Endometrial cancer, the most prevalent uterine cancer subtype, is the fourth most common cancer among women worldwide. In 2020, there were 97,370 additional deaths and 417,367 additional diagnoses across the globe. Incidence and fatality rates of endometrial cancer are rising globally and are expected to continually rise in the coming decades .
Advanced endometrial cancer has a poor prognosis with a 5-year survival rate of less than 20% and limited treatment options. Therefore, early-stage diagnosis of endometrial cancer and implementation of cutting-edge treatments like immunotherapy could lead to better long-term patient outcomes. For women with advanced endometrial cancer, immunotherapy is expected to become a more common treatment. However, recent clinical trials have demonstrated a significant increase in progression-free survival in endometrial cancer patients treated with immune checkpoint inhibitors in combination with conventional chemotherapy .
Dostarlimab, an immune checkpoint inhibitor is approved to treat endometrial cancer
Immune checkpoint inhibitors are a class of drugs that inhibits checkpoint proteins like programmed death 1 (PD-1, on T cells) and programmed death ligand 1 (PD-L1, on tumor cells). When PD-L1 binds to PD-1, T-cells are prevented from destroying tumor cells in the body. By inhibiting the binding of PD-L1 to PD-1, immune checkpoint inhibitors (anti-PD-L1 or anti-PD-1) can help T-cells to attack tumor cells. Endometrial cancer and other gynecological cancers are currently treated with checkpoint inhibitors like PD-1 and PDL-1 inhibitors.
Dostarlimab, one of such checkpoint inhibitors, has been approved in Europe and the United States for use as a monotherapy in adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has spread during or after receiving a platinum-containing regimen. The approval has been based on the preliminary findings from the GARNET trial [2,3].
How dostarlimab works?
Dostarlimab is a humanized monoclonal antibody that binds to PD-1 with high affinity, inhibiting binding to PD-L1 and PD-L2, allowing the immune system to combat the tumor. Mutations in endometrial cancer cause mismatch repair deficiency (dMMR), which can increase the expression of PD-L1 and PD-L2. Microsatellite instability (MSI) or dMMR is involved in roughly 13–30% of recurrent endometrial cancer, and 90% of dMMR endometrial malignancies are caused by somatic mutations. PD-1 is expressed by the T-cells and upon activation it prevents proliferation and the generation of cytokines. Thus, the interaction of these ligands with PD-1 serves as an immunological checkpoint that downregulates the anti-tumor immune response [2,3].
Dostarlimab is being developed by GlaxoSmithKline (GSK) under a license from AnaptysBio Inc for the treatment of various cancers, including endometrial cancer, ovarian cancer, colorectal cancer, head and neck cancers, small cell and non-small cell lung cancer, fallopian tube cancer, pancreatic cancer, squamous cell cancer, and many more.
Preclinical testing of dostarlimab revealed a favorable anti-PD-1 antibody profile, with efficient binding to PD-1 and antagonizing interactions with PD-L1 and PD-L2. The binding profiles of earlier approved PD-1 therapies including Nivolumab, Pembrolizumab, and Cemiplimab are similar, according to the preclinical research [2,3].
Dostarlimab in combination with other therapies is under trial
Dostarlimab is being evaluated for its interaction with existing standard of care (radiotherapy) and one or more chemotherapeutic drugs, including carboplatin, paclitaxel, cisplatin, niraparib, cabozantinib (VEGF inhibitor), and many more. Most of these investigations are still ongoing and some of them are described below:
Phase III, randomized trial evaluating the efficacy and safety of dostarlimab versus carboplatin-paclitaxel in patients with advanced endometrial cancer or MMR-deficient relapse [Identifier: NCT05201547].
Phase II study tested the effectiveness of the combination of radiation and dostarlimab in women with MMR-D/MSI-H endometrial cancer who received surgery [Identifier: NCT04774419].
Phase I trial investigated the safety and tolerability of chemoradiation, chemotherapy, and dostarlimab for stage III-C, node-positive, endometrial cancer [Identifier: NCT05819892].
Participants with recurrent or primary advanced (Stage III or IV) endometrial cancer were enrolled in the phase III RUBY trial (part 2), which was designed to compare the effectiveness and safety of dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib [Identifier: NCT03981796].
The encouraging results from these trials will add more evidence to the safety and effectiveness of both dostarlimab monotherapy and combination therapy in patients with recurrent and advanced endometrial cancer.
Are dostarlimab unlocking new possibilities?
Dostarlimab has shown encouraging results in adult patients with recurrent or advanced endometrial cancer with mismatch repair defects. Additional studies are required to utilize immune checkpoint inhibitors in the first-line metastatic setting and early-stage malignancies, as well as to comprehend the fundamental and secondary causes of immunotherapy resistance. Future clinical trials would focus on safety analyses to determine categories with higher risks.
1. Sung, H. et al. 'Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries'. CA Cancer J Clin. (2021) 71(3), 209–249. DOI: 10.3322/caac.21660.
2. Costa, B. et al. 'Dostarlimab: A Review'. Biomolecules. (2022) 12(8), 1031. DOI: 10.3390/biom12081031.
3. Singh, V. et al. 'Dostarlimab as a Miracle Drug: Rising Hope against Cancer Treatment'. Biosensors. (2022) 12(8), 617. DOI: 10.3390/bios12080617.