Naumann Dives into Case-by-Case Decision-Making in Ovarian and Endometrial Cancer

R. Wendel Naumann, MD

In an interview with OncLive^®, R. Wendel Naumann, MD, highlighted 3 case studies of patients with various endometrial cancer histologies that were presented by his colleagues at an OncLive State of the Science Summit (SOSS) on gynecologic oncology, which he chaired, and expanded further on how these case studies exemplify notable developments in the management of endometrial cancers. Such advancements include the tailored use of targeted therapies for patients with specific molecular profiles, and the increasing use of immunotherapy combinations as a standard approach in recurrent or advanced serous endometrial carcinoma.

“The number of trials in endometrial cancer that have read out in the last couple of years has been significant, [though] there are still gaps in our knowledge that will hopefully be answered by additional trials,” Naumann said in the interview, which followed the SOSS event.

Practice-changing studies in the space include both the phase 3 ENGOT-EN6-NSGO/ GOG-3031/RUBY (NCT03981796) and NY-GY018 (NCT03914612) trials investigating upfront dostarlimab-gxly (Jemperli) and pembrolizumab (Keytruda), respectively, in primary or recurrent endometrial cancer. The addition of these immunotherapies to treatment with carboplatin/paclitaxel improved progression-free survival (PFS) vs chemotherapy alone, particularly in patients with mismatch repair (MMR)–deficient (dMMR) and microsatellite instability–high disease.^1,2

Naumann, who is a gynecologic oncologist at Atrium Health Levine Cancer Institute in Charlotte, North Carolina, goes on to detail an additional 2 case studies in platinum-resistant ovarian cancer in a concurrent interview.

OncLive: What factors informed treatment decision-making for the 77-year-old patient with serous endometrial cancer, according to the third case study that Allison Puechl, MD, presented?

Naumann: This patient had high-grade serous endometrial carcinoma. These are generally p53-mutated [tumors]. Approximately 40% of these patients will express HER2 as a target, which is an actionable target, but unfortunately, this patient did not express HER2. She was treated with standard chemotherapy and had a good response. However, as many of these patients with advanced serous uterine cancers [do, she] eventually progressed.

[Standard] therapies have changed quite a bit in the HER2-positive, high-grade serous [endometrial cancer] space. We now add immunotherapy to chemotherapy based on data from both the NRG-GY018 and RUBY trials. Patients with p53-mutated cancers do [experience] a significantly better response rate with the addition of immunotherapy [vs chemotherapy alone.] Now, this patient didn’t receive immunotherapy in the up-front setting—it was used in the recurrent setting, where she was treated with lenvatinib [Lenvima] and pembrolizumab.

We don’t have a lot of [data] with this combination in patients with p53-mutated or MMR-proficient [pMMR] disease if they received immunotherapy up front, but this is still our best option for these patients when they recur. There are some ongoing clinical trials looking at different options for patients [in this setting], but the combination of lenvatinib and pembrolizumab is likely the best treatment option [for] this patient.

In Dr Puechl’s next case study, what up-front approach would you recommend for the 90-year-old patient with endometrioid adenocarcinoma?

This patient was an older patient with high-grade endometrial carcinoma [who expressed] wild-type p53. She had estrogen receptor–positive [and] progesterone receptor–positive disease even though the cancer was high grade. This is what we refer to as the nonspecific phenotype or the endometrioid high-grade phenotype. These patients [experience] benefit with the combination of chemotherapy and immunotherapy, although that benefit [is lower] than that observed for patients with dMMR [tumors] and patients with pMMR disease [with] p53-positive [tumors.]

We’re using up-front immunotherapy in this case, [and] the lenvatinib and pembrolizumab combination is probably our best option here. There are some ongoing trials that are looking at different options for these patients and [one of these] is selinexor [(Xpovio), which is being assessed as] a maintenance therapy after initial chemotherapy. If patients [with this tumor type] express HER2, we do have the option of fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd] in patients with 3+ HER2 expression [based on immunohistochemistry (IHC)], as per a tumor-agnostic approval that was recently granted to T-DXd. [We’re seeing] dramatic results with those compounds in patients who highly express HER2.

As per Dr Puechl’s final case study, what approaches should clinicians consider for a patient with advanced-stage serous carcinoma?

This patient was a 64-year-old woman with advanced-stage, high-grade serous carcinoma. Unlike the other case of a patient with HER2-nonexpressing disease, this patient had high HER2 expression of 3+, so she was a candidate for T-DXd. T-DXd is one of the most exciting drugs we have out there. It’s an ADC with a topoisomerase-I inhibitor [payload].

In patients with IHC 3+ endometrial cancer, we saw a high response rate of [approximately] 83% and a significant duration of [approximately] 2 years [with T-DXd] in this patient [population. This is] promising for patients who have advanced recurrent disease, particularly when they progress on other therapies. In this case, [the patient] had already been treated with chemotherapy as well as lenvatinib and pembrolizumab. [Notably,] the IHC staining [to identify HER2 expression] is performed similarly to the gastric staining as opposed to the breast staining that we traditionally use for trastuzumab [Herceptin] alone.

Why is it important to facilitate these case discussions in the gynecologic oncology field?

Immunotherapy plus chemotherapy in the up-front setting is likely the biggest [topic of conversation] for almost all patients. [However], our success has now led to some uncertainty in the recurrent setting because the types of treatments that patients have been exposed to are different from what patients [have had] in the recurrent setting, particularly with respect to lenvatinib and pembrolizumab. We [still] have a lot of discussions regarding who should be treated with lenvatinib and pembrolizumab. [The combination is] our best option in the second-line setting, but [the trials whose data support its use] included patients who were not [previously exposed to a] PD-1 [inhibitor]. Therefore, we don’t know how effective it’s going to be [in this patient subgroup].

[Lastly,] we have a new option for our patients with high HER2 expression, and there are other ADCs out there that look promising and [will likely] be used in the endometrial space. Hopefully, the trials [evaluating these agents] will mature in the future.

References

1. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2216334
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2302312