Treatment Advances Underscore Need for MMR/MSI Testing in Advanced Endometrial Cancer

Bhavana Pothuri, MD

Although the rates of real-world testing for mismatch repair (MMR) status and microsatellite instability (MSI) status have increased over time for patients with advanced or recurrent endometrial cancer, inequities still exist in different patient subgroups. Furthermore, despite an uptick in testing rates, therapies informed by MMR/MSI testing have not been broadly implemented, according to Bhavana Pothuri, MD.

At the 2024 ASCO Annual Meeting, Pothuri and colleagues presented findings from a retrospective study that investigated real-world testing rates, treatment patterns, and outcomes based on MMR/MSI status in patients with advanced endometrial cancer diagnosed between January 1, 2018, and June 30, 2023. Findings revealed that 83% of patients (n = 1441) received MMR/MSI testing; however, an earlier diagnosis between 2018 and 2020 (adjusted odds ratio [aOR] vs 2021 to 2023, 1.5; 95% CI, 1.1-2.1), Black or African American race (aOR vs White, 1.6; 95% CI, 1.1-2.4), Hispanic or Latinx ethnicity (aOR vs non-Hispanic or Latinx, 2.0; 95% CI, 1.2-3.5), and lower socioeconomic index (aOR, 1.8; 95% CI, 1.1-30) were all predictors of lower testing rates.1

Despite the introduction of new immunotherapies to the endometrial cancer treatment informed by MMR/SMI status, Pothuri and colleagues noted that less than 50% of patients included in this retrospective study received these therapies, highlighting the need for further study regarding their implementation.

“In the endometrial cancer arena, we have identified many tumor targets, and we're making progress with newer FDA approvals. However, [there are still] a lot of unmet needs and reasons to continue trials to bring newer treatment options to our patients,” Pothuri explained.

In an interview with OncLive®, Pothuri discussed the rationale for examining the real-world rates of MMR/MSI testing in endometrial cancer, expanded on the findings from the retrospective study, and highlighted ongoing research in the endometrial cancer field.

Pothuri is a professor in the Department of Medicine and Department of Obstetrics and Gynecology at New York University (NYU) Grossman School of Medicine, director of Gynecologic Oncology Research, director of Gynecologic Oncology Clinical Trials, and medical director of the Clinical Trials Office at Perlmutter Cancer Center of NYU Langone Health in New York.

OncLive: What was the rationale for evaluating real-world testing rates for MMR/MSI in patients with advanced or recurrent endometrial cancer?

Pothuri: The reason that we wanted to [conduct this research] is that we know biomarkers, especially MMR and MSI, are important in treating [patients with] advanced and recurrent endometrial cancer. We know that single-agent checkpoint inhibitors pembrolizumab [Keytruda] and dostarlimab-gxly [Jemperli] are approved for [patients with] MMR-deficient [dMMR] endometrial cancer in the second line. The combination of a checkpoint inhibitor [pembrolizumab] and the TKI lenvatinib [Lenvima] is approved [in the second-line setting for patients with] MMR-proficient [pMMR] endometrial cancer.

[In this study], we wanted to characterize real-world testing and treatment patterns given these advances in endometrial cancer treatment. This was a study that utilized the Flatiron Health electronic database, and we identified 1441 patients with advanced or recurrent endometrial cancer [diagnosed] between 2018 and 2023. We evaluated biomarker testing in these patients—mainly MMR and MSI testing. We also looked at real-world treatment patterns in terms of these immunotherapy treatments.

What were the key findings from this study?

We found that 83% of patients received MMR/MSI testing, and that increased over time. However, we found that patients who were Black or Hispanic had a lower likelihood of being tested. We also noted that 55% of patients received HER2 testing, and that's important because HER2 is emerging as an important biomarker in the treatment of endometrial cancer. Surprisingly, we found that less than 50% of patients accessed these new [immunotherapies].

What are the implications of these real-world findings?

[These data] show us that we need to improve biomarker testing in all patients. If we don't test, [patients] don't get access to these newer therapies. We need to test all patients. The immunohistochemistry [IHC] testing for MMR proteins is done with the initial surgery, and this is also a screen for Lynch syndrome. This [testing] can identify other cancers that the patient may be at risk for, such as colorectal cancer, and they can initiate screening. We can also identify other members in the family [at risk for cancer] via cascade testing, and then those individuals may benefit from screening and prevention measures. There are implications with MMR testing, not just for access to newer targeted therapies, but also as a screen for Lynch syndrome.

What ongoing research could help expand treatment options for patients with advanced or recurrent endometrial cancer?

We've made a lot of progress in recurrent and advanced endometrial cancer. We have targeted therapies available. We have been able to move immunotherapy into the frontline with chemotherapy. Dostarlimab is now FDA-approved [in combination] with chemotherapy [for the frontline treatment of all patients with primary advanced or recurrent endometrial cancer, irrespective of MRR status]. We saw an approval for pembrolizumab [plus chemotherapy in the frontline setting in June 2024] based on the phase 3 KEYNOTE-868 trial [NCT03914612] data. These are great advances, but especially in the subset of patients with pMMR disease, we have more room to go in the frontline, and that's where our HER2-targeted ADCs may be valuable.

In addition, we have newer therapies such as selinexor [Xpovio], which works on the nuclear transport of P53 and other tumor suppressor genes. Data from the [phase 3] SIENDO study [NCT03555422] showed [selinexor] was effective in the maintenance setting after chemotherapy. [Updated] long-term results presented [as part of the 2024 ASCO Plenary Series] at the 2024 annual meeting showed the median PFS in patients whose disease was pMMR and TP53 wild-type was 39.5 months.² We haven't seen results like this in pMMR subgroups. It’s important that we get that trial finished so we can have access to another therapy to help our patients in the frontline maintenance setting.

There are a lot of other antibody-drug conjugates [(ADCs) under exploration]. If we move immunotherapy into the frontline, we need newer therapies in the second line. We have folate receptor α–targeting ADCs. We have HER2-targeted ADCs, and fam-trastuzumab deruxtecan-nxki (Enhertu) received a pan-tumor indication from the FDA in HER2-positive [IHC 3+] advanced solid tumors as an accelerated approval [in April 2024]. We're already starting to see some of the newer ADCs move into the clinic. We have TROP-2–targeted ADCs, as well as CDH6-targeted [agents]. There's lots of activity in [the ADC] space.

Endometrial cancer used to be a disease where I had 1 or 2 treatments that were effective. Now I have patients on their fourth or fifth line [of treatment], and that's because we have clinical trials and newer therapies that have been approved.

References

1. Pothuri B, Thaker PH, Tymejczyk O, et al. Real-world treatment patterns and outcomes by mismatch repair/microsatellite instability (MMR/MSI) status in patients (pts) with advanced endometrial cancer (aEC), 2018-2023. J Clin Oncol. 2024;42(16_suppl):5601-5601. doi:10.1200/jco.2024.42.16_suppl.5601
2. Makker V, Slomovitz B, Fidalgo AP, et al. Long-term follow up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer—a pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/Siendo study. J Clin Oncol. 2023;41(suppl 36):427956. doi:10.1200/JCO.2023.41.36_suppl.427956