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A randomized trial compared standard chemotherapy plus dostarlimab or placebo. Patients with mismatch repair–deficient tumors had 2-year progression-free survival of 61.4% with dostarlimab and 15.7% with placebo.

ObjectiveIn the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin–paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin–paclitaxel, with manageable toxicity, in patients with primary advanced or recurrent endometrial cancer. Here we report on patient-reported outcomes in the mismatch repair-deficient/microsatellite instability-high population, a secondary endpoint in the trial.MethodsPatients were randomized 1:1 to dostarlimab+carboplatin–paclitaxel or placebo+carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo monotherapy every 6 weeks for ≤3 years or until disease progression. Patient-reported outcomes, assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Endometrial Cancer Module, were prespecified secondary endpoints. A mixed model for repeated measures analysis, a prespecified exploratory analysis, was conducted to generate least-squares means to compare between-treatment differences while adjusting for correlations across multiple time points within a patient and controlling for the baseline value. Results are provided with 2-sided, nominal p values.ResultsOf 494 patients enrolled, 118 were mismatch repair-deficient/microsatellite instability-high. In this population, mean change from baseline to end of treatment showed visual improvements in global quality of life (QoL), emotional and social function, pain, and back/pelvis pain for dostarlimab+carboplatin–paclitaxel. Meaningful differences (least-squares mean [standard error]) favoring the dostarlimab arm were reported for change from baseline to end of treatment for QoL (14.7 [5.45]; p=0.01), role function (12.7 [5.92]); p=0.03), emotional function (14.3 [4.92]; p<0.01), social function (13.5 [5.43]; p=0.01), and fatigue (−13.3 [5.84]; p=0.03).ConclusionsPatients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer receiving dostarlimab+carboplatin–paclitaxel demonstrated improvements in several QoL domains over patients receiving placebo+carboplatin–paclitaxel. The observed improvements in progression free survival and overall survival while improving or maintaining QoL further supports dostarlimab+carboplatin–paclitaxel as a standard of care in this setting.Trial registrationClinicalTrials.gov NCT03981796

Background: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin–paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting. Objectives: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial. Design: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared with CP alone in patients with primary advanced or recurrent EC. Methods: Patients were randomized 1:1 to dostarlimab 500 mg, or placebo, plus CP every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg, or placebo, every 6 weeks for up to 3 years. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events, version 4.03. Results: The safety population included 487 patients who received ⩾1 dose of treatment (241 dostarlimab plus CP; 246 placebo plus CP). Treatment-emergent AEs were experienced by 100% of patients in both arms. TRAEs occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm. The most common TRAEs occurred at similar rates between arms and were mostly low grade. IrAEs occurred in 58.5% of patients in the dostarlimab arm and 37.0% of patients in the placebo arm. Dostarlimab- or placebo-related irAEs were reported in 40.7% of patients in the dostarlimab arm and 16.3% of the placebo arm. Conclusion: The safety profile of dostarlimab plus CP was generally consistent with that of the individual components. Dostarlimab plus CP has a favorable benefit–risk profile and is a new standard of care for patients with primary advanced or recurrent EC. Trial registration: NCT03981796. Plain language summary Safety of dostarlimab plus carboplatin-paclitaxel compared with carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer For many years, patients with primary advanced or recurrent endometrial cancer were treated with chemotherapy, specifically with a combination of carboplatin and paclitaxel. Recently, new treatments called immune checkpoint inhibitors have been used to treat endometrial cancer. Dostarlimab, an immune checkpoint inhibitor, is being tested to treat many types of cancer, including endometrial cancer. In the RUBY trial, a combination of dostarlimab plus chemotherapy was compared with chemotherapy alone as treatment for primary advanced or recurrent endometrial cancer. Results showed that patients treated with dostarlimab plus chemotherapy had a lower risk of their cancer becoming worse and a lower risk of dying. Results in this article describe the safety of dostarlimab plus chemotherapy compared with chemotherapy alone. All patients in the RUBY trial experienced at least one adverse event (an undesired effect that happens while receiving treatment or shortly after stopping treatment); most were determined to be caused by the cancer treatments. No differences in the frequency of the overall cancer treatment-related adverse events were seen in patients who received dostarlimab plus chemotherapy compared with those patients who received chemotherapy alone. Some patients experienced an immune-related adverse event. These are a specific type of undesired effect that can occur when patients are treated with immune checkpoint inhibitors. Immune-related adverse events occurred more frequently in patients who received dostarlimab plus chemotherapy than in those who received chemotherapy alone. Physicians were generally able to treat the immune-related adverse events, and only a low percentage of patients discontinued treatment because they experienced an immune-related adverse event. The types of adverse events seen were similar to a combination of those seen in patients who received dostarlimab alone or patients who received chemotherapy alone as treatment for endometrial cancer. Dostarlimab plus chemotherapy is a new standard of care for patients with primary advanced or recurrent endometrial cancer.

Six months of treatment with dostarlimab followed by nonoperative management in case of clinical complete response (cCR) is the new standard-of-care for patients with microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) locally advanced rectal cancer (LARC). The most recent update of the seminal phase II trial by Cercek et al. shows a cCR rate of 100% that allowed sparing chemoradiation and surgery to all included patients. Here, we present three clinical cases of patients with dMMR and MSI-H LARC treated with neoadjuvant dostarlimab at three Italian institutions with radiological evidence of disease progression while on treatment and discuss potential similarities among them to understand when and how this apparently rare event may occur.

Dostarlimab (JEMPERLI) is a PD-1 monoclonal antibody for the treatment of adult patients, with mismatch repair deficient (dMMR), recurrent or advanced endometrial cancer that has progressed on or following prior therapy with a platinum-containing regimen. As determined by an FDA-approved test this indication was granted rapid approval based on the rate of tumor response and the duration of the response. Continued approval for this indication is conditioned on further confirmatory trials demonstrating and documenting clinical benefit. In June 2022, the clinical trial NCT04165772 reported a 100% remission rate for rectal cancer. This clinical trial brought proof that we can match a tumor and the genetics of what is driving it, with therapy. This clinical trial continues to enroll patient and is currently enrolling patients with gastric, prostate, and pancreatic cancers. Dostarlamib is being recommended for rectal cancer. The focus of this review is to summarize the existing knowledge regarding Dostarlimab and explore the possibilities of mono- and combination therapies.

We develop a mathematical model to investigate endometrial cancer progression and treatment response under dostarlimab and chemotherapy using nonlinear ordinary differential equations ( s), and extend the framework to fractional differential equations ( s) with the Caputo derivative to capture memory effects. Existence and uniqueness of solutions are established via the Banach fixed-point theorem, and stability analysis is performed using the Routh–Hurwitz criteria. An optimal control framework is formulated to evaluate single and combined therapies under both and settings. Numerical simulations are carried out in MATLAB, employing the ode45 solver for systems and the fde12 solver for systems. Results indicate that dostarlimab monotherapy is more effective than chemotherapy alone, while combined therapy achieves the greatest reduction in cancer cells and the strongest activation of CD8+   T -cells. The model provides faster tumor reduction and higher immune activation, whereas the model achieves lower overall therapeutic cost by balancing tumor reduction with reduced drug usage. These findings highlight the potential of optimal control strategies particularly combined therapy for improving treatment outcomes in endometrial cancer management.

Dostarlimab-gxly, a monoclonal anti–PD-1 antibody, has been recognized as being effective for rectal cancer in patients whose tumors are mismatch repair deficient. Even though promising preliminary clinical results have been obtained, further critical appraisal of the efficacy, safety, and use of this drug among the broader spectrum of patients will be required. To bridge this knowledge gap, a systematic review and meta-analysis was conducted involving literature from PubMed, Scopus, and Web of Science from January 2018 to November 2024. The studies that were analyzed based on these primary metrics were complete clinical response (cCR), pathologic complete response (pCR), progression-free survival (PFS), overall survival (OS), and safety profile. The process of screening and filtering of abstracts from PubMed, Scopus, and Web of Science generated 1,246 abstracts, of which 28 were included in the final analysis of dostarlimab-gxly treated patients, who totaled 1,567. Results demonstrated a pooled complete response rate of 32.5%, with notably higher pCR rates in deficient mismatch repair (dMMR) tumors compared to mismatch repair-proficient tumors. Patients who received dostarlimab-gxly with radiotherapy or chemotherapy showed higher response rates but increased risks of toxicity. The most common adverse effects were fatigue, diarrhea, and immune-related colitis. The meta-analysis put emphasis on large improvements in PFS and OS compared to control treatments. Dostarlimab-gxly represents a possible alternative treatment strategy for rectal cancer, predominantly effective in the dMMR context. Given its generally balanced safety profile, it is paramount to remain ever vigilant for potential immune-related adverse events. Future work should concentrate on making combination therapies maximally effective, establishing predictive biomarkers, and performing extensive research to further reinforce these findings.

Immunotherapy is one of the four pillars of cancer treatment that has recently emerged as a beacon of hope for cancer patients. Certain immunotherapies, for example, immune checkpoint inhibitor therapy, monoclonal antibody therapy and chimeric antigen T-cell therapy have garnered extensive interest in response to their exceptional properties that activate the immune system to respond to cancer cells, inhibiting their progression. In the era of rapid development, dostarlimab, an anti-programmed cell death protein (PD-1) monoclonal antibody has mesmerized the medical profession by showing complete (100%) cure of patients with colorectal cancer. Not only this, the results obtained from clinical trials revealed no major side effects in any of the participants in the study. Dostarlimab has also shown promising results in endometrial cancer, ovarian cancer, melanoma, head and neck cancer, and breast cancer therapy. This review focuses upon the action of immunotherapy, extensively emphasizing the miraculous therapy to activate T-cells for cancer treatment. Based on this, we discuss major ongoing clinical trials and combination immunotherapies to enlighten future clinicians and researchers about the response of dostarlimab against various cancers.

Endometrial cancer (EC) treatment has been revolutionized by the integration of immunotherapy, particularly for molecularly defined subsets of patients. The classification of EC into DNA polymerase epsilon-mutated (POLE-mutant), mismatch repair-deficient (dMMR), p53-abnormal, and no specific molecular profile (NSMP) subtypes provides a critical framework for predicting response to immune checkpoint blockade. dMMR and POLE-mutant tumors, with their hypermutated and immunogenic phenotypes, demonstrate exceptional sensitivity to Programmed Death-1(PD-1) inhibitors such as pembrolizumab and dostarlimab in clinical trials. In contrast, overcoming the immunoresistant nature of NSMP and p53-abnormal EC requires innovative combinations, exemplified by the success of pembrolizumab plus the multitargeted tyrosine kinase inhibitor lenvatinib. Recent practice-changing clinical trials have further established combination strategies incorporating PD-1 blockade with chemotherapy as a new first-line standard for advanced disease, marking a paradigm shift in the management of advanced EC. This review synthesizes the mechanistic basis for these approaches, the compelling clinical evidence supporting approved therapies, and the frontier of investigational strategies, including cellular therapies, novel immune checkpoints, and rational combination regimens—aimed at expanding the benefit of immunotherapy to a broader range of patients with EC.

A recent phase III clinical trial (NCT03981796) evaluated the efficacy and safety of dostarlimab combined with carboplatin-paclitaxel (DOS-CP) compared to placebo combined with carboplatin-paclitaxel (PLB-CP) as a first-line treatment for advanced endometrial cancer (EC). The NCT03981796 trial demonstrated that DOS-CP significantly improved progression-free survival and overall survival of patients with advanced EC while maintaining an acceptable safety profile. However, DOS-CP is expensive and its cost-effectiveness has not been evaluated. This study aims to evaluate the cost-effectiveness of DOS-CP compared to PLB-CP as a first-line treatment for advanced EC from the perspective of the Chinese healthcare system. A Markov model with three health states was developed to evaluate the cost-effectiveness of DOS-CP as a first-line treatment for advanced EC. Clinical efficacy data were derived from the NCT03981796 trial, and drug costs were determined based on national tender prices. Other costs and utility values were obtained from published literature. The outcomes assessed included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of the model was assessed through one-way sensitivity analysis and probabilistic sensitivity analysis. In comparison to PLB-CP, the ICER of DOS-CP was $98,276.61/QALY for the overall population, $53,063.61/QALY for the dMMR subgroup, and $124,088.56/QALY for the pMMR subgroup. All of these ICER values were higher than the willingness-to-pay threshold of $38,201 per QALY. The most important variable that affected the results of the model was the discount rate, the cost of dostarlimab, and the utility value for progressive disease. From the perspective of the Chinese healthcare system, DOS-CP is unlikely to be a cost-effective first-line treatment option for advanced EC.