Dostarlimab interacts in the following cases:
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.
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.
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. 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.
Dostarlimab is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether dostarlimab/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.
Dostarlimab 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 studies have not been conducted with dostarlimab.
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.
Dostarlimab has no or negligible influence on the ability to drive and use machines.
The safety of dostarlimab has been evaluated in 515 patients with endometrial cancer or other advanced solid tumours who received dostarlimab monotherapy in the GARNET study, including 129 patients with advanced or recurrent dMMR/MSI-H endometrial cancer. Patients received doses of 500 mg every 3 weeks for 4 cycles followed by 1000 mg every 6 weeks for all cycles thereafter. 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).
In patients with advanced or recurrent solid tumours(N = 515), the most common adverse reactions (>10%) were anaemia (25.6%), nausea (25.0%), diarrhoea (22.5%), vomiting (18.4%), arthralgia (13.8%), pruritus (11.5%), rash (11.1%), pyrexia (10.5%) and hypothyroidism (10.1%). Dostarlimab was permanently discontinued due to adverse reactions in 17 (3.3%) patients; most of them were immune-related events. Adverse reactions were serious in 8.7% of patients; most serious adverse reactions were immune-related adverse reactions. The safety profile for patients with dMMR/MSI-H endometrial cancer in the GARNET study (N=129) was not different from that of the overall monotherapy population presented in table 3.
Adverse reactions observed in 515 patients with advanced or recurrent solid tumours in the GARNET study of dostarlimab are listed in table 3. The median duration of treatment in 515 evaluated patients was 20 weeks (range: 1 week to 146 weeks). The frequencies included below are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.
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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Adverse reactions in patients treated with dostarlimab:
| System Organ Class | Frequency of all grades | Frequency of grades 3-4 |
|---|---|---|
| Blood and lymphatic system disorders | Very common: Anaemiaa | Common: Anaemia |
| Endocrine disorders | Very common: Hypothyroidism* Common: Hyperthyroidism*, adrenal insufficiency Uncommon: Hypophysitis, thyroiditisb | Uncommon: Adrenal insufficiency, hyperthyroidism |
| Metabolism and nutrition disorders | Uncommon: Type 1 diabetes mellitus, diabetic ketoacidosis | |
| Eye disorders | Uncommon: Uveitisc | |
| Respiratory, thoracic and mediastinal disorders | Common: Pneumonitis*d | Uncommon: Pneumonitis |
| Gastrointestinal disorders | Very common: Nausea, diarrhoea, vomiting Common: Colitis*e, pancreatitisf | Common: Nausea, vomiting, diarrhoea Uncommon: pancreatitisf, colitis |
| Hepatobiliary disorders | Uncommon: Hepatitisg | Uncommon: Hepatitis |
| Skin and subcutaneous tissue disorders | Very common: Pruritus, rashh | Common: Rashi Uncommon: Pruritus |
| Musculoskeletal and connective tissue disorders | Very common: Arthralgia Common: Myalgia | Uncommon: Arthralgia |
| Renal and urinary disorders | Uncommon: Nephritis*j | |
| General disorders and administration site conditions | Very common: Pyrexia Common: Chills | Uncommon: Pyrexia |
| Investigations | Very common: Transaminases increasedk | Common: Transaminases increasedk |
| Injury, poisoning and procedural complications | Common: Infusion-related reaction | Uncommon: Infusion-related reaction |
* See section 'Description of selected adverse reactions.'
a Includes anaemia and autoimmune haemolytic anaemia
b Includes thyroiditis and autoimmune thyroiditis
c Includes uveitis and iridocyclitis
d Includes pneumonitis and interstitial lung disease
e Includes colitis, enterocolitis and enterocolitis hemorrhagic f Includes pancreatitis and pancreatitis acute
g Includes hepatitis and hepatocellular injury
h Includes rash, rash maculopapular, erythema rash macular, rash pruritic, rash erythematous, rash papular, toxic skin eruption, exfoliative rash and pemphigoid i Includes rash andrash maculopapular
j Includes nephritis and tubulointerstitial nephritis
k Includes transaminases increased, alanine aminotransferases increased, aspartate aminotransferases increased and hypertransaminasaemia
The selected adverse reactions described below are based on the safety of dostarlimab in a combined monotherapy safety database of 515 patients in the GARNET study in patients with endometrial cancer 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.
Immune-related pneumonitis occurred in 7 (1.4%) of 515 patients, including grade 2 (1.2%) and grade 3 (0.2%) pneumonitis. Pneumonitis led to discontinuation of dostarlimab in 3 (0.6%) patients. Systemic corticosteroids (prednisone ≥ 40 mg per day or equivalent) were required in all 7 patients experiencing pneumonitis. Pneumonitis resolved in 6 (85.7%) patients.
Colitis occurred in 8 (1.6%) patients, including grade 2 (1.0%) and grade 3 (0.6%) colitis. Colitis did not lead to discontinuation of dostarlimab in any patients.
Systemic corticosteroids (prednisone ≥40 mg per day or equivalent) were required in 2 (28.6%) patients. Colitis resolved in 6 (75.0%) patients experiencing colitis.
Hepatitis occurred in 1 (0.2%) patient, which was grade 3. Systemic corticosteroids (prednisone ≥40 mg per day or equivalent) were required. Hepatitis did not lead to discontinuation of dostarlimab and resolved.
Hypothyroidism occurred in 37 (7.2%) patients, all of which were grade 2. Hypothyroidism did not lead to discontinuation of dostarlimab and resolved in 13 (35.1%) patients.
Hyperthyroidism occurred in 10 (1.9%) patients, including grade 2 (1.7%) and grade 3 (0.2%). Hyperthyroidism did not lead to discontinuation of dostarlimab and resolved in 8 (80%) patients.
Thyroiditis occurred in 2 (0.4%) patients; both were grade 2. Neither event of thyroiditis resolved; there were no discontinuations of dostarlimab due to thyroiditis.
Adrenal insufficiency occurred in 7 (1.4%) patients, including grade 2 (0.8%), and grade 3 (0.6%). Adrenal insufficiency resulted in discontinuation of dostarlimab in 1 (0.2%) patient and resolved in 2 (28.6%) patients.
Nephritis, including tubulointerstitial nephritis, occurred in 3 (0.6%) 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 2 of 3 (66.7%) patients.
Immune-related rash (rash, rash maculo-papular, rash macular, rash pruritic, pemphigoid) occurred in 17 (3.3%) patients, including Grade 3 in 6 (1.2%) patients receiving dostarlimab. The median time to onset of rash was 41 days(range 2 days to 407 days). Systemic corticosteroids (prednisone ≥40 mg per day or equivalent) were required in 5 (29%) patients experiencing rash. Rash did not lead to discontinuation of dostarlimab and resolved in 13 (76.5%) patients.
Immune-related arthralgia occurred in 21 (4.1%) patients. Grade 3 immune-related arthralgia was reported in 3 (0.6%) patients receiving dostarlimab. The median time to onset of arthralgia was 87 days (range 1 day to 783 days). Systemic corticosteroids (prednisone ≥40 mg per day or equivalent) were required in 2 (9.5%) patients experiencing arthralgia. Arthralgia did not lead to discontinuation of dostarlimab and resolved in 8 (38%) patients experiencing arthralgia.
Infusion-related reactions including hypersensitivity occurred in 7 (1.4%) patients, including grade 2 (1.2%) and grade 3 (0.2%) infusion-related reactions. All patients recovered from the infusion-related reaction.
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. In the patients who developed anti-dostarlimab antibodies, there was no evidence of altered efficacy or safety of dostarlimab.
Of the 515 patients treated with dostarlimab monotherapy, 50.7% were under 65 years, 37.9% were 65-75 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).
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