Dostarlimab
Overview
Dostarlimab is a humanized IgG4 monoclonal antibody that binds to the programmed death‑1 (PD‑1) receptor on T-cells. By blocking PD‑1 interaction with its ligands (PD-L1/PD-L2), dostarlimab lifts immune suppression imposed by tumors, enabling the patient’s immune system to recognise and destroy cancer cells. Given by intravenous infusion, dostarlimab belongs to the class of immune checkpoint inhibitors and represents immunotherapy rather than conventional cytotoxic chemotherapy. This mechanism makes dostarlimab particularly useful in tumors that are mismatch repair deficient (dMMR) or have high microsatellite instability (MSI‑H), where immune activation may yield substantial therapeutic benefit.
Background and Date of Approval
Dostarlimab emerged from preclinical development as a PD‑1 blocking antibody and entered clinical trials in the late 2010s under the name Jemperli (dostarlimab‑gxly). In April 2021, the U.S. Food and Drug Administration granted accelerated approval to dostarlimab for adult patients with recurrent or advanced endometrial cancer whose tumors are mismatch repair deficient (dMMR) and who had progressed after platinum-based chemotherapy. In the same period, the European Commission granted conditional marketing authorisation for dostarlimab for dMMR/MSI‑H recurrent or advanced endometrial cancer, making it the first anti‑PD‑1 therapy approved for that indication in Europe. On August 17, 2021, the FDA expanded approval of dostarlimab for adult patients with dMMR recurrent or advanced solid tumors that had progressed after prior treatment. In February 2023, the FDA converted the earlier accelerated approval for endometrial cancer to regular approval. In July 2023, the FDA further approved dostarlimab in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab, for primary advanced or recurrent endometrial cancer regardless of dMMR/MSI status. Over time, dostarlimab has become an established immunotherapy option for a range of dMMR/MSI‑H tumors, reflecting growing evidence and regulatory support.
Uses
Dostarlimab is indicated for adult patients with mismatch repair deficient (dMMR) or microsatellite instability–high (MSI‑H) recurrent or advanced solid tumors that have progressed after prior treatment. It is also indicated for recurrent or advanced endometrial cancer that is dMMR/MSI‑H in patients who have received prior platinum‑based chemotherapy. For endometrial cancer, dostarlimab may also be used in combination with chemotherapy (carboplatin + paclitaxel), followed by maintenance single-agent therapy. Use in other cancer types or in tumor‑agnostic settings depends on regulatory approval, molecular profile (dMMR/MSI‑H), and clinical judgement.
Administration
Dostarlimab is administered by intravenous infusion. For the dMMR/MSI‑H solid tumor indication, the approved dosing regimen involves 500 mg every 3 weeks for the first four doses, followed by 1,000 mg every 6 weeks thereafter until disease progression or unacceptable toxicity. For endometrial cancer in combination with chemotherapy, dosing begins with 500 mg every 3 weeks alongside carboplatin and paclitaxel for six cycles, followed by single-agent maintenance at 1,000 mg every 6 weeks. Infusion is typically over 30 minutes. Baseline assessments of organ function and tumor molecular status should precede treatment, and regular monitoring during therapy is advised.
Side Effects
Commonly reported side effects include fatigue, nausea, diarrhea or constipation, decreased appetite, anemia, rash or itching, arthralgia, vomiting, and general weakness. Given its immune‑modulating mechanism, immune‑related adverse events affecting various organ systems are also frequent.
Warnings
Serious risks with dostarlimab predominantly arise from immune‑mediated toxicities, which may include pneumonitis, colitis, hepatitis, endocrinopathies (thyroid, adrenal), nephritis, and skin or systemic autoimmune reactions. These events can be severe and life‑threatening. Patients should be monitored carefully and therapy discontinued if severe immune adverse reactions occur. Special caution is advised in patients with pre‑existing autoimmune conditions or impaired organ function.
Precautions
Before initiating dostarlimab, assess baseline organ function including liver, renal, endocrine, and pulmonary status. Because dostarlimab affects immune response, concurrent use of immunosuppressive therapy or live vaccines may be contraindicated or require careful evaluation. While classic small-molecule drug–drug interactions are unlikely, any concurrent therapy that alters immune function or could exacerbate immune toxicity should be managed cautiously. During and after treatment, patients must be monitored for new or worsening symptoms, especially involving lungs, gastrointestinal tract, liver, kidneys, or endocrine system, to detect immune‑related toxicity early.
Expert Tips
Before starting therapy, verify tumor molecular profile (dMMR/MSI‑H) and assess baseline organ function. Counsel patients about the nature of immunotherapy, potential immune-related side effects, and the importance of reporting any new symptoms immediately. Ensure infusion scheduling, proper handling, and safe storage per product guidelines. During treatment, schedule periodic monitoring of organ function and immune-related laboratories. When combining dostarlimab with chemotherapy or other agents, coordinate treatment regimens carefully and provide supportive care and toxicity monitoring.
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References
1) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00299-4/fulltext
2) https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-endometrial-cancer
3) https://www.ema.europa.eu/en/medicines/human/EPAR/jemperli
4) https://www.nejm.org/doi/full/10.1056/NEJMoa2201445