Bhavana Pothuri, MD

Bhavana Pothuri, MD, professor in the Department of Obstetrics and Gynecology and Department of Medicine at NYU Grossman School of Medicine, and director of Gynecologic Oncology Clinical Trials at NYU Langone Health’s Perlmutter Cancer Center, discusses ongoing and potential studies of copy-number low and high subgroups of patients with endometrial cancer.

The combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) showed efficacy in some subgroups of endometrial cancer in the KEYNOTE-775 trial (NCT03517449). According to Pothuri, more research is needed for the copy-number low subgroup, which is correlated to lower-grade endometrioids that are responsive to hormonal therapy. Megestrol acetate, which is a common frontline option for these patients, was approved for treatment of endometrial cancer in 1971 and newer options could improve its fairly short progression-free survival (PFS).

Pothuri suggests that combinations of hormonal therapy with CDK4/6 inhibitors could be effective in this subgroup, as established by the phase 2 ENGOT-EN3/NSGO-PALEO study (NCT02730429) of palbociclib (Ibrance) plus the aromatase inhibitor letrozole.

The copy-number high group is also in need of targeted inhibitors based on specific 

 mutations, Pothuri says. More information is needed on the role of trastuzumab (Herceptin) following its demonstration of improved PFS with chemotherapy in a phase 2 trial (NCT01367002) of patients with advanced HER2-positive uterine serous carcinoma. Ongoing and future studies will offer better outcomes by targeting the key subgroups of patients with endometrial cancer.

 While [lenvatinib/pembrolizumab] is efficacious, can we look at this subset even further and look at the copy-number low group which is more of the endometrioids that are grade 1 that may be responsive to hormones? At present, all we have approved in terms of hormonal therapy is megestrol acetate, which was approved in 1971, with response rates that are between around 20%, but really short PFS, 2 and a half to 3 months. So, I think looking at that subgroup and further evaluating data, like the role of CDK4/6 inhibitors with hormonal therapy, like the PALEO study did, is going to be important.

Then also now branching to the other side and looking at the copy-number high [subgroup], can we look at specific 

 mutations and the role of trastuzumab or other combinations as well as the role of—we want inhibitors in that copy-number high subgroups. So I think we've definitely started to make progress in our understanding, but I think there's more to come. And we're already kind of seeing that as some of these studies are ongoing.

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Bhavana Pothuri, MD, discusses ongoing and potential studies of copy-number low and high subgroups of patients with endometrial cancer. 

Subgroup-Targeted Agents Are Needed for Endometrial Cancer

Bhavana Pothuri, MD, professor in the Department of Obstetrics and Gynecology and Department of Medicine at NYU Grossman School of Medicine, and director of Gynecologic Oncology Clinical Trials at NYU Langone Health’s Perlmutter Cancer Center, discusses the results of the KEYNOTE-775 trial (NCT03517449) in patients with advanced endometrial cancer in relation to microsatellite instability (MSI) status.

According to Pothuri, the randomized phase 3 KEYNOTE-775 trial of pembrolizumab (Keytruda) and lenvatinib (Lenvima) showed superior progression-free survival (PFS) and overall survival (OS) versus doxorubicin or paclitaxel in patients who had been previously treated with platinum-based chemotherapy. However, the combination of pembrolizumab and lenvatinib was approved for patients without MSI-high (MSI-H) status or a mismatch repair deficiency (dMMR) based on the study results.

Therefore, Pothuri says that it is important to test for MSI status using polymerase chain reaction or next-generation sequencing testing to identify patients who are microsatellite stable (MSS) and can receive a checkpoint inhibitor combination as second-line therapy.

 It's really important to know which patients are MSI-H, or which patients are MSS, and for MSS tumors, they are candidates for combination treatment with lenvatinib and pembrolizumab. And this is based on the data that were presented and published from KEYNOTE-775, which was a randomized phase 3 trial. The trial met its end points of both PFS, as well as OS. So really, these findings have led to the full approval of this combination in the treatment of recurrent endometrial cancer that's MSS. And that's why I say at minimum, it's really important to at least sort out those 2 subgroups: the MSS and MSI-H, or dMMR.

Bhavana Pothuri, MD, discusses the results of the KEYNOTE-775 trial in patients with advanced endometrial cancer in relation to microsatellite instability status.

Use of Inhibitor Combination Based on MSI Status in Endometrial Cancer

Bhavana Pothuri, MD, professor in the Department of Obstetrics and Gynecology and Department of Medicine at NYU Grossman School of Medicine, and director of Gynecologic Oncology Clinical Trials at NYU Langone Health’s Perlmutter Cancer Center, discusses the importance of determining biomarkers of patients with endometrial cancer to decide on treatment options.

According to Pothuri, there are several classifications of endometrial cancer, including microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR), that influence the efficacy of later lines of treatment following first-line platinum-based chemotherapy. Approximately 25% to 30% of patients with endometrial cancer have dMMR tumors. Immunohistochemistry can identify dMMR, while polymerase chain reaction (PCR) testing or next-generation sequencing (NGS) can determine the degree of microsatellite instability, Pothuri stated.

Dostarlimab (Jemperli), an anti-PD-1 monoclonal antibody, was approved by the FDA in April 2021 for patients with advanced or recurrent dMMR endometrial tumors following a 42.3% overall response rate (ORR) in the phase 1 GARNET trial (NCT02715284). The phase 2 KEYNOTE-158 trial (NCT02628067) of pembrolizumab (Keytruda) showed a 48% ORR in patients with heavily pretreated, advanced MSI-H or dMMR endometrial cancer, and the FDA is currently reviewing the application for use of pembrolizumab for this population based on these data.

For patients with advanced endometrial cancer that is not MSI-H or dMMR, a combination of pembrolizumab and lenvatinib (Lenvima) was approved in July 2021 based on the results of the phase 3 KEYNOTE-775 trial (NCT03517449).

 It's really important at minimum to classify tumors as either MSI-H, dMMR, or microsatellite stable. And this can be done with immunohistochemistry for the mismatch repair proteins, or MSI testing, which can be done by PCR testing of 5 distinct microsatellite loci, or through tumor NGS of the microsatellite loci and assessment of tumor mutation burden or TMB. The reason I say that this is important is because the treatment of first recurrence after chemotherapy has—the landscape and treatment paradigm has been completely evolving. And at present, if a tumor is MSI-H or dMMR, pembrolizumab, based on the KEYNOTE-158 data, or dostarlimab, which is based on the GARNET data, are 2 [immune] checkpoint inhibitors that have shown to be pretty efficacious with response rates of 45% to 50%. Both of these agents have received FDA accelerated approval.

Bhavana Pothuri, MD, discusses the importance of determining biomarkers of patients with endometrial cancer to decide on treatment options.

Bhavana Pothuri, MD | Authors

Articles

Subgroup-Targeted Agents Are Needed for Endometrial Cancer

Use of Inhibitor Combination Based on MSI Status in Endometrial Cancer

Role of Biomarkers in Choosing Advanced Endometrial Cancer Treatment