Individual Disease Histology and Local Control Are Key Considerations in Endometrial Cancer Care

Hope Cottrill, MD

Systemic therapy and surgery have become mainstays in the treatment of patients with endometrial cancer, although further research is necessary to delineate the optimal use of radiation and later-line immunotherapy in this patient population, according to Hope Cottrill, MD.

The phase 3 NRG-GY018 trial (NCT03914612) evaluated the efficacy and safety of pembrolizumab (Keytruda) or placebo plus paclitaxel and carboplatin in patients with recurrent endometrial cancer. Patients with mismatch repair–deficient (dMMR) disease who received pembrolizumab (n = 112) experienced an estimated 12-month progression-free survival (PFS) rate of 74% vs 38% for those who received placebo (n = 113; HR, 0.30; 95% CI, 0.19-0.48; P < .001).¹

Additionally, the phase 3 RUBY trial (NCT03981796) demonstrated that dostarlimab-gxly (Jemperli) plus carboplatin and paclitaxel led to a 71% reduction in the risk of disease progression or death vs chemotherapy alone in patients with dMMR/microsatellite instability–high primary advanced or recurrent endometrial cancer.² The findings from RUBY supported the July 2023 FDA approval of dostarlimab plus chemotherapy in this patient population.

Furthermore, in the phase 3 DUO-E trial (NCT04269200), patients with newly diagnosed advanced or recurrent endometrial cancer who received durvalumab (Imfinzi) plus carboplatin and paclitaxel followed by durvalumab maintenance with (n = 239) or without (n = 238) olaparib (Lynparza) achieved statistically significant PFS benefits compared with those who received chemotherapy plus placebo followed by placebo maintenance (n = 241).3 The hazard ratios for the durvalumab and durvalumab/olaparib arms vs the control arm were 0.71 (95% CI, 0.57-0.89; P = .003) and 0.55 (95% CI, 0.43-0.69; P < .0001), respectively.

“With the novel use of immunotherapy [IO] agents, this is an opportunistic time for us and our patients,” Cottrill, a gynecologic oncologist at Baptist Health Medical Group in Lexington, Kentucky, said in an interview with OncLive® following a State of the Science Summit on gynecologic oncology, which she chaired.

In the interview, Cottrill highlighted key points that were presented at the meeting, including practice-changing developments in endometrial cancer care, the benefits of local control with radiation in patients with locally aggressive disease, and questions that remain regarding treatment sequencing with immunotherapy.

OncLive: How has endometrial cancer management evolved over the past year?

Cottrill: This is an amazing time for the care of patients with endometrial cancer. We’ve learned much more recently about how the disease has been changing. New guidelines are coming out regarding treatment and the molecular genomics of individual patients’ cancers, which will continue to influence how we treat patients.

The 2 groundbreaking studies I referred to [in my presentation were] the [NRG-GY018] trial investigating carboplatin, paclitaxel and pembrolizumab, with pembrolizumab being continued as maintenance therapy, and the RUBY trial, which investigated carboplatin, paclitaxel, and dostarlimab, with dostarlimab being continued as a maintenance drug. Those [regimens] are game changers for patients with recurrent and advanced endometrial cancers. I’ve been employing those regimens and the data from those trials when I council and care [for] patients with advanced endometrial cancer. We’re seeing much more advanced endometrial cancer and more aggressive histologic types than we have before, so having the opportunity to impact these patients’ outcomes has been paramount to [this] change of practice.

What treatment advances are still to come in endometrial cancer?

One of the trials presented at [the 2023 ESMO Congress] that I discussed was the [phase 3] DUO-E trial, employing an IO agent that targets PD-L1 plus a PARP inhibitor. Preclinical data [indicate] that theoretically, there should be synergy between those 2 treatments. [We need to see] how that will play out.

There are also challenges regarding sequencing these therapies. We’ve gone from an era where patients received only radiation and chemotherapy to [an era where patients with] recurrent disease [are] being treated with immunotherapy, [such as] pembrolizumab plus or minus lenvatinib [Lenvima]. However, now that you can use IO in the upfront setting, how will we approach [the treatment of] these patients? It’s great that we’re getting data. DUO-E investigated pembrolizumab and olaparib for patients with endometrial cancer. However, if we have already used IO, we are left with the question: Can you use IO after IO? That’s a question that hasn’t been answered yet.

Jonathan Feddock, MD, of Baptist Health Medical Group, gave a case presentation of a patient with endometrial cancer. Please describe the details of the case that was presented and any pertinent discussion points surrounding this case that arose during the meeting.

[Dr Feddock] focused on a shared patient of ours who had aggressive cancer that was perforating the uterus clinically at the time of surgery. My technique for extraction of large uteruses, or this situation where the tumor was perforating the uterus, is to put [the uterus] in a bag and extract it in a piecemeal fashion to avoid laparotomy, if possible, for the patient and facilitate the recovery. Facilitating recovery leads to early treatment. [Dr Feddock and I] had a conversation about the best way to treat this patient because of the extent of local disease. The challenges regarding the histology were [that the uterus] was removed in a piecemeal fashion, so clinically, [the tumor] was perforating the uterus, but the pathology did not reflect that.

[Dr Feddock also highlighted] the benefits of local control, because right now we’re focused on systemic treatment. He brought forward that in the studies that compared radiation with chemotherapy, the patients who received radiation received less chemotherapy. If you can try to manage toxicities more appropriately, you would be in a position to ensure the patient receives adequate systemic therapy as well.

Some of the challenges with radiation oncology trials is that traditionally they have not been powered to show survival. Additionally, some of the earlier trials were stopped prior to maturation of the data because [the investigators] thought that statistically the findings were going to end up a certain way, and they didn’t have enough data to say there was statistical significance. Dr Feddock also pointed out that for some of the more recent trials, you have to do a deep dive and see how many patients were pretreated with radiation. In his opinion, if you do a deep dive and evaluate the detailed information, there is still benefit, particularly [with] local control, when it comes to treating patients with locally aggressive cancer.

What is your main message for colleagues regarding developments across gynecologic oncology?

There have been a lot of changes. It’s important to stay on top of the data and the new information that is coming out, so your patients have the best treatment opportunities. Being able to connect with colleagues at these types of educational events is important so you can see what other [oncology professionals] are doing and grow your practice and your own personal knowledge.

References

1. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312
2. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endome-trial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed November 29, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/
3. Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. Published online October 21, 2023. doi:10.1200/JCO.23.02132