CE / CME
ABIM MOC: maximum of 1.00 Medical Knowledge MOC point
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: September 18, 2023
Expiration: September 17, 2024
Background
There is a pressing need for better treatment strategies to manage advanced or recurrent endometrial cancer. Until recently, most clinical trials in gynecologic cancers focused on ovarian cancer rather than endometrial cancer. However, the need to shift our focus to include endometrial cancer has grown as the incidence and mortality associated with endometrial cancer continue to rise.1 In 2023, approximately 66,000 women in the United States will be diagnosed with endometrial cancer—a number anticipated to double by 2030.1,2 In this focused micromodule, I review promising new strategies for the treatment of advanced or recurrent endometrial cancer.
Many of the investigational therapies in late-stage development are targeted agents for patients with specific molecular profiles. Our modern molecular classification system was initially published in 2013 by The Cancer Genomic Atlas project.3,4 Their analysis of 373 tissue samples categorized endometrial cancer into 4 molecular subgroups based on shared genomic features that correlated with the clinical outcome:
Molecular Subtyping of EC: PORTEC-3 Trial
In addition to being prognostic, these molecular characteristics are also predictive of benefit from adjuvant treatment. In a 2020 analysis of available tissue from the phase III PORTEC 3 trial, those with copy number–high disease were the only group found to significantly benefit from the combination of adjuvant chemotherapy and radiation vs radiation therapy alone. The 5-year relapse-free survival rate with combination adjuvant treatment was 58.6% vs 36.2% with radiation therapy alone, yielding an HR of 0.52 (95% CI: 0.30-0.91; P = .021).
By contrast, the groups with mismatch repair deficiency (dMMR)—which causes MSI—or copy number low did not significantly benefit from adjuvant therapy escalation. The POLE-ultramutated group also did not benefit. We should note that the 5-year relapse-free survival rate for this group was exceptionally high (96%-100%), reflecting the excellent prognosis of this molecular profile and suggesting that those with POLE-ultramutated disease might do well with therapy de-escalation. At the end of this module, we discuss an interesting clinical trial evaluating de-escalation in this group.
Molecular Profile and Potential Drugs by TCGA Classification
These 4 molecular profiles also have distinct patterns of PD-L1 expression and mutations in other genes, with implications for which therapeutics may be most active in each group.5,6 For example, the copy number–low/NSMP group usually has tumors expressing the estrogen and progesterone receptors and predominantly present with an endometrioid histology.7 This group is more likely to benefit from hormonal treatment with an aromatase inhibitor plus a CDK4/6 inhibitor—an investigational regimen in endometrial cancer that has shown benefit in breast cancer.
As another example, approximately 25% of patients in the copy number–high group have HER2 protein overexpression and/or gene amplification, providing an opportunity to target this alteration with HER2-directed therapy. Indeed, targeting HER2 with carboplatin/paclitaxel plus trastuzumab has been established as standard of care for treatment of patients with HER2-positive endometrial cancer.8 Later in this module, we discuss promising early data for the HER2-directed antibody–drug conjugate trastuzumab deruxtecan, along with considerations on testing for HER2/neu status.
As a third example, we can see that the POLE-ultramutated and MSI groups are characterized by both PD-1/PD-L1 overexpression and MSI-H status, although the latter is more variable in the POLE group. These characteristics suggest that anti–PD-1/PD-L1 antibodies—immune checkpoint inhibitors (ICIs)—may have greater activity in these groups.
Phase III Trials of Immunotherapy Plus Chemotherapy for Advanced or Recurrent EC
Moving forward, we will briefly discuss a key development in the standard of care that will affect the design and focus of other clinical trials. In spring 2023, phase III data from the NRG-GY018 and ENGOT-EN6/GOG-3031/RUBY trials were reported that changed our standard of care from carboplatin/paclitaxel to carboplatin/paclitaxel plus an ICI for treatment of frontline advanced or recurrent endometrial cancer.8-10 The ICI was pembrolizumab in NRG-GY018 and dostarlimab in RUBY.
We also briefly review the key data from these trials and how these results have made it even more important for us to study whether immunotherapy can be sequenced after immunotherapy. For more extensive discussion of these trials, please see this micromodule from my colleague, Lauren Prescott, MD, MPH, on our current standard-of-care management of advanced or recurrent endometrial cancer.
NRG-GY018: PFS
The NRG-GY018 trial met its coprimary endpoints, demonstrating that the addition of pembrolizumab to carboplatin/paclitaxel significantly prolonged progression-free survival (PFS) vs placebo plus carboplatin/paclitaxel in the dMMR cohort and in the mismatch repair–proficient (pMMR) cohort.9 The risk of progression was significantly reduced by 70% and 46%, respectively (both P <.001).
ENGOT-EN6/GOG-3031/RUBY: PFS and OS
Turning to RUBY, we can see that the trial met the first of its 3 hierarchically tested primary endpoints, PFS in the dMMR/MSI-H cohort.10 RUBY demonstrated a statistically and clinically significant improvement in the 2 year PFS rate with of 61.4% with dostarlimab plus carboplatin/paclitaxel vs 15.7% with placebo plus carboplatin/paclitaxel (P <.001).
Shown here are also the results from the pMMR cohort, which had a more modest improvement in the 2-year PFS rate from 18.8% with the addition of placebo to 28.4% with the addition of dostarlimab.
Safety in NRG-GY018 and ENGOT-EN6/GOG-3031/RUBY
The RUBY trial reported more comprehensive safety analyses than did the NRG-GY018, but the results of both trials were consistent with the established profiles for immunotherapy and carboplatin/paclitaxel.9-13 Although most patients in each trial experienced adverse events (AEs), the addition of either ICI to standard chemotherapy did not result in substantially higher rates of toxicities.
An outstanding question is whether there are any significant differences in the safety profiles of dostarlimab vs pembrolizumab, which are both PD-1–directed ICIs. Personally, I think any differences that do exist are subtle—perhaps similar to our experience with the safety profiles of established PARP inhibitors.
To learn more about monitoring for and managing immune-related AEs in patients receiving immunotherapy-based treatments for endometrial cancer, please see this micromodule from my colleague, Lauren Prescott, MD, MPH.
Open Questions After NRG-GY018 and RUBY
The NRG-GY018 and RUBY trials demonstrated that patients with dMMR/MSI-H disease gain a great deal of PFS benefit from the addition of immunotherapy to standard chemotherapy for frontline advanced or recurrent endometrial cancer.
I have some reservations about the benefit of this regimen in those with pMMR disease. In RUBY, the pMMR cohort was not part of the original hierarchical testing plan—meaning that the trial may be underpowered to detect a real benefit in this population. Later in this module, we discuss trials that are evaluating therapies in patients with pMMR/microsatellite-stable (MSS) endometrial cancer.
Another question is whether the combination of immunotherapy plus chemotherapy significantly improves overall survival (OS) in the frontline and recurrent settings. We do not yet have mature OS data from RUBY—that will likely take several more years—or any OS data from NRG-GY018. Given that many patients prioritize OS benefit over PFS benefit when choosing treatments, this is an important open question.14
Clinical Trials Evaluating Immunotherapy After Immunotherapy
Now that immunotherapy plus chemotherapy is standard of care for advanced/recurrent endometrial cancer, it is even more important to investigate how to treat patients who experience progressive disease with this regimen.
An open question is whether patients treated with frontline immunotherapy can be rechallenged with immunotherapy in later lines. I am not aware of any large late-phase clinical trials evaluating this strategy, but multiple smaller trials are looking into immunotherapy after immunotherapy, such as these ongoing multicohort phase II trials:
Phase III SIENDO: Selinexor vs Placebo Maintenance in Recurrent Endometrial Cancer
Moving forward, another promising treatment option under investigation is selinexor. By inhibiting XPO1, a nuclear export protein, selinexor induces nuclear localization of p53, BRCA1, and other tumor suppressor proteins.15 This, in turn, inhibits DNA damage repair and induces apoptosis.
The utility of selinexor as maintenance therapy was assessed in the phase III SIENDO trial.16 This study enrolled patients with stage IV or first recurrence of endometrial cancer who had a complete or partial response on a frontline carboplatin/taxane regimen. The patients were then randomized to selinexor at 80 mg weekly vs placebo until disease progression, with randomization stratified by primary stage IV vs recurrent disease and whether the patient had a complete vs partial response.
The primary endpoint was PFS with secondary endpoints including OS.
SIENDO: PFS
In the intent-to-treat population, there was a statistically significant 30% reduction in the risk of progression when the patients received selinexor vs placebo as maintenance therapy (P = .024).17 Of interest, an exploratory analysis suggested that patients with wild type TP53 had the greatest PFS benefit from selinexor.16 Selinexor maintenance was associated with a 58% reduction in the risk of progression vs placebo in those with wild-type TP53 (P = .0003).
SIENDO: TEAEs
The most common any-grade treatment-emergent AEs (TEAEs) with selinexor included nausea, vomiting, thrombocytopenia, and fatigue.17 TEAEs led to treatment discontinuation in 10.5% of the selinexor arm and 1.1% of the placebo arm. There were no TEAEs leading to death.
SIENDO reported high rates of nausea and vomiting, which occurred at any grade in 84% and 52% of the selinexor arm, respectively. When this study was initiated in endometrial cancer, there was concern about nausea and vomiting based on experience with selinexor in multiple myeloma. Selinexor was dosed at 80 mg weekly in SIENDO, whereas for multiple myeloma, the FDA has approved selinexor at 100 mg weekly in combination with bortezomib/dexamethasone or 80 mg twice weekly in combination with dexamethasone.17,18 The high rates of these events reported for SIENDO may reflect the experiences of patients treated earlier in the trial before nausea/vomiting prophylaxis was implemented. Our institution participated in this trial, and after we implemented a prophylactic plan, observed much less nausea and vomiting than has been reported.
Clinical Relevance and Further Study of Selinexor
Based on these data, the confirmatory phase III XPORT-EC-042 trial (NCT05611931) was initiated to compare selinexor vs placebo as maintenance therapy in patients with advanced or recurrent endometrial cancer and wild-type TP53.
It is important to consider the clinical relevance of these trials examining maintenance after systemic therapy, given that both NRG-GY018 and RUBY had a maintenance phase with single-agent immunotherapy. Personally, I consider these trials of selinexor maintenance to be relevant. As we discussed earlier, although immunotherapy plus chemotherapy is quite beneficial in the setting of dMMR/MSI-H disease, there are still open questions about its benefit in pMMR/MSS disease. Recall from our discussion of molecular profiles that the copy number–low group is characterized by a lack of POLE ultramutation, MSS, and wild-type TP53. These are the patients who may benefit from selinexor maintenance.
Trastuzumab Deruxtecan in Endometrial Cancer
As we discussed earlier, HER2/neu testing is an important part of routine care because 25% to 30% of patients with serous endometrial cancer have HER2 overexpression and/or gene amplification, rendering them eligible for trastuzumab-based therapy.8,19 National Comprehensive Cancer Network guidelines recommend that HER2 testing be performed in patients with advanced or recurrent serous endometrial carcinoma or carcinosarcoma and considered for those with TP53-aberrant disease regardless of histology. Testing relies on HER2 IHC to assess protein levels with reflex to HER2 FISH to assess gene amplification if the IHC results are equivocal.
Trastuzumab deruxtecan consists of the anti-HER2 antibody trastuzumab conjugated to deruxtecan, a topoisomerase I inhibitor.20 This antibody–drug conjugate is under investigation in endometrial cancer and is approved by the FDA for multiple indications in various HER2-positive malignancies and HER2-low breast cancer. Preliminary data from the phase II STATICE trial in 32 Japanese patients with advanced or recurrent uterine carcinosarcoma reported antitumor activity in those with high and low expression of HER2.21 The overall response rate (ORR) was 54.5% in patients with high HER2 expression (defined as IHC ≥2+) and 70.0% with low HER2 expression (IHC 1+).
Trastuzumab deruxtecan is under investigation in the ongoing phase II DESTINY-PanTumor02 trial, which we will discuss now.
Phase II DESTINY-PanTumor02: Trastuzumab Deruxtecan in Cohort With HER2-Positive EC
The multicohort phase II DESTINY PanTumor02 trial is evaluating trastuzumab deruxtecan in the second-line and later-line setting for patients with advanced solid tumors who are ineligible for curative therapy.22 The tumors must express HER2, defined as IHC 3+ or 2+. Of note, prior HER2-targeted therapy was permitted, and 35 out of 267 treated patients (13%) had previously received an anti-HER2 antibody or TKI. Patients received trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR per investigator.
At ASCO 2023, Meric-Bernstam and colleagues presented an interim analysis, which included efficacy and safety data on the cohort of 40 patients with endometrial cancer.
DESTINY-PanTumor02: Response and Safety Outcomes
The ORR was 57.5% in the cohort with endometrial cancer, which was the highest ORR observed in any of the 7 cohorts with various solid tumors.22 Patients responded regardless of whether they had higher or lower HER2 expression, with an ORR of 84.6% in the 13 patients with a HER2 IHC 3+ score and 47.7% in the 17 patients with a HER2 IHC 2+ score.
Shown here are safety data for all 267 treated patients with various malignancies. Most patients experienced a drug-related TEAE, and almost 40% had a grade ≥3 event. Interstitial lung disease/pneumonitis is an established risk with trastuzumab deruxtecan and was observed in 20 patients (7.5%). Most of these events were low grade, but there was 1 death (0.4%) related to interstitial lung disease/pneumonitis.
I consider these results to be very promising for the use of trastuzumab deruxtecan in patients with HER2-positive endometrial cancer.
Clinical Relevance of DESTINY-PanTumor02
Given these results, it is interesting to consider when and why a healthcare professional would consider enrolling a patient on a trial like DESTINY-PanTumor02 evaluating trastuzumab deruxtecan rather than recommending trastuzumab.
Currently, trastuzumab is recommended for HER2-positive uterine serous carcinoma or carcinosarcoma in either the adjuvant setting for stage III/IV disease or the recurrent setting.8
The DESTINY-PanTumor02 trial enrolled a different patient population than that covered by this recommendation. Recall that the patients had advanced solid tumors in the second-line and later-line setting, rather than the adjuvant/recurrent setting.22 Furthermore, patients on the DESTINY-PanTumor02 trial were ineligible for curative treatment. Finally, DESTINY-PanTumor02 permitted prior HER2-directed therapy, meaning that patients already treated with trastuzumab were eligible.
Select Ongoing Phase II/III Trials in Advanced EC—Adjuvant Setting
We close our discussion with an overview of several ongoing later-phase trials. As the clinical trial director in gynecologic malignancies at my institution, I consider these studies to be particularly exciting and important. Some of my patients are on these trials.
In the adjuvant setting, the phase II/III RAINBO umbrella trial program (NCT05255653) has been launched to investigate tailoring adjuvant therapy to each of the 4 molecular classification groups in patients with newly diagnosed endometrial cancer after surgical resection. This initiative aims to reduce toxicity and improve quality of life through treatment individualization, including treatment de escalation. I consider this to be very important and look forward to seeing the results.
The phase III MK3475-B21/ENGOT EN-11/GOG-3053 trial (NCT04634877) is assessing immunotherapy plus chemotherapy in the high-risk adjuvant setting. Patients will receive carboplatin/paclitaxel with placebo vs with pembrolizumab as adjuvant therapy and then continue either single-agent pembrolizumab or placebo as maintenance treatment.
I am also interested in the phase II/III NRG-GY026 trial (NCT05256225), which is looking at HER2-targeted treatment options in the adjuvant setting or at first recurrence. NRG-GY026 is comparing carboplatin/paclitaxel alone vs in combination with either trastuzumab/hyaluronidase or trastuzumab/ pertuzumab/hyaluronidase.
Select Ongoing Phase II/III Trials in Advanced EC—Frontline, Second-line, and Maintenance Settings
In the frontline setting, multiple phase III trials are assessing the addition of a PARP inhibitor to immunotherapy and chemotherapy. The phase III DUO E/GOG 3041/ENGOT-EN10 trial (NCT04269200) is evaluating frontline treatment with the PD-L1 inhibitor durvalumab plus carboplatin/paclitaxel followed by maintenance with either durvalumab plus olaparib, durvalumab alone, or olaparib alone. We anticipate a report soon because the primary competition date is estimated for the end of September 2023.
The second part of the RUBY trial (NCT03981796) that we discussed earlier will be comparing carboplatin/paclitaxel with vs without dostarlimab followed by dostarlimab plus niraparib vs placebo maintenance. It will be interesting to see whether adding a PARP inhibitor to maintenance improves on the benefit demonstrated by immunotherapy plus chemotherapy.
As I mentioned earlier, the phase III XPORT-EC-042 trial (NCT05611931) is evaluating selinexor as maintenance treatment in endometrial cancer with wild-type TP53.
Several studies are comparing immunotherapy-based regimens vs standard carboplatin/paclitaxel therapy, which could benefit patients who either cannot or do not want to receive standard systemic chemotherapy. The phase III DOMENICA trial (NCT05201547) is comparing frontline carboplatin/paclitaxel vs dostarlimab, and the phase III GOG-3064/KEYNOTE-C93 trial (NCT05173987) is comparing carboplatin/paclitaxel vs pembrolizumab in patients with dMMR/MSI-H advanced or recurrent endometrial cancer.
The phase III LEAP 001/ENGOT-EN9 trial (NCT03884101) is comparing carboplatin/paclitaxel vs lenvatinib/pembrolizumab in the frontline and second-line settings.
Conclusion
We have covered just some of the exciting recent developments in advanced endometrial cancer. These range from moving immunotherapy-based combinations into the frontline setting to emerging data on promising therapies for patients with wild-type TP53 or HER2-expressing disease. With many interesting late-phase trials in the pipeline, I am looking forward to seeing results soon that potentially could change our management of newly diagnosed and recurrent disease.
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