Emma L. Barber, MD, assistant professor, Gynecologic Oncology, the Northwestern University Feinberg School of Medicine, director, Robotic Surgery, the Division of Gynecologic Oncology, Northwestern Medicine, discusses how key data from the phase 3 KEYNOTE-775 study (NCT03517449) improved the identification of patient populations within endometrial cancer that benefit from second-line immunotherapy.

The multicenter, randomized trial evaluated the efficacy of pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) for patients with advanced endometrial cancer who progressed on prior platinum-based chemotherapy, Barber begins. Patients were randomized to receive either the immune checkpoint inhibitor (ICI) combination or to physician's

choice of doxorubicin or paclitaxel. The trial specifically included patients with mismatch repair–proficient (pMMR) and mismatch repair–deficient (dMMR) disease. Notably, patients with pMMR typically experience poorer responses to ICI treatment, Barber states. The study's primary end points were progression-free survival (PFS) and overall survival (OS).

Results demonstrated that the combination significantly improved both median PFS and OS vs physician's choice of chemotherapy in the overall population, Barber reports. In the pMMR cohort, median PFS was 6.6 months and median OS was 17.4 months with pembrolizumab and lenvatinib. Comparatively, patients with pMMR in the chemotherapy arm achieved a median PFS of 3.8 months and median OS of 12 months. Regarding the regimen's safety profile, 88.9% of patients receiving the experimental regimen experienced grade 3 or higher adverse effects compared with 72.7% of those who received chemotherapy.

These findings revolutionized the treatment of endometrial cancer, Barber says. The previous standard of care (SOC) for patients without a biomarker was chemotherapy alone, she explains. However, this trial supported the use of ICI combinations as a new second-line SOC for patients in this population, regardless of their MMR expression, Barber concludes.

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Emma L. Barber, MD, discusses how key data from the phase 3 KEYNOTE-775 study improved the identification of patient populations within endometrial cancer that benefit from second-line immunotherapy.

Dr Barber on the Significance of the KEYNOTE-775 Trial for the Second-line Treatment of Endometrial Cancer

Emma L. Barber, MD, assistant professor, Gynecologic Oncology, the Northwestern University Feinberg School of Medicine, director, Robotic Surgery, the Division of Gynecologic Oncology, Northwestern Medicine, discusses the role of molecular profiling for treatment considerations in patients with endometrial cancer.

When a patient presents with endometrial cancer, the first step is to test for 

mutations with an ultra-mutated phenotype are associated with a good prognosis, Barber begins. However, a patient’s histology and stage could take precedence over the presence of a POLE mutation in certain situations, Barber explains. For example, if patient with stage III endometrial cancer has a 

 mutation, chemotherapy could still be the preferred option. For patients with stage IB, grade 3 endometrial cancer, the current guidelines recommend vaginal brachytherapy or whole pelvic radiation; however, if a patient with stage IB, grade 3 harbors a 

 mutation, treatment could be de-escalated with vaginal brachytherapy, Barber notes. 

 mutation, molecular profiling could next be used to examine mismatch repair status. Patients with mismatch repair–deficient (dMMR) endometrial cancer have been shown to be more likely to respond to radiation therapy compared with chemotherapy, based on a reanalysis of data from the phase 3 PORTEC-3 trial (NCT004111380), Barber explains. Additionally, platinum-based chemotherapy remains the standard first-line therapy for patients with dMMR metastatic endometrial cancer; however, a clinical trial that adds a checkpoint inhibitor could be an options for some patients, and a single-agent checkpoint inhibitor could be considered if a patient is too sick to treat with chemotherapy, Barber notes.

 mutations could also affect treatment decisions. Although patients who are copy number–high or have 

 mutations tend to have a poorer prognosis, they may also respond better to chemotherapy, based on data from PORTEC-3, Barber notes. In patients with stage IB, grade 3 disease or isolated tumor cells in a sentinel lymph node with a 

 mutation, escalating care may be considered due to associations with a poorer prognosis, Barber concludes.

Emma L. Barber, MD, discusses the role of molecular profiling for treatment considerations in patients with endometrial cancer.

Dr. Barber on the Role of Molecular Profiling for Treatment Considerations in Endometrial Cancer

Emma Barber, MD, UNC Department of Obstetrics and Gynecology, UNC School of Medicine, UNC Lineberger Comprehensive Cancer Center, discusses the importance of the SCORPION trial in ovarian cancer.

The trial that Barber is excited to see the results of regarding neoadjuvant chemotherapy is the SCORPION trial that is currently ongoing in Italy, she explains. Criticisms of previous randomized controlled trials in this area have been that the surgery wasn’t as aggressive as it is done in the United States. Barber says there were low rates of optimal cytoreduction, and therefore there was lower survival.

In that trial, investigators have published their short-term morbidity outcomes, and are doing very aggressive surgery. The question will be, she adds, is whether that is associated with a survival benefit in the long term, because that will be new data to inform this question.

Dr. Barber on SCORPION Trial in Ovarian Cancer

Emma Barber, MD, UNC Department of Obstetrics and Gynecology, UNC School of Medicine, UNC Lineberger Comprehensive Cancer Center, discusses neoadjuvant chemotherapy lowering readmission rates for patients with ovarian cancer.

According to Barber, the use of neoadjuvant chemotherapy will reduce the readmission rate, even in populations that are at higher risks for readmission.

It is important to individualize treatments to decide what will be benefit the patient long-term, explains Barber.

Dr. Barber on Neoadjuvant Chemotherapy in Ovarian Cancer

Emma Barber, MD, UNC Department of Obstetrics and Gynecology, UNC School of Medicine, UNC Lineberger Comprehensive Cancer Center, discusses neoadjuvant chemotherapy versus surgery for patients with ovarian cancer. 

Physicians tend to think of neoadjuvant chemotherapy as reserved for people who are not going to do well with surgery, cannot have a resection, and have no gross residual disease when the tumor is removed, state Barber. 

In European randomized trials, the 2 approaches are surgery first, followed by chemotherapy, or chemotherapy first, followed by surgery, which have been shown to be equivalent. But in some patients with stage IIIC disease, even in those trials with patients with a smaller burden of disease, upfront surgery improves their survival. Even in that population, surgery first is going to be associated with more short-term morbidity.

Emma Barber, MD, UNC Department of Obstetrics and Gynecology, UNC School of Medicine, UNC Lineberger Comprehensive Cancer Center, discusses neoadjuvant chemotherapy versus surgery for patients with ovarian cancer.

Dr. Barber on Chemotherapy Versus Surgery for Ovarian Cancer

Emma Barber, MD, UNC Department of Obstetrics and Gynecology, UNC School of Medicine, UNC Lineberger Comprehensive Cancer Center, discusses surgical readmission and survival in patients with ovarian cancer.

There has been a big push to decrease readmissions to hospitals for patients due to the Affordable Care Act, explains Barber. This is challenging for patients with ovarian cancer due to the difference between short-term and long-term morbidity.

Aggressive surgery for these patients is associated with more complications but long-term outcomes. Neoadjuvant chemotherapy has been shown to decrease surgical morbidity, lowering the complication rates and risk of death.

Emma Barber, MD

Articles

Dr Barber on the Significance of the KEYNOTE-775 Trial for the Second-line Treatment of Endometrial Cancer

Dr. Barber on the Role of Molecular Profiling for Treatment Considerations in Endometrial Cancer

Dr. Barber on SCORPION Trial in Ovarian Cancer

Dr. Barber on Neoadjuvant Chemotherapy in Ovarian Cancer

Dr. Barber on Chemotherapy Versus Surgery for Ovarian Cancer

Dr. Barber on Surgical Readmission and Survival in Ovarian Cancer