Clinical Trials in Endometrial Cancer Need Improved Diversity to Address Rising Mortality Rates

Bhavana Pothuri, MD

As novel treatments are developed and enter the treatment paradigm for patients with endometrial cancer, improved representation of minority populations in clinical trials is required to ensure the needs of all patients are properly addressed, according to Bhavana Pothuri, MD.

“Endometrial cancer is a disease that is increasing in both incidence and mortality. The rise in incidence is related to the obesity epidemic, as well as the incidence of increasing higher-risk histologic subtypes that are now seen in greater proportion in Black patients. That is also contributing to the increase in mortality,” Pothuri said in an interview with OncLive^® following an OncLive State of the Science Summit^™ on gynecologic cancers, which she chaired. “[We need to] be thoughtful about inclusivity in clinical trials, ensuring that we represent Black, Hispanic, and other underrepresented patients.”

In the interview, Pothuri expanded on challenges that still need to be addressed for the treatment of patients with endometrial cancer, highlighted potential practice-changing data from the phase 3 NRG-GY018 (NCT03914612) and RUBY (NCT03981796) trials,^1,2 detailed the evolving role of PARP inhibitors for patients with ovarian cancer, and touched on key emerging data from trials for patients with cervical cancer. Pothuri is a professor in the Department of Obstetrics and Gynecology and the Department of Medicine at the New York University (NYU) Grossman School of Medicine, and director of Gynecologic Oncology Research, medical director of the Clinical Trials Office, and director of Gynecologic Oncology Clinical Trials at NYU Langone’s Perlmutter Cancer Center.

OncLive: What were the key findings presented from the RUBY and NRG-GY018 trials?

Pothuri: Coming back from the 2023 Society of Gynecological Oncology [SGO] Annual Meeting, the data presented were practice changing, and we all left the meeting very energized. [These] studies [include] the RUBY trial, which looked at the addition of dostarlimab—a checkpoint inhibitor—to the standard chemotherapy backbone [of] paclitaxel and carboplatin. This was a randomized, phase 3 trial, which showed that there was benefit with the addition of the immunotherapy agent. [Regarding progression-free survival], this trial showed a hazard ratio [HR] of 0.28 [95% CI, 0.16-0.50; P < .001] in the mismatch repair–deficient [dMMR] subgroup of [patients with] endometrial cancer [for dostarlimab plus chemotherapy vs chemotherapy alone].

The other [pivotal] trial that was presented was NRG-GY018 by Ramez N. Eskander, MD, [of University of California, San Diego Health]. That was also a large, randomized trial and had 2 cohorts that were powered statistically to determine if there was a difference [between pembrolizumab plus chemotherapy vs placebo plus chemotherapy]. In the dMMR subgroup, there was a clinically meaningful and statistically significant improvement in PFS [HR, 0.30; 95% CI, 0.19-0.48; P < .00001]. In the mismatch repair–proficient [pMMR] cohort, [there was also a PFS] benefit [HR, 0.54; 95% CI, 0.41-0.71; P < .00001].

The nice thing about [NRG-GY018] was that [there were] 2 separate statistically powered subgroups, and this trial showed that there was benefit in both cohorts. Follow-up was short, and we need to see the data as they continue to mature.

Based on the results of these studies, what could the findings mean for the potential use of immunotherapy in earlier settings for patients with endometrial cancer?

We're always looking at ways to improve the outcomes of our patients, and if we can incorporate an agent in earlier lines of therapy, we have a greater chance of achieving cure. The data that we're seeing, especially in the dMMR subgroups, point to us being able to achieve that.

We need longer-term data to show improvements in overall survival [OS]. That will come with time, and the RUBY trial is going to be the only trial that will show us OS data, because NRG-GY018 unblinded once the primary end point of PFS was met.

What treatment challenges still exist for patients with endometrial cancer, and how could these unmet needs be addressed with future studies?

Paying particular attention to the higher-risk histologic subtypes is important, and increasing accrual of diverse patients to clinical trials [is vital] so that [the data for] the medicines we are developing will be reflective of all the patients who use it and could benefit from them.

Immunotherapy is going to be moved up into an earlier line of therapy, [and] we're all eagerly awaiting those approvals from the FDA. However, there is now a greater need for therapies after patients have utilized chemotherapy and immunotherapy. In addition, the way we look at endometrial cancer has changed. We classify it based on a molecular classification that originated with the Cancer Genome Atlas, and we now have 4 distinct molecular subtypes.

The [patients] who have the worst prognosis are copy number–high patients. [Attempting] to look for better therapies in that subgroup will help us in terms of trying to affect mortality. Some of those exciting agents include the newer emerging HER2-directed therapies. The HER2[-directed] antibody-drug conjugates [ADCs] are promising, and those are therapies that can be utilized even in low HER2 expressers. Additionally, looking at other agents, such as WEE1 inhibitors, may be beneficial for those patients who have CCNE1 amplification in the higher-risk subgroup. These are interesting and exciting targets that are being evaluated.

Endometrial cancer is a molecularly driven disease, and we should be testing all [patients with] endometrial cancers, whether it be through a more rudimentary way using immunohistochemistry or more sophisticated ways with next-generation sequencing. The future [will involve] looking for newer targeted therapies and identifying therapies based on more molecular classification.

Whitfield B. Growdon, MD, of NYU Langone’s Perlmutter Cancer Center, discussed PARP inhibitors in the management of ovarian cancer. In 2022, following evidence of safety concerns, the manufacturers of niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca) withdrew indications for these agents in patients with heavily pretreated, BRCA-mutated ovarian cancer. How has this affected their use in patients with ovarian cancer?

There have been treatment indications with PARP inhibitors that have been withdrawn in the recurrent setting. In addition, maintenance recommendations [for niraparib]in the platinum-sensitive recurrent setting have also been narrowed to include only [germline] BRCA-mutated [patients]. Rucaparib [is now indicated for patients with germline] or somatic BRCA mutations who [are in a complete or partial response to platinum-based chemotherapy].

Given that this landscape has evolved, the key message there is to utilize PARP inhibitors early in the disease course. The frontline maintenance setting is the best time to utilize PARP inhibitors in the management of ovarian cancer.

Edward A. Jimenez, DO, of NYU Langone’s Perlmutter Cancer Center, led a case discussion on the use of these PARP inhibitors in ovarian cancer. How did these examples demonstrate the use of PARP inhibitors in the frontline setting?

One of the important discussion points was the utilization of bevacizumab [Avastin]. In patients who you've already started on bevacizumab, how do you treat them with a PARP inhibitor? We have data from the [phase 3] PAOLA-1 study [NCT02477644] that allow us to continue bevacizumab with olaparib in the maintenance setting. Additionally, that treatment indication is for patients who have homologous recombination deficiency.

In patients who have BRCA mutations, your treatment options include olaparib and niraparib based on the [phase 3] SOLO-1 [NCT01844986] and the [phase 3] PRIMA [NCT02655016] trial data, [respectively]. We have seen the OS data with olaparib, which always gives us reassurance. Additionally, we've also seen long-term PFS data from PRIMA, which are very consistent.

Finally, in the homologous recombination–proficient subgroup, niraparib is approved and [could be considered] in terms of utilizing a PARP inhibitor in that setting.

Kari E. Hacker, MD, PhD, of NYU Langone’s Perlmutter Cancer Center, discussed ADCs in ovarian cancer. Could you highlight some of the ADCs under development beyond mirvetuximab soravtansine-gynx (Elahere)?

ADCs are the next frontier in targeted therapy, in that there is a specific biomarker on the tumor that is targeted. We are fortunate in ovarian cancer to have mirvetuximab soravtansine approved for the treatment of [patients with] recurrent platinum-resistant ovarian cancer that has high folate receptor α [FRα] expression, which is defined as greater than 75%. Although we are excited, that is a narrow window for FRα expression. However, we are testing all patients with recurrent ovarian cancer for FRα expression to potentially utilize this new agent.

As we have these new agents, it's important to keep in mind that they come with new toxicities. An important [toxicity] is ocular toxicity. With mirvetuximab soravtansine, we need to worry about the ocular toxicity and encourage an eyecare plan, as well as consultation with an optometrist or ophthalmologist during treatment.

The other thing that is exciting about ADCs is that we have one approval [for an agent that] specifically targets the FRα receptor. However, other [ADCs] are being studied, and we're excited because some [studies] are looking at FRα at a lower expression, such as [a phase 1 trial (NCT05200364) evaluating] STRO-002.

Additionally, there are other ADCs, such as upifitamab rilsodotin [UpRi; XMT-1536], that [have] a different target, NaPi2b. Other agents are directed at HER2, as well. This area is only expanding, and I foresee that we'll have a number of ADCs in our pocket to treat patients with ovarian cancer [in the future].

Lesli R. Boyd, MD, NYU Langone’s Perlmutter Cancer Center, discussed the cervical cancer landscape. What are some of the differentiating factors of available treatment regimens in clinical practice, and what classes of agents in development could bridge the unmet need between the frontline and recurrent settings?

Even the cervical cancer landscape has changed. We are fortunate that the [data from the phase 3] KEYNOTE-826 trial [NCT03635567] led to approval of pembrolizumab [plus chemotherapy with or without bevacizumab] in [patients with] cervical cancer who are PD-L1 positive. [In] that study, [88.1%] of patients had [positive PD-L1] expression. Therefore, [this approval] is applicable to a large cohort of the patients with cervical cancer that we treat.

Prior to this, the backbone had been paclitaxel and carboplatin with bevacizumab, based on the [phase 3] GOG-0240 trial [NCT00803062] regimen. [KEYNOTE-826] added pembrolizumab to that backbone and showed an improvement both in PFS and OS. This was practice changing in terms of our cervical cancer treatment.

In addition, tisotumab vedotin-tftv [Tivdak] was the first ADC to be approved in gynecologic cancers. This ADC targets tissue factor, and because tissue factor is well expressed in nearly all patients [with cervical cancer], it is not a differentiating biomarker. Even with this agent, there are ocular toxicities that we need to be mindful of. The mechanism is a little bit different vs mirvetuximab soravtansine. The major eye toxicity with tisotumab vedotin is conjunctivitis. This requires an eyecare plan and consultation with an eyecare specialist.

It's important to discuss the [phase 3] CALLA trial [NCT03830866], which did not show a benefit with [durvalumab (Imfinzi) given concurrently with] chemoradiation for locally advanced cervical cancer. This may have been patient selection, but we are also awaiting [data for pembrolizumab plus chemoradiation from the phase 3] KEYNOTE-A18 trial [NCT04221945]. That [study], which had a little bit of a different patient population, may shed light on whether there is a role for adding immunotherapy to chemotherapy and radiation therapy as the initial treatment in locally advanced cervical cancer.

The recurrent setting is still an unmet need. We have few effective therapeutic options. Tumor-infiltrating lymphocyte [TIL] therapy is an area that is undergoing active investigation. There are some provocative phase 2 data. Although [TIL therapy] is a more difficult treatment, it does offer us a therapeutic choice.

Other interesting agents are under study, such as bispecific [antibodies]. In patients who have had immunotherapy, can you add another type of agent to improve efficacy? Could you combine a PD-L1 [inhibitor] with a CTLA-4, LAG-3, or TIM-3 [inhibitor]?

The other area that is interesting is therapeutic DNA vaccines. I'm really interested in looking [at mRNA vaccines] in all gynecologic cancers, and maybe even all cancers. There are some very provocative phase 2 data that were presented for [mRNA vaccines] in melanoma. This is very promising and something that we're excited about.

Are there any ongoing or upcoming trials in gynecologic cancers at NYU Langone that you would like to highlight?

We have some interesting trials in each of our disease sites that are open at NYU Langone, and we have a robust pipeline. In ovarian cancer, we have several ADC trials open, targeting NaPi2b and FRα. These trials are both in the platinum-sensitive [setting] as maintenance therapy, as well as in the platinum-resistant recurrent setting as treatment.

In endometrial cancer, we have an exciting [phase 1/2] trial [NCT05150691] with [DB-1303], which is a HER2-targeted ADC. In addition, we have trials looking to use immunotherapy in the first-line setting in place of chemotherapy. Can we use pembrolizumab alone in lieu of chemotherapy? This is another trial that we have open in the dMMR population.

Additionally, we have a [phase 1/2] trial [NCT05705505] evaluating a novel CDK4/6 inhibitor with narazaciclib [ON 123300] and letrozole in low-grade endometrial cancer.

In cervical cancer, we will soon open a frontline trial that will combine chemoradiation with a bispecific [antibody]. For the treatment of patients with recurrent cervical cancer, we have a [phase 2] trial [NCT05032040] that is looking at [vudalimab (XmAb 20717)], a bispecific [antibody targeting] PD-L1 and CTLA-4.

References

1. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. March 27, 2023. doi:10.1056/NEJMoa2302312
2. 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