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CancerNetwork® spoke with Ritu Salani, MD, about the expanded 

FDA approval of dostarlimab-gxly (Jemperli) in combination with carboplatin/paclitaxel

 for patients with primary advanced or recurrent endometrial cancer.

Salani, a board-certified gynecologic oncologist and director of Gynecologic Oncology at the University of California, Los Angeles Health, discussed the clinical benefit the dostarlimab combination showed for patients with endometrial cancer, particularly those with mismatch repair-deficient (dMMR) tumors, in the 

 Data leading to the approval showed a statically significant progression-free survival (PFS) and overall survival (OS) benefit in patients with dMMR or microsatellite-instability high (MSI-H) endometrial cancer, as well as for those across the overall population.

Noting the significant impact dostarlimab had on survival benefit without significant added toxicity, which investigators reported as early as March 2023, Salani said it was “wonderful” to have a relatively short turnaround time in making the combination therapy available for patients with primary advanced or recurrent endometrial cancer. Beyond the particular benefit among patients with dMMR tumors, she expressed the need to improve outcomes for patients with mismatch repair-proficient (pMMR) or microsatellite stable (MSS) tumors, who did not experience as much of a pronounced benefit from treatment with dostarlimab.

Salani also addressed the role of immunotherapy in subsequent lines of treatment following frontline therapy. Being thoughtful about sequencing agents in this setting may be an optimal strategy to give patients the greatest survivability and quality of life. She also considered alternative treatment strategies for certain patients, such as those with pMMR tumors.

“The thing that is interesting is the study highlighted patients who had residual disease or measurable disease present when they were getting this therapy, and that seems to be where the most significant impact [is],” Salani said. “Seeing more data on the right selection of patients will be really important. There are other avenues of treatment for these patient populations, particularly the pMMR population, where you might see some other therapies that may have an equally profound impact as immunotherapy. Maybe that will lend itself to leading immunotherapy for second-line treatment, if needed.”

FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. News release. FDA. August 1, 2024. Accessed August 15, 2024. https://tinyurl.com/mtr6tpyp

Dostarlimab/Chemotherapy in Advanced or Recurrent Endometrial Cancer

Ritu Salani, MD, highlights data from the RUBY trial supporting the FDA approval of dostarlimab/chemotherapy for primary advanced endometrial cancer.

Optimizing Benefits Following Dostarlimab Approval in Endometrial Cancer 

Endometrial tumors form in the tissue that lines the uterus. The National Cancer Institute estimates that about 52,000 new cases of endometrial cancer are diagnosed each year, and about 8,600 women die each year of the disease. Today, we are speaking with Emma Rossi, MD, assistant professor of obstetrics and gynecology at Indiana University in Indianapolis, about the diagnosis and treatment of endometrial cancer.

Dr. Rossi, is endometrial cancer a tumor type that has distinct symptoms? 

 It is. Most endometrial cancer, and by that I mean 90% of women with endometrial cancer, presents with uterine bleeding that is abnormal. For a woman who has stopped having her period, usually for a woman of 50 or over, that means she has new onset bleeding that she has not had for many years, and if it occurs in younger women, it usually means that their regular periods are usually much more abnormal, either heavier or they may be bleeding in between periods. This is the classic way that the cancer is typically diagnosed initially, with abnormal uterine bleeding or new emergent bleeding after menopause. Very, very occasionally it is diagnosed in a routine Pap smear, but Pap smears are designed to detect cervical cancer and do not reliably detect uterine or endometrial cancer, although occasionally the shed uterine cancer cells can show up in the Pap smear.

Are there regular screening methods specifically for endometrial cancer? And are most women diagnosed with early-stage disease?

 Yes. About 70% of women are diagnosed with cancer confined to the uterus, which is stage I cancer and that is associated with good prognosis. The reason that most women are diagnosed at an early stage is because this type of cancer really does present with symptoms early in its course, and a woman who is clued into these symptoms typically communicates this with her doctor. There are no specific screening tests for endometrial cancer, not like a Pap smear for cervical cancer. But what we teach women, as clinicians, is to understand their bodies and their normal symptoms, particularly abnormal bleeding in a premenopausal woman, and to seek a doctor’s advice if there is a new pattern of bleeding-bleeding in between periods and an onset of heavier period bleeding. We also teach women to let their doctors know if they have bleeding postmenopause. There are some tests that have been looked at, such as using ultrasounds, but these would have to be internal ultrasounds, or doing biopsies of the endometrium, but these are both fairly invasive tests that we don’t think will be helpful for the general population. We only reserve these types of tests for women who are really at high risk for developing uterine or endometrial cancer.

Are there any known genetic and lifestyle risk factors that put women at risk for endometrial cancer?

 Certainly. The number one risk factor for uterine or endometrial cancer is obesity. And that’s an increasing problem across the United States and the Western world in general. As a result, we are seeing increasing rates of endometrial cancer incidence. Obesity can actually cause the uterine cancer because it is associated with changes in a woman’s hormones. The fat cells actually make hormonal material that stimulates the endometrial lining and can turn those cells into cancerous cells. Other medical conditions that are in some way associated with obesity, but not always, are diabetes and high blood pressure, which may cause an increased risk of endometrial cancer. There are some medications that increase a woman’s risk, such as estrogen therapy without progesterone therapy, which has a balancing-out effect on the estrogen therapy. Estrogen therapy alone increases risk. Medications such as tamoxifen, which is a common medication for breast cancer treatment, and prophylaxis treatment, which has a stimulatory effect on the endometrium, also result in an increased risk for endometrial cancer.

The number one genetic or inherited risk for endometrial cancer is a condition called Lynch syndrome. About 10% to 20% of women with endometrial cancer will have this cancer as a result of being born with a predisposition for cancer. This is Lynch syndrome, which is a condition in both men and women that causes an increased risk for colon cancer in men and for endometrial cancer and colon cancer in women, as well as some other cancers, such as breast, ovarian, and urinary tract cancers. Those women are not only likely to be diagnosed at a younger age in general, but often also are at a significant risk of being diagnosed with another cancer in another organ type. When we see women who have developed endometrial cancer at a very young age and with a strong family history of colon, endometrial, breast, or ovarian cancer, we begin to be concerned about the presence of Lynch syndrome in that family. We often test them for it, and then know that we have to screen them closely for other cancers.

What are the current methods for diagnosing endometrial cancer, and can you talk about the role of sentinel node biopsy?

 Right now endometrial cancer is diagnosed typically with a biopsy of the uterine lining, which usually occurs in a clinical office. A physician will perform the exam, which is very much like having a Pap smear. They will place a very thin tube into the uterine cavity and obtain some cells, which will include uterine lining cells that are then examined in a laboratory. That same test can also be done in an operating room if the woman cannot tolerate the office exam. Once endometrial cancer is diagnosed, the cancer needs to be staged and determined whether it has spread to other organs. The way we do that is less by using scans (although in some patients we will use CT scans to look to see if there is any obvious cancer spread), the best and recommended way to diagnose spreading of the cancer is in the operating room. For the surgery, we perform a complete hysterectomy, removing the uterus, tubes, cervix, and ovaries, and evaluate the lymph nodes to which endometrial or uterine cancer commonly spread to. The lymph node assessment used to be done predominantly with a big open incision in the abdomen, which is associated with some pretty significant post-operative complication rates because most patients with endometrial cancer are obese, and obesity in combination with a big open surgery is particularly risky for development of complications, especially wound complications.

So, what has been developed over time are a series of minimally invasive surgical techniques that have been shown in large randomized studies to be equivalent to the big open operation in terms of being able to remove the relevant tissues and diagnose cancer spread, but have much fewer surgical complications-particularly, after the surgery, better and faster recovery, improved quality of life, less infection, and less blood loss. We do these surgeries through small keyhole incisions or laproscopically with or without robotic assistance-these are the two most common ways in the United States to do these surgeries. And patients usually stay overnight in the hospital and recover well. We are decreasing the toxicity of the surgery, and we are also scaling down on removal of tissues. Traditionally, we would remove all the lymphatic tissue in the body that potentially might drain the cancer and look at these under the microscope, knowing that at least 70% of patients will have negative results.

Now, we try to stratify patients who are most at risk for lymph node disease and only expose those patients to a lymph node dissection, or alternatively, to a technique called a sentinel node biopsy. This is where we inject a dye into the cervix or the uterus after the patient has received anesthesia so they do not feel the injection, and then during the operation we can see the flow of the lymph fluid from the uterus, from the cancer, to where the cancer cells would have gone to if it had spread to the lymph nodes. We can see which individual lymph nodes are most likely to be involved in cancer and remove those individually, rather than removing all of the lymph node tissue that potentially could be involved in the cancer drain. This is a technique that is now routinely used in early-stage breast cancer and is now being explored for uterine and cervical cancers. And from preliminary studies, it is looking to be a very accurate technique in diagnosing cancer spread without missing anything important, and it has the potential to reduce the toxicities and complications associated with surgery.

Lastly, what is the standard course of intervention for women with early-stage endometrial cancer?

 The standard course would be a diagnosis made through a biopsy, typically in the clinical office. At that point, the clinician may decide to do some preoperative evaluation. Depending on the patient and the biopsy results, this may be a CT scan or blood work. Ultimately, if the cancer looks like it is confined to the uterus, that patient usually needs surgery to confirm the diagnosis and remove the organ that has cancer. The patient is scheduled for an operation, which is now typically a minimally invasive hysterectomy and lymph node evaluation.

Thank you so much for joining us today, Dr. Rossi.

In this interview we discuss the diagnosis and treatment of endometrial cancer, a gynecologic cancer that forms in the tissue lining the uterus.

Diagnosis and Treatment of Endometrial Cancer

Data from the phase 1/2 RAINFOL-01 trial support the agency’s regulatory decision on rinatabart sesutecan in advanced endometrial cancer.

Rina-S Earns FDA Breakthrough Therapy Designation in Endometrial Cancer

Factors such as language spoken, social vulnerability index characteristics, and insurance type were found to alter endometrial cancer diagnoses and led to worse outcomes. 

Social Determinants of Health Negatively Affected Endometrial Cancer Diagnosis

Patients who had recurrence in the radiation field experienced similar responses vs those with recurrence outside the radiation field.

Immunotherapy Sustains Responses in Radiated Endometrial/Cervical Cancer

The adverse effect profile of abemaciclib plus hormonal therapy was comparable with prior reports of CDK4/6 inhibitors.

Abemaciclib Plus Hormonal Therapy Shows Promising Efficacy in LGSOC/EEC

The median PFS in patients with pMMR TP53 wild-type endometrial cancer was 39.5 months with selinexor and 4.9 months with placebo. 

Selinexor Maintenance Improves PFS in TP53 Wild-Type Endometrial Cancer

Select comorbidities, ECOG status, and the receipt of radiation were among the differences between a real-world cohort and the RUBY trial population.

Real-World Data Support Dostarlimab Combo Benefit in RUBY Trial 

CancerNetwork® spoke with Taliya Lantsman, MD, a hematology and oncology fellow at Beth Israel Deaconess Medical Center, about considerations for sequencing dostarlimab-gxly (Jemperli) and chemotherapy with other therapeutic options in patients with advanced endometrial cancer, as well as key differences between the real-world analysis she conducted and those of the

Lantsman presented a real-world, retrospective analysis on the efficacy and safety of dostarlimab combination therapy in advanced endometrial cancer at the 

2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO)

Lantsman began by iterating the survival benefit of dostarlimab with platinum-based chemotherapy, a combination that has demonstrated enhanced progression-free survival (PFS) and overall survival (OS) in patients with advanced endometrial cancer. She further expressed that she recommends dostarlimab with chemotherapy based on phase 3 RUBY trial findings.

Then, despite emphasizing some differences between the real-world cohort in the analysis she presented at SGO and the phase 3 RUBY trial population, she explained that one key difference was a disparity in the inclusion of patients with comorbidities on respective studies. Furthermore, her trial included patients with an ECOG performance status of 2, which the phase 3 RUBY trial did not assess.

Finally, Lantsman expressed that the most prominent difference between the analysis she conducted and the RUBY trial was regarding the receipt of radiation for stage III disease, which was done in her analysis but not in the RUBY trial.

At this point, following what RUBY demonstrates––that adding dostarlimab to upfront platinum-based chemotherapy demonstrates a PFS and OS benefit for patients [with advanced endometrial cancer]—I would continue to recommend, based on those [RUBY] findings, to use that treatment.

We found a lot of similarities [between the real-world population and patients enrolled on the RUBY trial]. Some differences [include the fact] that we were looking at patients who had other comorbidities who may not have been included in this trial. We also included patients who had an ECOG [performance status score of] 2, which was not evaluated in the trial. The biggest difference that we saw between our patients and the trial was what we [were] doing about radiation. Our patients did, in fact, receive radiation if they [had] stage III disease.

Powell MA, Auranen A, Willmott LJ, et al. Overall survival among patients with primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in the ENGOT-EN6-NSGO/GOG-3031/RUBY Trial. Presented at: Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.

Lantsman T, Jia L, Edmiston C, Shea M, Widick P. Real-world RUBY: safety and efficacy of combination chemotherapy plus dostarlimab in advanced endometrial cancer. Presented at: 2025 SGO Annual Meeting on Women’s Cancer; March 14-17, 2025; Seattle, WA. Abstract 1280.

Conference

Ritu Salani, MD, discussed investigational endometrial cancer treatment options for patients with varying subtypes of endometrial cancer.

Selinexor, HER2-Targeting ADC May Provide Options for Endometrial Cancer

CancerNetwork® spoke with Ritu Salani, MD, a board-certified gynecologic oncologist and director of gynecologic oncology at the University of California, Los Angeles Health, about other developments in endometrial cancer that have the potential clinical implications. In particular, a mismatch repair proficient (pMMR) 

 wild-type maintenance strategy and antibody-drug conjugates (ADCs) were discussed.

Salani noted early data for selinexor (Xpovio) in the treatment of patients with pMMR 

 wild-type tumors. Although she said treatment with selinexor was being evaluated in a clinical trial, she expressed excitement for the therapy as it could serve as an alternative option to frontline immunotherapy.

3 ENGOT-EN5/GOG-3055/SIENDO (NCT03555422)

 trial, a statistically significant PFS benefit for selinexor vs placebo was found for patients with advanced or recurrent endometrial cancer.

 .049). Furthermore, median PFS was 13.7 months with selinexor vs 3.7 months in placebo among patients with 

Salani also highlighted upcoming developments in both TROP2 ADCs and folate receptor–alpha targets, which she believes may help inform patient outcomes in later lines of therapy. Particular emphasis was given to HER2-targeting ADCs in combination with chemotherapy, which has shown compelling data in small trials to amplify HER2 expression. Salani concluded that these options help to optimize patient outcomes by providing individualized care based on tumor profile vs cancer type.

trial results found that fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) achieved a 57.5% (95% CI, 40.9%-73.0%) investigator-assessed overall response rate in patients with endometrial cancer.

 Additionally, the investigator-assessed median PFS was 11.1 months and the duration of response was not reached in the endometrial cohort.

[W]e have a target for a maintenance strategy, particularly for the pMMR 

 wild-type called selinexor, which has had some provocative early data. It is being validated in a study right now. I am excited for that, because that might be a way to strategize which patients get immunotherapy up front and which patients may benefit from this alternative option.

There are other new agents. I was talking about that needs gap—about creating that second-line gap in therapy. There are exciting things on the horizon, including TROP2 antibody-drug conjugates [ADCs] and folate receptor–alpha targets, which are helping to inform how patients may do in these later lines of therapy. We also have HER2 [ADCs], which [have] some provocative or compelling data in small numbers; that's being further evaluated.

We have ongoing trials looking at HER2 expression or amplification in combination with chemotherapy, so trastuzumab (Herceptin) in combination with chemotherapy. The thing that this really highlights is that the treatment is shifting from “you have endometrial cancer” to “you have this tumor profile,” and really focusing on a personalized approach for patients, which may optimize outcomes and minimize toxicities from unnecessary or ineffective therapies.

Vergote I, Pérez-Fidalgo JA, Hamilton EP, et al. Oral selinexor as maintenance therapy after first-line chemotherapy for advanced or recurrent endometrial cancer. 

 2023;41(35):5400-5410. doi:10.1200/jco.22.02906

Meric-Bernstam F, Makker F, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. 

 2023;42(1):47-58. doi:10.1200/JCO.23.02005

The second interim analysis of the phase 3 RUBY trial found the safety profile was consistent with the first interim analysis and no new deaths due to AEs were observed.

Comparable Safety Observed in Dostarlimab for Endometrial Cancer Subtypes

No new safety signals or significant toxicities were found in treatment with dostarlimab-gxly (Jemperli) combined with carboplatin/paclitaxel in patients with primary advanced endometrial cancer, according to Ritu Salani, MD.

CancerNetwork® spoke with Salani, director of Gynecologic Oncology at the University of California, Los Angeles Health, about the 

phase 3 RUBY trial (NCT03981796) findings

 which evaluated dostarlimab in combination with carboplatin/paclitaxel in patients with primary advanced or recurrent endometrial cancer, following the 

recent FDA expanded approval for the drug in this population

Despite repeated use of immunotherapy and chemotherapy across different disease sites, Salani noted that nuances that occur with these treatment types and toxicities should be readily recognized and managed. Additionally, monitoring for thyroid disease and adrenal insufficiency, as well as less common toxicities, are important to ensure easy implementation of immunotherapy and chemotherapy and toxicity management.

The second interim analysis from the RUBY trial found the safety profile was consistent with the first interim analysis and no new deaths due to adverse effects (AEs) were observed.

 For this analysis, the median duration of treatment was 43.0 weeks (range, 3.0-192.6) in the dostarlimab arm and 36.0 weeks (range, 2.1-193.1) in the placebo arm.

Across the overall population, any-grade treatment-emergent adverse effects (TEAEs) relating to dostarlimab were noted in 84.2% vs 74.4% relating to the placebo. Furthermore, grade 3 or higher TEAEs related to dostarlimab in 36.1% vs 19.9% related to placebo.

Grade 1 or 2 AEs occurring in 40% or more of patients were mostly related to chemotherapy, including anemia in the placebo plus carboplatin-paclitaxel arm, which was grade 2 or 3 in most patients. Serious TEAEs occurred in 19.5% and 12.2% in the dostarlimab and placebo arms, respectively, with discontinuation rates occurring in 19.1% and 8.1% of patients, respectively.

There is not anything that stands out. We have been using immunotherapy and chemotherapy for several years in different disease sites. We have all found that there are always some nuances with it, and it is important to be able to recognize and manage toxicities readily. There are no new safety signals that we are seeing, particularly in the endometrial cancer population, but monitoring for thyroid disease and adrenal insufficiency and then having acuity for other less common toxicities, even like myocarditis or cardiac implications, pneumonitis; things of that sort are important. We will all find that these therapies are easy to implement and manage with appropriate monitoring.

FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. News release. FDA. August 1, 2024. Accessed August 16, 2024. https://tinyurl.com/mtr6tpyp

Powell MA, Bjørge L, Willmont L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. 

 2024;35(8):728-738. doi:10.1016/j.annonc.2024.05.546

The phase 3 RUBY trial evaluated dostarlimab in combination with carboplatin/paclitaxel in patients with primary advanced or recurrent endometrial cancer.

Dostarlimab Benefits Appear More Pronounced in dMMR Endometrial Cancer

Although a statistically significant progression-free survival (PFS) benefit was seen with dostarlimab-gxly (Jemperli) in combination with chemotherapy for primary advanced endometrial cancer in patients with mismatch repair deficient tumors (dMMR), more can be done to improve outcomes for those with mismatch repair proficient (pMMR) disease, according to Ritu Salani, MD.

CancerNetwork® spoke with Salani, a board-certified gynecologic oncologist and director of Gynecologic Oncology at the University of California, Los Angeles Health, about the 

Salani explained that the dMMR population had the most pronounced PFS impact with the potential to cure patients from their disease when treated with the combination therapy. Additionally, Salani suggested that treatment using other biomarkers may produce more meaningful outcomes for patients in the pMMR setting.

Topline data showed that across the overall trial population, treatment with dostarlimab/chemotherapy produced statistically significant improvements in overall survival (OS; HR, 0.69; 95% CI, 0.54-0.89; 

 = .002) and progression-free survival (PFS; 95% CI, 0.64; 95% CI, 0.51-0.80; 

Previous findings from an exploratory analysis comparing outcomes across different tumor types found a significant OS benefit in dMMR tumors, with deaths occurring in 22.6% of the dostarlimab group and 53.8% of the placebo group; data for OS reached 40% maturity at the time of the analysis (HR, 0.32; 95% CI, 0.17-0.63; 

 = .0002). At 55% OS maturity for pMMR tumor types, deaths occurred in 50.5% and 59.2%, respectively (HR, 0.79; 95% CI, 0.60-1.04; 

The dMMR population, which are patients who have deficiency in their mismatch repair proteins, really had the most pronounced impact in PFS, and we’re seeing that trend for prolonged periods of time; we may be curing many of these patients. I think the pMMR data from the RUBY trial leaves a little bit more to be desired. Although we see a PFS benefit and a clinical trend towards overall survival, it is not statistically significant. It just reminds us that we need to do better for these patients. There are still some opportunities to capitalize on tumor profiles or other biomarkers that may be more meaningful.

Data May Support Pembrolizumab/Chemo as New SOC in Endometrial Cancer

Eskander SGO 1

Findings may help usher in pembrolizumab (Keytruda) plus chemotherapy as a treatment option for patients with endometrial cancer and establish a “new standard” for this population, said Ramez N. Eskander, MD.

Although immature, overall survival data from the KEYNOTE-868 trial may support the use of pembrolizumab plus chemotherapy in patients with endometrial cancer.

Endometrial Cancer

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