreted in human milk, and a risk to the newborn cannot be excluded. It should not be used during breastfeeding, which should be avoided for at least 4 months after the last dose.
• Fertility: fertility studies have not been conducted.

Polysorbate 80 and Sodium

• Each dose contains polysorbate 80 (2 mg per vial), which may cause allergic reactions.
• Each 500 mg dose contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free. It may be diluted in sodium chloride 9 mg/mL (0.9%) solution, which matters for patients on a controlled sodium diet.

Effect on Driving

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

Store the vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in its original carton to protect it from light. Dostarlimab is a cold-chain product, so the temperature should be kept within this range during transport and storage. Each carton holds one 10 mL glass vial. For storage after dilution, see Shelf Life.

• Unopened vial: 5 years.
• After dilution: chemical and physical in-use stability has been shown for 96 hours at 2–8 °C followed by 6 hours at room temperature (up to 25 °C), counted from preparation until the end of administration.
• From a microbiological point of view, the diluted product should be used immediately. If it is not, the user is responsible for in-use times and conditions, which would normally not exceed 24 hours at 2–8 °C or 6 hours at room temperature (up to 25 °C), unless dilution took place under controlled and validated aseptic conditions.
• The diluted solution must not be frozen. If refrigerated, it must reach room temperature before use.

Prescription only (Rx), on restricted medical prescription (Annex II B): treatment is started and supervised by a specialist physician experienced in cancer treatment. Dostarlimab is given as an intravenous infusion in a hospital or clinic, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.