Dostarlimab

Dostarlimab is a humanized monoclonal antibody and immune-checkpoint inhibitor that targets programmed death receptor-1 (PD-1) on immune cells. By binding PD-1 and blocking its interaction with PD-L1 and PD-L2, dostarlimab reduces an inhibitory signal that can limit T-cell activity against cancer cells. It is administered by intravenous infusion and is generally given as a 30-minute infusion. Its clinical role is particularly associated with tumors showing mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), biomarkers that can indicate increased susceptibility to immune-checkpoint blockade. In the United States, dostarlimab is approved both in combination with carboplatin and paclitaxel followed by dostarlimab monotherapy for adults with primary advanced or recurrent endometrial cancer, and as monotherapy for certain dMMR endometrial cancers and dMMR recurrent or advanced solid tumors. The latter solid-tumor indication remains an accelerated approval based on response rate and durability of response. Dostarlimab is clinically important because it provides a biomarker-directed immunotherapy option and has demonstrated activity both as monotherapy and in combination with chemotherapy in advanced or recurrent endometrial cancer.

Dostarlimab was developed as a PD-1-directed monoclonal antibody for cancer immunotherapy. The GARNET clinical program supported its initial regulatory development, including evaluation in patients with advanced solid tumors and dMMR endometrial cancer. The U.S. FDA granted accelerated approval for dMMR recurrent or advanced endometrial cancer in April 2021, followed by regular approval for the dMMR endometrial-cancer indication on February 9, 2023. FDA approval was expanded on July 31, 2023 to include dostarlimab with carboplatin and paclitaxel followed by dostarlimab for primary advanced or recurrent dMMR/MSI-H endometrial cancer, and on August 1, 2024 the chemotherapy-combination indication was expanded to primary advanced or recurrent endometrial cancer regardless of dMMR/MSI-H status. The FDA also maintains an accelerated approval for dMMR recurrent or advanced solid tumors with no satisfactory alternative treatment options. In the European Union, the EMA granted conditional marketing authorisation for Jemperli on April 21, 2021, which was converted to a standard marketing authorisation on December 7, 2023. Current EMA authorization covers first-line combination treatment for primary advanced or recurrent endometrial cancer and monotherapy for dMMR/MSI-H recurrent or advanced endometrial cancer after platinum-containing treatment.

Dostarlimab is used in adults with primary advanced or recurrent endometrial cancer in combination with carboplatin and paclitaxel, followed by dostarlimab alone. In the United States, this combination indication currently applies regardless of tumor dMMR/MSI-H status. As monotherapy, it is approved for adults with dMMR recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen and who are not candidates for curative surgery or radiation. FDA labeling also includes monotherapy for adults with dMMR recurrent or advanced solid tumors that have progressed during or after prior treatment when there are no satisfactory alternative treatment options; this indication is under accelerated approval. The RUBY phase 3 trial established important evidence for combining dostarlimab with carboplatin and paclitaxel in advanced or recurrent endometrial cancer. Dostarlimab has also produced significant responses in small clinical studies of dMMR locally advanced rectal cancer, but this investigational use should not be presented as an approved rectal-cancer indication.

Dostarlimab is administered intravenously over approximately 30 minutes. For primary advanced or recurrent endometrial cancer treated with combination therapy, the U.S. prescribing information specifies 500 mg every 3 weeks for six cycles with carboplatin and paclitaxel, followed by 1,000 mg as monotherapy every 6 weeks. For approved monotherapy indications, the usual regimen is 500 mg every 3 weeks for four cycles followed by 1,000 mg every 6 weeks. Combination treatment is continued until disease progression, unacceptable toxicity, or a maximum of 3 years, while monotherapy is generally continued until disease progression or unacceptable toxicity. Dose reductions are not recommended; treatment may instead be withheld or permanently discontinued according to the severity and type of adverse reaction. Tumor biomarker testing for dMMR is required for the relevant single-agent indications.

Side effects vary according to whether dostarlimab is used alone or with chemotherapy. With combination treatment, commonly reported adverse reactions and laboratory abnormalities include decreased hemoglobin and other blood-cell counts, increased creatinine, peripheral neuropathy, fatigue, nausea, hair loss, changes in glucose or electrolytes, rash, diarrhea, constipation, abdominal pain, joint pain, decreased appetite and increased liver enzymes. In monotherapy studies of dMMR solid tumors, common adverse reactions included fatigue or asthenia, anemia, diarrhea and nausea. When dostarlimab is combined with chemotherapy, some symptoms may also reflect the effects of carboplatin or paclitaxel rather than dostarlimab alone.

Dostarlimab can cause immune-mediated adverse reactions that may affect almost any organ and can occasionally be severe or fatal. Important toxicities include pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis and other endocrine disorders, nephritis with renal dysfunction, dermatologic reactions, neurological toxicity and myocarditis. Infusion-related reactions can also occur. Treatment may need to be interrupted for significant immune-mediated toxicity and permanently discontinued for certain life-threatening, recurrent or otherwise severe reactions. The prescribing information recommends baseline and periodic assessment of liver enzymes, creatinine and thyroid function, together with clinical evaluation for symptoms suggesting immune toxicity. Serious complications can also occur in patients undergoing allogeneic hematopoietic stem-cell transplantation before or after PD-1/PD-L1 blockade. Dostarlimab can cause fetal harm, so pregnancy and reproductive-potential considerations should be addressed before treatment.

Before treatment, clinicians should establish the tumor biomarker status required for the intended monotherapy indication and assess relevant baseline laboratory parameters, including liver function, renal function and thyroid function. Patients with a history of immune-mediated disease, organ transplantation, previous thoracic radiation or other factors relevant to immune-related toxicity may require additional assessment. Patients should be monitored for new respiratory, gastrointestinal, hepatic, endocrine, renal, dermatologic or neurological symptoms during treatment and after treatment because immune-mediated reactions can occur after discontinuation. Because dostarlimab is a monoclonal antibody, classic cytochrome-P450 metabolic drug interactions are not generally expected. However, concomitant immunosuppressive treatment may affect management of immune-mediated toxicity, and vaccination decisions should be discussed with the treating clinician; particular caution is appropriate with live or live-attenuated vaccines during active immunotherapy. Pregnancy should be avoided during treatment, and breastfeeding is not recommended according to the U.S. prescribing information.

Confirm the indication and required dMMR/MSI-H testing before initiating single-agent treatment, and document baseline liver enzymes, creatinine and thyroid function. For combination therapy, administer dostarlimab before carboplatin and paclitaxel when given on the same day. Infusion preparation should follow the approved product instructions, with intravenous administration over 30 minutes and no IV push or bolus administration. Pharmacists and oncology teams should educate patients to report new cough or breathlessness, persistent diarrhea, abdominal symptoms, jaundice, marked fatigue, headache or visual changes, reduced urine output, rash, or other new systemic symptoms promptly. For suspected immune-mediated toxicity, investigate alternative causes such as infection while assessing whether treatment should be withheld or discontinued and whether corticosteroid-based management is appropriate. Coordination between oncology, pharmacy and relevant specialty teams is important when endocrine, pulmonary, hepatic, renal, neurologic or cardiac immune toxicities develop.