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Dostarlimab

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Dostarlimab
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPDCD1
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
AHFS/Drugs.comMonograph
MedlinePlusa621030
License data
Pregnancy
category
Routes of
administration		Intravenous
Drug classAntineoplastic
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem SID
DrugBank
UNII
KEGG
Chemical and physical data
FormulaC6420H9832N1690O2014S44
Molar mass144325.73 g·mol−1

Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as an anti-cancer medication for the treatment of endometrial cancer.[5][6][10] Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.[5][6][8]

The most common side effects reported in the US include fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[5][6] Additional side effects reported in the European Union include vomiting, joint pain, itching, rash, fever, and hypothyroidism (low levels of thyroid hormones).[8]

Dostarlimab was approved for the treatment of endometrial cancer in both the United States and the European Union in April 2021.[5][6][11][8][12]

Based on the Garnet trial, dostarlimab gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021,[6] and full approval in February 2023.[7]

Medical uses

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Dostarlimab has been approved to treat specific cancers in various jurisdictions.

Endometrial cancer

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In endometrial cancer cancerous cells reside in the lining of the uterus (endometrium).[13] The four stages in endometrial cancer range from settling in the endometrium to metastasizing to other organs.[13] This disease can be treated if discovered early enough.[14] Studies report that chemoresistant MSI-high tumors can be treated with dostarlimab and pembrolizumab.[14]

In the European Union, dostarlimab is indicated as monotherapy for the treatment of adults with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-based regimen such as cisplatin, carboplatin or oxaliplatin.[15]

Dostarlimab is approved in the US for adults with dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who lack satisfactory alternative treatment options.[16][17] Dostarlimab, in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab, is approved for primary advanced or recurrent dMMR endometrial cancer.[18][19] Efficacy was evaluated in RUBY (NCT03981796), a randomized, multicenter, double-blind, placebo-controlled trial. Efficacy was assessed in a pre-specified subgroup of 122 participants with dMMR/MSI-H primary advanced or recurrent endometrial cancer. MMR/MSI tumor status was assessed by local testing assays (IHC, PCR, or NGS), or central testing (IHC), using the Ventana MMR RxDx Panel, when local results were unavailable.[19] In August 2024, the Food and Drug Administration approved dostarlimab with carboplatin and paclitaxel, followed by single-agent dostarlimab, for adults with primary advanced or recurrent endometrial cancer.[20] Dostarlimab previously was approved with carboplatin and paclitaxel, followed by single-agent dostarlimab, for primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H).[20]

Solid tumors

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Diagram showing a monoclonal antibody attached to a cancer cell CRUK 070 from Cancer Research UK.[21]

Solid tumors are tumors that do not contain any liquid or cysts, which can occur in many places including bones, muscles and organs. The most common types of solid tumors are sarcomas and carcinomas.[22] Dostarlimab can be used to treat recurrent or advanced tumors for patients who have tried alternative treatment options.[23]

Colorectal cancer

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In a Phase II clinical trial, dostarlimab-gxly completely eradicated tumors in all 42 patients. dMMR cancers comprise 5-10% of colorectal cancers. Traditional surgery patients often experience life-long impacts, such as bowel, urinary and sexual dysfunction, as well as secondary cancers and infertility.[24][25]

Side effects

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Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and fever (pyrexia).[5][6]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrine disease (endocrinopathies), and nephritis.[5][6]

The most common side effects reported while taking this medication during a trial were dyspnea, asthenia, fatigue, and nausea.[26]

Symptoms of overdose are similar to the side effect profile of the medication, so it could involve significant immune-mediated reactions.[27]

Immune-mediated adverse reactions

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Dostarlimab is a monoclonal antibody that binds to PD-1 to block it from binding PD-1 ligands to remove inhibition of immune response.[5] With this, it causes risk for immune-mediated adverse reactions.[5] These reactions can be severe or fatal and occur in any part of the body: organs or tissues.[5]

Examples of immune-mediated adverse reactions include immune-mediated pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, thyroid disorders, nephritis with renal dysfunction, and dermatologic reactions.[5]

Pregnancy and lactation

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Dostarlimab can cause harm to a fetus.[5] The death of the fetus can occur from the immune system's reaction to the fetus through the examination of its mechanism in animal studies.[5] Dostarlimab is a human immunoglobulin G (IgG4), which could permeate through the placental barrier.[5] This may risk harm to the developing fetus as the drug may be passed on from the mother.[5]

Data is not available regarding the presence of dostarlimab in breastmilk.[5]

Hepatotoxicity

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Dostarlimab causes mild to moderate elevations to serum aminotransferase and alkaline phosphatase in 15-25% of recipients.[27] Serum ALT elevation above five times the normal range occurs in 2-3% of recipients.[27] Some people treated with dostarlimab can develop immune related liver injury.[27]

Some symptoms of liver injury or acute liver failure can include jaundice, pain in the upper right abdomen, ascites, nausea/vomiting, and disorientation or confusion.[28]

Pharmacology

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Dostarlimab is a humanized IgG4 monoclonal antibody that was derived from a mouse antibody which was humanized via Complementarity Determining Region (CDR) grafting.[29] Its serum half-life is 25.4 days.[5]

Other PD-1 antibodies included nivolumab (Opdivo) and pembrolizumab (Keytruda), both of which have uses in many different types of cancers which include classical Hodgkin lymphoma, renal cell carcinoma, and breast cancer.[29] Another PD-1 antibody is cemiplimab (Libtayo) which was approved for treatment of squamous cell carcinoma, basal cell carcinoma and non-small cell lung cancer.[29]

Mechanism of action

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Dostarlimab binds to the PD-1 receptor, with high affinity, to block its activity with PD-1 ligands (PD-L1 and PD-L2).[15][30] PD-1 is a co-inhibitory receptor that is an important checkpoint protein for regulating T-cell tolerance.[5][29] When PD-1 is constantly stimulated by PD-1 ligands, which are highly expressed in cancer cells, it allows cancer cells to dodge T-cell mediated immune responses.[29] Therefore, blocking the binding of PD-1 to these ligands can allow T-cells to function normally and prevent tumor cells from bypassing immune surveillance.[29] In mouse tumor models, it was shown that inhibiting PD-1 activity decreased tumor growth.[5]

Efficacy

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In the Garnet Trial, dostarlimab achieved favorable results in decreasing the size of the tumor in those with endometrial cancer.[31] The study observed people with endometrial cancer from seven different countries and the size of the tumor was reduced in 42% of the population studied.[31]

Dostarlimab exhibits better efficacy than PD-L1 inhibitors, such as avelumab and durvalumab, in dMMR advanced endometrial cancers.[32] Efficacy of the drug is measured by the response rate, which is 47% for dostarlimab.[32]

History

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In 2020, dostarlimab, a PD-1 inhibitor, was undergoing phase I/II and phase III clinical trials.[31][33][34]

In 2020, the manufacturer, Tesaro, announced preliminary successful results from the phase I/II GARNET study.[31][35]

In 2020, the Garnet study announced that dostarlimab had promising potential to treat a specific subset of individuals with recurrent or advanced endometrial cancer.[31]

In April 2021, dostarlimab was approved for the treatment of recurrent or advanced endometrial cancer with mismatch repair deficient (dMMR), which are genetic abnormalities that disrupt DNA repair, in individuals who had previously been treated with platinum-containing regimens.[36]

In April 2021, the US Food and Drug Administration (FDA) granted accelerated approval to dostarlimab-gxly (Jemperli, GSK).[6] Efficacy was evaluated based on cohort (A1) in Garnet Trial (NCT02715284), a multicenter, multicohort, open-label trial in participants with advanced solid tumors.[6] The FDA approved dostarlimab based on evidence from the GARNET trial (NCT02715284) of 71 participants with advanced or recurrent endometrial cancer that was shown to be mismatch repair deficient (dMMR), and for which certain types of chemotherapy did not work or was no longer working.[37] The cohort used for the approved indication was conducted at 40 sites in 7 countries in North America and Europe.[37]

In 2022, an early clinical study of dostarlimab reported a 100% remission rate in 14 patients with rectal cancer who had mismatch repair deficiency, a type of genetic mutation that only affects 5-10% of cases.[38][39][40]

In February 2023, the FDA approved dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation.[7]

Society and culture

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Dostarlimab is the international nonproprietary name (INN),[41] and the United States Adopted Name (USAN).[42]

[edit]

In February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[43] The applicant for this medicinal product is GSK (Ireland) Limited.[43] Dostarlimab was approved for medical use in the European Union in April 2021.[8]

Economics

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In the United States, dostarlimab costs around US$11,000 per dose.[44]

Among those who are insured, those who have Medicaid insurance are less likely to receive full care for gynecologic cancer.[45] Those insured through private insurance still experience economical hardships while getting treatment.[45] Uninsured patients do not tend to get screened regularly, which results in late diagnosis of the disease.[45]

References

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  1. ^ a b "Jemperli APMDS". Therapeutic Goods Administration (TGA). 2 March 2022. Archived from the original on 19 March 2022. Retrieved 5 March 2022.
  2. ^ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ^ "Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24]". Health Canada. 24 January 2022. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
  4. ^ "Summary Basis of Decision (SBD) for Jemperli". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  5. ^ a b c d e f g h i j k l m n o p q r s "Jemperli- dostarlimab injection". DailyMed. Archived from the original on 1 March 2022. Retrieved 28 April 2021.
  6. ^ a b c d e f g h i j "FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer". U.S. Food and Drug Administration (FDA) (Press release). 22 April 2021. Archived from the original on 22 April 2021. Retrieved 22 April 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ^ a b c "FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer". U.S. Food and Drug Administration (FDA). 9 February 2023. Archived from the original on 10 February 2023. Retrieved 10 February 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ a b c d e "Jemperli EPAR". European Medicines Agency (EMA). 24 February 2021. Archived from the original on 14 May 2022. Retrieved 16 July 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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  10. ^ Kasherman L, Ahrari S, Lheureux S (March 2021). "Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer". Future Oncology. 17 (8): 877–892. doi:10.2217/fon-2020-0655. PMID 33251877. S2CID 227234713.
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  12. ^ "European Commission Approves Jemperli (dostarlimab), the First Anti-PD-1 Therapy Approved for Recurrent or Advanced dMMR/MSI-H Endometrial Cancer in Europe" (Press release). AnaptysBio Inc. 23 April 2021. Archived from the original on 17 July 2021. Retrieved 13 July 2021 – via GlobeNewswire.
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  16. ^ "FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors". U.S. Food and Drug Administration (FDA). 18 August 2021. Archived from the original on 18 August 2021. Retrieved 18 August 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  17. ^ "GSK receives FDA accelerated approval for Jemperli (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumors". GlaxoSmithKline (Press release). 17 August 2021. Archived from the original on 10 June 2022. Retrieved 18 August 2021.
  18. ^ "FDA Roundup: August 1, 2023" (Press release). U.S. Food and Drug Administration (FDA). 1 August 2023. Retrieved 2 August 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  19. ^ a b "FDA approves dostarlimab-gxly with chemotherapy for endometrial cancer" (Press release). U.S. Food and Drug Administration (FDA). 31 July 2023. Retrieved 2 August 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  20. ^ a b "FDA Roundup: August 2, 2024". U.S. Food and Drug Administration (Press release). 2 August 2024. Retrieved 8 August 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  21. ^ Cancer Research UK (30 July 2014), Diagram showing a monoclonal antibody attached to a cancer cell., archived from the original on 6 August 2022, retrieved 4 August 2022
  22. ^ "What is a Solid Tumor?". www.stjude.org. Archived from the original on 30 January 2022. Retrieved 4 August 2022.
  23. ^ Oaknin A, Tinker AV, Gilbert L, Samouëlian V, Mathews C, Brown J, et al. (November 2020). "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 Oncology. 6 (11): 1766–1772. doi:10.1001/jamaoncol.2020.4515. PMC 7530821. PMID 33001143. Archived from the original on 23 June 2022. Retrieved 1 August 2022.
  24. ^ Thompson B (5 June 2024). "100% of cancer patients cured long-term in 'remarkable' human trial". New Atlas. Retrieved 8 June 2024.
  25. ^ Cercek A, Bachet JB, Capdevila J, Starling N, Chen EX, Di Bartolomeo M, et al. (1 June 2023). "Phase II, single-arm, open-label study of dostarlimab monotherapy in previously untreated patients with stage II/III dMMR/MSI-H locally advanced rectal cancer". Journal of Clinical Oncology. 41 (16_suppl): TPS3639. doi:10.1200/JCO.2023.41.16_suppl.TPS3639. ISSN 0732-183X.
  26. ^ Moreno V, Roda D, Pikiel J, Trigo J, Bosch-Barrera J, Drew Y, et al. (May 2022). "Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non–small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial". Clinical Lung Cancer. 23 (7): e415–e427. doi:10.1016/j.cllc.2022.05.013. hdl:10668/22104. PMID 35729005. S2CID 249032757.
  27. ^ a b c d Costa B, Vale N (July 2022). "Dostarlimab: A Review". Biomolecules. 12 (8): 1031. doi:10.3390/biom12081031. PMC 9331682. PMID 35892341.
  28. ^ "Acute liver failure - Symptoms and causes". Mayo Clinic. Archived from the original on 27 June 2022. Retrieved 4 August 2022.
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  30. ^ Aghanejad A, Bonab SF, Sepehri M, Haghighi FS, Tarighatnia A, Kreiter C, et al. (May 2022). "A review on targeting tumor microenvironment: The main paradigm shift in the mAb-based immunotherapy of solid tumors". International Journal of Biological Macromolecules. 207: 592–610. doi:10.1016/j.ijbiomac.2022.03.057. PMID 35296439. S2CID 247461488.
  31. ^ a b c d e Clinical trial number NCT02715284 for "A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)" at ClinicalTrials.gov
  32. ^ a b Green AK, Feinberg J, Makker V (March 2020). "A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer". American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting. 40 (40): 238–244. doi:10.1200/EDBK_280503. PMID 32213091. S2CID 214682066.
  33. ^ Clinical trial number NCT03981796 for "A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)" at ClinicalTrials.gov
  34. ^ Clinical trial number NCT03602859 for "A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)" at ClinicalTrials.gov
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  36. ^ Mulcahy N (22 April 2021). "FDA Approves New Immunotherapy for Endometrial Cancer". Medscape. Archived from the original on 22 April 2021. Retrieved 23 April 2021.
  37. ^ a b "Drug Trial Snapshot: Jemperli". U.S. Food and Drug Administration (FDA). 13 March 2023. Archived from the original on 13 March 2023. Retrieved 13 March 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  38. ^ Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. (June 2022). "PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer". The New England Journal of Medicine. 386 (25): 2363–2376. doi:10.1056/NEJMoa2201445. PMC 9492301. PMID 35660797.
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  42. ^ "Statement On A Nonproprietary Name Adopted By The USAN Council - Dostarlimab" (PDF). searchusan.ama-assn.org. 24 September 2018. Archived (PDF) from the original on 24 September 2018. Retrieved 13 March 2023.
  43. ^ a b "Jemperli: Pending EC decision". European Medicines Agency (EMA) (Press release). 25 February 2021. Archived from the original on 23 April 2021. Retrieved 22 April 2021.
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  45. ^ a b c Bodurtha Smith AJ, Pena D, Ko E (February 2022). "Insurance-Mediated Disparities in Gynecologic Oncology Care". Obstetrics & Gynecology. 139 (2): 305–312. doi:10.1097/AOG.0000000000004643. PMC 8759538. PMID 34991133.

Further reading

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