Dostarlimab-gxly, a humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody, is an antineoplastic agent.1 The drug is an IgG4 immunoglobulin.1
Dostarlimab-gxly is used as a single agent for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen in any setting and are not candidates for curative surgery or radiation.1, 2 An FDA-approved diagnostic test is required to confirm dMMR tumor status prior to initiation of therapy.1
Dostarlimab-gxly is also used in combination with carboplatin and paclitaxel, followed by dostarlimab-gxly as a single agent, for the treatment of adults with primary advanced or recurrent endometrial cancer that is dMMR, as determined by an FDA-approved diagnostic test , or microsatellite instability-high (MSI-H).1 An FDA-approved test for detection of MSI-H is not currently available.1
There are limited therapeutic options following standard treatment with a platinum-containing chemotherapeutic regimen for women with advanced or recurrent endometrial cancer.3, 4 An estimated 25-30% of patients with advanced disease have dMMR tumors.3
The indication for dostarlimab as a single agent in the treatment of recurrent or advanced dMMR endometrial cancer is based principally on data from a cohort of 141 patients in a multicenter, non-randomized, open-label trial (GARNET).1, 5 Patients received dostarlimab-gxly 500 mg IV every 3 weeks for 4 doses followed by 1000 mg IV every 6 weeks until disease progression, unacceptable toxicity, death, or study withdrawal occurred.1, 5 The primary endpoints were overall response rate and duration of response according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), as evaluated by a central independent review committee (IRC).5 The median age of patients in this cohort was 65 years (53% of patients were ≥65 years of age); 77% of patients were white, 4% were Asian, 4% Hispanic or Latino, and 3% were Black.1 The most common histology was endometrioid carcinoma type 1 (65%).1 All patients with dMMR endometrial cancer had received prior treatment, with 89% of patients receiving surgery and 71% receiving radiotherapy; 63% had one prior line of anticancer treatment and 37% of patients had received at least 2 prior therapies.1
Results revealed that the overall response rate for patients in the dMMR endometrial cancer cohort of the GARNET trial was 45.4%; complete response was achieved in 15.6% of patients and a partial response in 29.8%.1 At a median follow-up of 27.9 months, the median duration of response had not been reached; however, 85.9% of patients who responded to treatment had durable responses of 12 months or more and 54.7% had durable responses of >24 months.1
The indication for dostarlimab in combination with carboplatin and paclitaxel is based prinicipally on data from a cohort of 122 patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer in a randomized, multicenter, double-blind, placebo-controlled trial (RUBY).1 Patients were randomly assigned to dostarlimab 500 mg, carboplatin AUC 5 mg/mL/min, and paclitaxel 175 mg/m2 IV on Day 1 of each 21-day cycle for 6 doses followed by dostarlimab 1000 mg IV every 6 weeks or carboplatin AUC 5 mg/mL/min, paclitaxel 175 mg/m2, and placebo IV on Day 1 of each 21-day cycle for 6 doses followed by IV placebo every 6 weeks.1 Treatment with dostarlimab continued until disease progression, unacceptable toxicity, or for a maximum of 3 years.1 The major efficacy outcome for the dMMR/MSI-H cohort was progression-free survival accoring to RECIST 1.1 criteria; overall survival, objective response rate, and duration of response were additional efficacy outcomes.1 The median age of patients in this cohort was 65 years (50% of patients were ≥65 years of age); 83% of patients were white, 9% were Black, and 3% were Asian.1
Results revealed that median progression-free survival was increased in the dostarlimab combination group as compared to placebo (30.3 vs 7.7 months); the percentage of patients with an event was reduced with dostarlimab in combination with carboplatin and paclitaxel compared to placebo (38.3% vs 75.8%).1 The objective response rate for patients receiving dostarlimab combination therapy was 73.8%; complete response was achieved in 26.2% of patients and a partial response in 47.6%.1 The objective response rate in the placebo combination group was 62.2%, with a complete response rate of 11.1% and partial response rate of 51.1%.1 The median duration of response was not reached in the dostarlimab combination group and was 5.4 months in the placebo combination group; 61.3% of patients in the dostarlimab combination group who responsed to treatment had a durable response of >12 months as compared to 14.3% in the placebo combination group.1 Overall survival data was immature in this cohort with 27% fatalities.1
Solid Tumors with Mismatch Repair Deficiency
Dostarlimab-gxly is used as a single agent for the treatment of adults with dMMR recurrent or advanced solid tumors that have progressed during or following prior treatment and for which there are no satisfactory alternative treatment options.1 An FDA-approved diagnostic test is required to confirm dMMR tumor status prior to initiation of therapy.1 The accelerated approval of dostarlimab-gxly for this indication is based on tumor response rate and durability of response.1 Continued FDA approval for this indication may be contingent on verification and description of clinical benefit in confirmatory studies.1
An estimated 14% of patients with solid tumors have dMMR tumors, which are most commonly found in endometrial, colorectal, and other GI cancers.7 Use of dostarlimab-gxly in the treatment of dMMR recurrent or advanced solid tumors is based principally on collective data from the dMMR endometrial cancer cohort and the dMMR solid-tumor (non-endometrial cancer) cohort of the multicenter, non-randomized, open-label, GARNET trial.1, 7 The efficacy population included a total of 209 patients with dMMR recurrent or advanced solid tumors who had progressed following systemic therapy and had no satisfactory alternative treatment options.1 Patients received dostarlimab-gxly 500 mg IV every 3 weeks for 4 doses followed by 1000 mg IV every 6 weeks until disease progression, unacceptable toxicity, death, or study withdrawal occurred.1 The primary endpoints were overall response rate and duration of response according to RECIST 1.1.1 The median age of patients was 63 years (47% were ≥65 years); 63% of patients were white, 3% were Asian, and 2% were Black.1 In addition, 97.2% of patients with non-endometrial dMMR solid tumors had Stage IV disease, and 68.0% of patients with dMMR endometrial tumors had FIGO Stage IV disease.1 Approximately 21% of patients received 3 or more prior therapies.1 In the pooled cohort of patients with dMMR solid tumors, the objective response rate was 41.6%; a complete response was achieved in 9.1% of patients and 32.5% experienced a partial response.1 The median duration of response was 34.7 months (range: 2.6-35.8+ months) and 95.4% of patients had a duration of response of 6 months or more.1
Dostarlimab is being investigated in other ongoing clinical trials in patients with non-endometrial cancer solid tumors (e.g., AMBER, IOLite).2
In patients with locally advanced rectal cancer,† neoadjuvant chemotherapy and radiation with subsequent surgical resection of the rectum is a standard treatment approach.100 However, 5-10% of patients with rectal cancer have dMMR/MSI-H disease, which is often resistant to chemotherapy.100, 101 Dostarlimab-gxly has been evaluated as a potential treatment option in this setting in a prospective, single-group, single-center, phase 2 study.101, 102
Adult patients (≥18 years of age) with dMMR/MSI-H stage II or III rectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, and no evidence of distant metastases were eligible for study enrollment.100 Additionally, eligible patients were without active autoimmune or infectious disease conditions, receipt of immunosuppressive therapy within the prior 7 days, or prior administration of immunotherapy, chemotherapy, or radiation for the rectal tumor.100 Patients received dostarlimab-gxly at a dose of 500 mg IV every 3 weeks for 6 months (9 cycles), potentially followed by standard radiation therapy with concurrent administration of capecitabine at usual recommended doses and subsequent total mesorectal excision.100 Patients who experienced a clinical complete response, defined as the absence of residual disease on digital and endoscopic rectal examination and rectal MRI, with no restricted diffusion on T2-weighted imaging, after completion of either dostarlimab-gxly induction therapy or chemoradiotherapy underwent nonoperative follow-up.100 Digital and endoscopic rectal examinations were conducted at baseline, 6 weeks, 3 months, 6 months, and then every 4 months after treatment initiation.100 Clinical imaging (T2- and diffusion-weighted MRI, FDG-PET, and CT) of the chest, abdomen, and pelvis was also conducted at baseline, 3 months, 6 months, and every 4 months.100 With each endoscopy, biopsies of the tumor were performed.100
Of the initial 16 patients (of a planned enrollment of 30 patients), 12 were enrolled for >6 months and completed all 9 cycles of dostarlimab-gxly therapy; the median follow-up time for these patients was 12 months (range, 6 to 25 months).100 The other 4 patients were administered at least a single dostarlimab dose and continued to receive treatment at the time of preliminary data publication.100 Of all enrolled patients, 62% were female and the median age was 54 years (range, 26 to 78 years).100 Most patients (75%) enrolled in the study had a baseline ECOG performance status of 0 and stage III disease was present in 15 patients.100 The most commonly occurring presenting symptoms of disease included rectal bleeding (88%), constipation (31%), and abdominal pain (25%).100 The primary study end points included: 1) sustained clinical complete response 12 months after completion of dostarlimab-gxly therapy (in patients who did not undergo surgery) or pathological complete response (in patients who underwent surgery) with or without chemoradiotherapy and 2) overall response to dostarlimab-gxly therapy with or without chemoradiotherapy.100
The overall response rate was evaluated using a one-sample hypothesis.100 The null hypothesis was that the percentage of patients with an overall response would be <25%; this was established based on a study in which the observed chemotherapy response among patients with mismatch repair-deficient rectal cancers was 7%.100 Successful rejection of the null hypothesis required 6 or more patients with an overall response by the end of the initial stage of the study (after 15 patients were enrolled) and 11 or more patients with an overall response by the end of the second stage of the study (after 30 patients were enrolled).100 Initial results revealed that all 12 patients who completed treatment with dostarlimab-gxly and underwent at least 6 months of follow-up experienced a clinical complete response (100%; 95% confidence interval, 74-100), with no evidence of tumor on MRI or PET scans, endoscopic evaluation, digital rectal examination, or biopsy.100 Additionally, no patients had been administered chemoradiotherapy or underwent surgery and no cases of progression or recurrence were reported during follow-up.100 A rapid therapeutic response was seen, with symptom resolution within 9 weeks after dostarlimab-gxly initiation in 81% of patients.100 Regarding safety, no adverse events of grade 3 or higher were reported.100 Adverse events of any grade were observed in 12 (75%) of the 16 enrolled patients; the most common grade 1 or 2 adverse events were rash or dermatitis (31%), pruritus (25%), fatigue (25%), and nausea (19%).100 A single patient was noted to experience thyroid-function abnormalities.100
An updated analysis of data involving 23 patients who completed 6 months of dostarlimab-gxly therapy has been presented since publication of initial results.102 The rate of clinical complete response was 100% in these 23 consecutive patients.102 During the median follow-up period of 9.3 months (range, 0.0-36.3 months), no patients were administered chemoradiotherapy and none underwent surgical resection.102 No grade 3 or 4 adverse events were observed in the updated data analysis.102
Based on current evidence, dostarlimab-gxly as neoadjuvant therapy for adult patients with locally advanced, dMMR/MSI-H rectal cancer† has Level 2 (moderate strength/quality) evidence supporting its use and is a reasonable choice (accepted, with possible conditions) in this setting. Currently available data show a complete clinical response to dostarlimab-gxly therapy in 100% of patients, with none requiring chemoradiotherapy or surgery and no grade 3 or 4 adverse events observed.100, 102 However, the number of patients enrolled in the only prospective, single-center, phase 2 study is small (n=23) and data on survival and the duration of complete response are not available to date.100, 102
Administer dostarlimab-gxly by IV infusion after dilution.1 Do not administer as an IV push or bolus injection.1
Do not co-administer with other drugs through the same infusion line.1 Consult the manufacturer's labeling for detailed information on infusion system requirements and procedures for IV infusion of dostarlimab-gxly.1
Store unopened vials at 2-8°C in the original carton to protect the drug from light.1 After the drug is diluted, the prepared dose may be stored either at room temperature for up to 6 hours (including infusion time) or under refrigeration (2- 8°C) for up to 24 hours (including infusion time).1 If the drug is refrigerated, allow the diluted solution to reach room temperature prior to administration.1
Must dilute injection concentration prior to administration.1 Visually inspect vials of dostarlimab-gxly solution for discoloration or particulate matter prior to dilution.1 Undiluted solutions should be clear to slightly opalescent, and colorless to yellow; do not use if visible particles are observed.1
To prepare a 500-mg dose of dostarlimab-gxly, withdraw 10 mL of the solution from a vial using a polypropylene sterile syringe.1 Dilute the solution in an infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection to a final concentration of 2-10 mg/mL (maximum 250 mL).1, 1 Do not shake the diluted solution; mix by gentle inversion.1
To prepare a 1000-mg dose of dostarlimab-gxly, withdraw 10 mL of the solution from each of 2 vials (20 mL total) using a polypropylene sterile syringe.1 Dilute the solution in an infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection to a final concentration of 4 -10 mg/mL (maximum 250 mL).1 Do not shake the diluted solution; mix by gentle inversion.1
Dostarlimab is compatible with an infusion bag made of polyolefin, ethylene vinyl acetate, or polyvinyl chloride with di(2-ethylhexyl) phthalate (DEHP).1
Dostarlimab-gxly injection concentrate is intended for single use only; discard any unused portion in the vial.1
Dostarlimab-gxly is administered by IV infusion over 30 minutes through an IV line using tubing made of polyvinyl chloride or platinum cured silcon; fittings made of polyvinyl chloride or polycarbonate; and a sterile, non-pyrogenic, low-protein binding, 0.2 micron, in-line or add-on filter.1
For the treatment of dMMR recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen, the recommended adult dosage of dostarlimab-gxly monotherapy is 500 mg every 3 weeks by IV infusion for the first 4 doses.1 Subsequent dosages beginning 3 weeks after the fourth dose are 1000 mg every 6 weeks by IV infusion.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
For the treatment of dMMR/MSI-H primary advanced or recurrent endometrial cancer, the recommended adult dosage of dostarlimab-gxly is 500 mg every 3 weeks by IV infusion for 6 doses followed by 1000 mg as monotherapy every 6 weeks.1 The initial 6 doses of dostarlimab-gxly are given in combination with carboplatin and paclitaxel.1 Administer dostarlimab-gxly prior to carboplatin and paclitaxel when administered on the same day.1 Continue therapy until disease progression, the occurrence of unacceptable toxicity, or for up to 3 years.1
For the treatment of dMMR recurrent of advanced solid tumors that have progressed on or following prior treatment, the recommended adult dosage of dostarlimab-gxly monotherapy is 500 mg every 3 weeks by IV infusion for the first 4 doses.1 Subsequent dosages beginning 3 weeks after the fourth dose are 1000 mg every 6 weeks by IV infusion.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
When dostarlimab-gxly is used as neoadjuvant therapy for adult patients with dMMR/MSI-H locally advanced rectal cancer†, the usual dosage is 500 mg IV every 3 weeks for 6 months (9 cycles).100
Dosage Modification for Toxicity
If immune-mediated adverse effects occur, temporary interruption or discontinuance of therapy may be required (see Table 1).1 Permanently discontinue therapy in patients experiencing life-threatening (grade 4) immune-mediated adverse reactions or recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, and in those not able to reduce corticosteroid dosage to <10 mg of prednisone daily (or equivalent) within 12 weeks of initiating steroids.1
Adverse Reaction | Dosage Modification |
|---|---|
Pneumonitis | Grade 2: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid tapera Grade 3 or 4 or recurrent grade 2: Permanently discontinue therapy |
Colitis | Grade 2 or 3: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid tapera Grade 4: Permanently discontinue therapy. |
Hepatitis with no tumor involvement of the liver | AST or ALT elevations >3 times but ≤8 times the upper limit of normal (ULN) or total bilirubin concentrations >1.5 but ≤ 3 times the ULN: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid tapera AST or ALT elevations >8 times the ULN or total bilirubin concentrations >3 times the ULN: Permanently discontinue therapy |
Hepatitis with tumor involvement of the liverb | Baseline AST or ALT is >1 but ≤3 times the ULN and increases to >5 but ≤10 times the ULN or baseline AST or ALT is >3 but ≤5 times the ULN and increases to >8 but ≤10 times the ULN: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid taper a AST or ALT elevations >10 times the ULN or total bilirubin concentrations >3 times the ULN: Permanently discontinue therapy |
Endocrinopathies | Grade 2, 3, or 4: Withhold therapy until clinically stable or permanently discontinue, depending on severity; may resume after recovery to grade 0 to 1 and completion of corticosteroid tapera |
Nephritis with renal dysfunction | Grade 2 or 3 increased serum creatinine concentrations: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid tapera Grade 4 increased serum creatinine concentrations: Permanently discontinue therapy |
Exfoliative dermatologic conditions | Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS): Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid tapera Confirmed SJS, TEN, or DRESS: Permanently discontinue therapy |
Myocarditis | Grade 2, 3, or 4: Permanently discontinue therapy |
Neurologic toxicities | Grade 2: Withhold therapy until recovery to grade 0 to 1; may resume after corticosteroid tapera Grade 3 or 4: Permanently discontinue therapy |
Infusion-related reactions | Grade 1 or 2: Interrupt or slow the rate of infusion Grade 3 or 4: Permanently discontinue therapy |
aPermanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce corticosteroid dosage to <10 mg of prednisone daily (or equivalent) within 12 weeks of initiating steroids.
bIf AST and ALT ≤ ULN at baseline in patients with liver involvement, withhold or permanently discontinue based on recommendations for hepatitis with no liver involvement.
The manufacturer makes no specific dosage recommendations for geriatric patients or for patients with renal or mild to moderate hepatic impairment.1
Immune-mediated Adverse Reactions
Severe and fatal immune-mediated adverse reactions can occur at any time in any organ system or tissue after initiating treatment with an anti-programmed-death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) antibody.1 Early identification and management of such reactions are essential to ensure safe use of these agents.1
If an immune-mediated adverse effect is suspected, evaluate patient to exclude alternative etiologies, including infection.1 Promptly initiate appropriate management and withhold or permanently discontinue dostarlimab depending on severity.1 If treatment interruption or discontinuation of therapy is required, administer systemic corticosteroid therapy (1-2 mg/kg of prednisone daily [or equivalent]) until toxicity improves to grade 1 or less, and then initiate and continue a corticosteroid taper over at least 1 month.1 Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is uncontrolled with corticosteroids.1 Permanently discontinue dostarlimab if there is no partial or complete resolution within 12 weeks of steroid initiation or if the corticosteroid dosage is not able to be decreased to <10 mg of prednisone daily (or equivalent) within 12 weeks of steroid initiation.1
Immune-mediated pneumonitis occurred in 2.3% (14 out of 605) of patients receiving dostarlimab-gxly.1 Systemic corticosteroids were required in 79% (11 out of 14) of patients, and pneumonitis resolved in 11 of the 14 patients.1 Dostarlimab-gxly was withheld for 9 patients.1 Five patients reinitiated therapy after symptom improvement; of these patients, 2 experienced pneumonitis recurrence.1 The risk of pneumonitis appears to be higher in patients who received prior thoracic radiation.1
Depending on the severity, interrupt or discontinue dostarlimab-gxly therapy.1
Immune-mediated colitis occurred in 1.3% (8 out of 605) of patients receiving dostarlimab-gxly.1 Systemic corticosteroids were required in 75% (6 out of 8) of patients, and colitis resolved in 5 of the 8 patients.1 Dostarlimab-gxly was withheld for 4 patients.1 All patients reinitiated therapy; of these patients, 1 experienced colitis recurrence.1
Depending on the severity, interrupt or discontinue dostarlimab-gxly therapy.1
Immune-mediated hepatitis occurred in 0.5% (3 out of 605) of patients receiving dostarlimab-gxly; all were grade 3 events.1 Hepatitis led to treatment discontinuation in 1 (0.2%) patient.1 Systemic corticosteroids were required in 2 patients and the event resolved in 2 of the 3 total patients.1
Depending on severity, interrupt or discontinue dostarlimab-gxly therapy.1
Immune-mediated Endocrinopathies
Dostarlimab can cause primary or secondary adrenal insufficiency.1 Adrenal insufficiency occurred in 1.2% (7 out of 605) of patients receiving dostarlimab-gxly, and resolved in 4 of the 7 patients.1 Of the 4 patients in whom dostarlimab-gxly was withheld, all reinitiated treatment.1 Systemic corticosteroid therapy was required in 5 of the 7 patients with adrenal insufficiency.1 Monitor patients for manifestations of adrenal insufficiency.1 In patients with grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated.1 Withhold or permanently discontinue therapy depending on severity.1
Dostarlimab can also cause other endocrinopathies such as thyroid disorders, type 1 diabetes mellitus, and hypophysitis.1 Evaluate thyroid function prior to initiation and periodically during therapy.1 Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated; withhold or permanently discontinue drug depending on severity.1 Monitor for hypophysitis; symptoms may include headache, photophobia, or visual field cuts.1 Hypophysitis can cause hypopituitarism.1 Initiate hormone replacement as clinically indicated; withhold or permanently discontinue drug depending on severity.1 Monitor patients for hyperglycemia or other signs and symptoms of diabetes mellitus.1 Initiate treatment with insulin as clinically indicated; withhold or permanently discontinue drug depending on severity.1
Immune-mediated Nephritis with Renal Dysfunction
Immune-mediated nephritis occurred in 0.5% (3 out of 605) of patients receiving dostarlimab-gxly in clinical studies; all were grade 2 events.1 Dostarlimab-gxly was discontinued due to nephritis in 1 patient and resolved in all patients.1 Systemic corticosteroids were required in 2 of the 3 patients experiencing nephritis.1
Evaluate serum creatinine concentrations prior to initiation of therapy and periodically during therapy.1 Depending on severity, interrupt or permanently discontinue dostarlimab-gxly therapy.1
Immune-mediated Dermatologic Adverse Reactions
Immune-mediated rash or dermatitis including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) can occur with dostarlimab use.1 Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.1 Depending on severity, interrupt or discontinue dostarlimab-gxly therapy.1
Other Immune-Mediated Adverse Reactions
Other clinically significant immune-mediated adverse reactions that can affect any organ system or tissue (including solid organ transplant rejection) have occurred in patients receiving dostarlimab or other PD-1/PD-L1-blocking antibodies; some reactions were severe or fatal.1 These adverse reactions occurred in <1% of the 605 patients treated with dostarlimab-gxly.1
Depending on severity, interrupt or discontinue dostarlimab-gxly therapy.1
Severe or life-threatening infusion-related reactions have been reported with anti-PD-1 monoclonal antibodies.1 Grade 3 infusion-related reactions occurred in 0.2% (1 out of 605) of patients receiving dostarlimab-gxly.1 All patients recovered from the infusion-related reactions.1
Monitor patients for signs and symptoms of infusion-related reactions.1 Interrupt or slow the rate of infusion or permanently discontinue the drug based on severity of the reaction.1
Complications of Allogeneic HSCT
Serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after treatment with dostarlimab.1 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).1 These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.1
Follow patients closely for evidence of transplant-related complications and intervene promptly.1 Consider the benefits versus risks of treatment with a PD-1/PD-L1-blocking antibody prior to or after an allogeneic HSCT.1
Fetal/Neonatal Morbidity and Mortality
Dostarlimab may cause fetal harm when administered to pregnant women based on its mechanism of action.1 There are no clinical data on the use of dostarlimab-gxly in pregnant women.1 Human IgG4 immunoglobulins are known to cross the placental barrier; therefore, dostarlimab has the potential to be transmitted from the mother to the developing fetus.1 Animal reproduction studies have not been conducted in dostarlimab specifically to evaluate its effect on reproduction and fetal development.1 Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death.1
The manufacturer recommends confirmation of pregnancy status prior to initiation of dostarlimab in women of childbearing potential and the use of effective contraception during treatment and for 4 months after the drug is discontinued.1 If dostarlimab is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise patient of the potential fetal hazard.
In the GARNET study, treatment-emergent anti-drug antibodies (ADAs) were detected in 2.1% of patients (8 out of 384) who received dostarlimab-gxly at the recommended dosage.1 In 1% of patients, neutralizing antibodies were detected.1
In the RUBY study, there was no formation of treatment-emergent ADAs or neutralizing antibodies in 225 patients administered dostarlimab-gxly at the recommended dosage.1
Dostarlimab may cause fetal harm if administered to pregnant women based on its mechanism of action.1
Verify pregnancy status in women of childbearing potential prior to initiation of dostarlimab therapy.1
It is not known whether dostarlimab is distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Maternal IgG is known to be present in human milk.1 The effects of local GI exposure and limited systemic exposure in the breastfed child to dostarlimab are unknown.1 Because of the potential for adverse reactions in nursing infants, advise women not to breast-feed while receiving the drug and for 4 months after the drug is discontinued.1
Females and Males of Reproductive Potential
Fertility studies have not been performed with dostarlimab.3 Women of childbearing potential should use effective contraception during treatment and for 4 months after the drug is discontinued.1
Safety and efficacy of dostarlimab have not been established in pediatric patients.1
Among patients receiving dostarlimab-gxly as a single agent in clinical trials, 36.9% were 65-75 years of age, and 11.5% were ≥75 years of age.1 Among patients administered dostarlimab-gxly in combination with carboplatin and paclitaxel in clinical trials, 36.5% were 65-75 years of age, and 11.2% were ≥75 years of age.1 No overall differences in safety or effectiveness were observed between geriatric patients and younger adults.1
No clinically significant differences in the pharmacokinetics of dostarlimab were observed based on mild to moderate hepatic impairment.1
No clinically significant differences in the pharmacokinetics of dostarlimab were observed based on renal impairment (based on the estimated creatinine clearance).1
Most common adverse reactions (≥20%) reported with dostarlimab-gxly as a single agent in patients with dMMR solid tumors include fatigue/asthenia, nausea, diarrhea, and anemia.1
Most common adverse reactions (≥20%) reported with dostarlimab-gxly as combination therapy in patients with dMMR/MSI-H endometrial cancer include rash, diarrhea, hypothroidism, and hypertension.1
When given in combination with carboplatin and paclitaxel in patients with recurrent or advanced endometrial cancer, there was no evidence to suggest a clinically relevant change of dostarlimab clearance over time and exposure was comparable to administration of dostarlimab as a single agent.1
Dostarlimab is a humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.1, 2 PD-1 receptors are expressed on the cell surface of activated T cells.8 Binding of PD-1 ligands (PD-L1 and PD-L2) to the PD-1 receptor inhibits T cell proliferation and cytokine production.1, 8 Dostarlimab binds to the PD-1 receptor on T cells, which blocks its interaction with PD-L1 and PD-L2 ligands and prevents PD-1 pathway mediated inhibition of the immune response.1, 2
Peak plasma concentrations and systemic exposure of dostarlimab-gxly are dose proportional over the dose range of 1-10 mg/kg.1 The exposures of dostarlimab-gxly given in combination with carboplatin and paclitaxel and as a single agent were comparable.1 The mean half-life of the drug is 23.5 days.1 Dostarlimab is expected to be metabolized by catabolic pathways into small peptides and amino acids.1 Clinically important effects on dostarlimab exposure have not been observed based on age, sex, race, tumor type, mild to moderate renal impairment, or mild to moderate hepatic impairment.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Concentrate for injection, for IV infusion | 50 mg/mL (500 mg) | Jemperli® | GlaxoSmithKline LLC |
1. GlaxoSmithKline. Jemperli® (dostarlimab) prescribing information. Philadelphia, PA; 2023 Jul. [Web]
2. Markham A. Dostarlimab: First Approval. Drugs . 2021; 81:1213-1219. [PubMed 34106455]
3. Food and Drug Administration. FDA Approves lmmunotherapy for Endometrial Cancer with Specific Biomarker. 2021, April 22. From the FDA website. [Web]
4. GlaxoSmithKline LLC. GSK presents new data from the GARNET study demonstrating potential of dostarlimab to treat a subset of women with recurrent or advanced endometrial cancer. From GlaxoSmithKline website. 2020, April 23. Accessed September 13, 2021. [Web]
5. Oaknin A, Tinker AV, Gilbert L et al. Clinical Activity and Safety of the Anti-Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair-Deficient Endometrial Cancer: A Nonrandomized Phase 1 Clinical Trial. JAMA Oncol . 2020; 6:1766-1772. [PubMed 33001143]
7. GlaxoSmithKline. GSK receives FDA accelerated approval for JEMPERLI (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumours. From GlaxoSmithKline website. 2021, August 17. Accessed September 14, 2021. [Web]
8. Kasherman L, Ahrari S, Lheureux S. Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer. Future Oncol . 2021; 17:877-892. [PubMed 33251877]
100. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386:2363-76.
101. Rose S. Dostarlimab: an answer for rectal cancer? Cancer Discov. 2022;12(8):1828-29.
102. Cercek A. PD-1 blockade as curative-intent therapy in mismatch repair deficient locally advanced rectal cancer. Presented at the Japanese Society of Medical Oncology (JSMO) Annual Meeting, March 16-18, 2023, Fukoka, Japan.