Personalized Medicine Is Gaining Momentum in Advanced Endometrial Cancer

David M. O’Malley, MD

Molecular characterization of endometrial tumors has resulted in a boom of investigative efforts aimed at ushering in a new era of tailored therapeutic regimens for patients with these malignancies. Although radiation and chemotherapy have been the cornerstone of treatment for patients with advanced or recur-rent endometrial cancer, knowledge of these tumors’ molecular signa-ture has led to a plethora of clinical trials examining the accuracy of these predicative characteristics. “We can be curing more patients while limiting toxic therapies and providing better qual-ity of life and less long-term morbidity; that’s because of molecular signature,” David M. O’Malley, MD, said during a recent OncLive Peer Exchange®.

A panel of gynecologic oncology experts discussed some of the molecular character-istics that have thus far been identified and what these might mean for prognosis and treatment decision-making. They also shared their insights on the promising ongoing phase 3 trials that are examining a variety of adjuvant and maintenance approaches as well as highlighted novel targets of interest. “We are amid a very impressive moment for the treatment of endometrial cancer. We’re moving forward,” Nicoletta Colombo, MD, PhD, said.

Using Molecular Features to Guide Adjuvant Therapy Selection

In 2013, the Cancer Genome Atlas Research Network published the results of an integrated genomic, transcriptomic, and proteomic characterization of nearly 400 endometrial carcinomas using array- and sequencing-based technologies. This analysis identified 4 new tumor types: POLE ultramutated, microsatellite instability (MSI) hypermutated, copy-number low, and copy-number high.¹ The molecular characterization data indicate that 25% of tumors classified as high-grade endometrioid by pathologists had a molecular phenotype similar to uterine serous carcinomas, including frequent TP53 mutations and extensive somatic copy number alterations. Based on these findings, investigators concluded that treating copy number–altered endometrioid tumors with chemotherapy rather than adjuvant radiotherapy should be considered and assessed in clinical trials.

Results of the PORTEC-3 trial (NCT00411138), which assessed adjuvant chemotherapy vs radiotherapy alone for patients with high-risk endometrial cancer, demonstrated that adjuvant chemotherapy did not improve 5-year overall survival (OS). Applying The Cancer Genome Atlas molecular classification findings, investigators conducted a retrospective analysis of tissue samples from more than 400 participants enrolled in PORTEC-3 and results signaled that response to treatment varies significantly based on tumors’ molecular profile.^2,3

“In particular, the patients with POLE mutations have a good prognosis; they probably don’t need any adjuvant treatment,” Domenica Lorusso, MD, PhD, said. “On the contrary, the tumors with TP53 mutations have a worse prognosis and seem to benefit with chemotherapy. The intermediate prognosis is that the mismatch repair–deficient [dMMR] population seems not to have such a good response to chemotherapy when we combine chemotherapy plus radiation treatment. These patients would require another kind of treatment, such as I/O [immuno-oncology] therapy. The last group—the group with no specific molecular characteristics—gained a little benefit from chemotherapy.” She added that these data have helped investigators design “a new generation of clinical trials that use this information to guide adjuvant treatment.”

One example is the PORTEC-4a trial (NCT03469674), a multicenter, international, phase 3 randomized trial of molecular-integrated risk profile-based adjuvant treatment vs standard adjuvant vaginal brachytherapy.⁴ “PORTEC-4a is very interesting because it divides patients into 3 groups based on molecular characteristics: low-risk, intermediate-risk, and high-risk,” Lorusso said. “The study doesn’t offer any treatment—no radiation—to the low-risk group while offering radiation treatment only to the intermediate- and high-risk groups.”

Lorusso noted that while PORTEC-4a is the f irst trial to use molecular characteristics of patient tumors to guide adjuvant treatment, similar trials are also in development, including the international RAINBO trials program, which comprises 4 trials.5 These trials will select and compare adjuvant treatments based on molecular group for patients with high-risk and advanced-stage endometrial cancer into 1 of 4 subgroups: TP53-mutant, dMMR, no specific molecular profile, and POLE-mutant. “Patients with tumors that have TP53 mutations will receive chemotherapy and then PARP inhibitors for 2 years. Those with dMMR tumors will receive radiation treatment and then immunotherapy for 1 year. Those with MMSP [malignant melanoma of soft parts] tumors will receive radiation treatment and hormonal treatment, with adjuvant chemotherapy as maintenance. Those with POLE-mutant tumors do not receive adjuvant treatment; it’s a completely different way to approach treating endometrial cancer,” Lorusso said.

Bradley J. Monk, MD

Bradley J. Monk, MD, highlighted an exciting large international trial in this space, the phase 3 KEYNOTE-B21 trial (NCT04634877), which is expecting to enroll almost 1000 participants.6 “It’s basically taking patients with newly diagnosed endometrial cancer with positive nodes—including patients with T53 mutations—and treating them with chemotherapy and adding a placebo or pembrolizumab [Keytruda]. Radiation is elective,” he said.

“The most important step forward in endometrial cancer treatment is molecular profiling,” Lorusso said. “We’ll use this information to guide our treatments: surgical treatment, possibly medical treatment, advanced disease treatment. We performed [molecular profiling] more than in the treatment of other tumors, [such as] ovarian and cervical cancers. Endometrial cancer treatment is a step ahead of all the others in terms of the ecological malignancies.”

Phase 3 Trials for Advanced or Recurrent Endometrial Cancer

The panelists proceeded to share their thoughts several ongoing phase 3 clinical trials that have the potential to reshape the endometrial cancer treatment landscape in the next few years. They discussed trials that are combining a single-agent checkpoint inhibitor with other treatments to try to improve efficacy, such as VEGF inhibitors (KEYNOTE-775; NCT03517449) or chemotherapy (RUBY [NCT03981796]; NRG-GY018 [NCT03914612]; AtTEnd [NCT03603184]). They also reviewed several maintenance strategies under investigation, including the use of PARP inhibitors in the DUO-E trial (NCT04269200) as well as selinexor (Xpovio) in the ENGOT-EN5/SIENDO trial (NCT03555422).

Vicky Makker, MD

Keynote-775

Investigators are evaluating lenvatinib (Lenvima) plus pembrolizumab vs physician’s choice as a first-line treatment for patients with advanced endometrial cancer (stage III or stage IV) in the KEYNOTE-775 trial.⁷ “Patients will be randomized 1:1 to lenvatinib at 20 mg orally once daily plus pembrolizumab at 200 mg every 3 weeks vs the standard paclitaxel-carboplatin IV [intravenous] every 3 weeks,” Vicky Makker, MD, explained. “The study has a dual primary end points of PFS [progression-free survival] and OS.”

The first data from this pivotal trial were reported by Makker at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer in March.⁸ After a median follow-up of 12.2 months for patients receiving lenvatinib plus pembrolizumab (n = 411) and 10.7 months for those receiving physician’s choice of treatment (n = 416), lenvatinib plus pembrolizumab showed statistically significant and clinically meaningful improvements in PFS, OS, and overall response rate (ORR) vs physician’s choice of treatment, regardless of patients’ MMR status, thereby meeting its primary and secondary end points (TABLE^8,9). Among the patients who responded, the duration of response (DOR) among all-comers was 14.4 months in the lenvatinib/ pembrolizumab arm compared with 5.7 months in the physician’s choice arm, whereas the DOR in the mismatch repair–proficient cohort was 9.2 months vs 5.7 months, respectively.⁹

“I was a little skeptical [of this regimen] until I saw the results of KEYNOTE-775,” Monk said. “Whoa—this whole idea of a chemotherapy-free regimen, which is what the study is, is so exciting.” Based on these data, the FDA granted priority review to the supplemental biologics application for the combination in May.¹⁰

TABLE. Preliminary Findings From the KEYNOTE-775

RUBY, NRG-GY018, AtTEnd Trials

RUBY, NRG-GY018, and AtTEnd are seeking to answer the question of whether an I/O approach in combination with chemotherapy has a clinical benefit in patients with advanced or recurrent endometrial cancer.^11-13 “[These] trials include the same populations more or less,” Columbo said. “[Individuals] are stratified according to their MSI status, but all-comers are included.” Each of the trials will evaluate PFS as its primary end point.

RUBY is assessing the addition of dostarlimab (Jemperli) to paclitaxel and carboplatin in women with recurrent or primary advanced endometrial cancer.¹¹ On April 22, 2021, the FDA granted accelerated approval to dostarlimab for adult patients with dMMR-recurrent or advanced endometrial cancer that progressed on or after a platinum-containing regimen.¹⁴ Approval was based on data from the GARNET trial (NCT02715284), a multicenter, multicohort, open-label trial that included patients with a variety of advanced solid tumors, including 71 with dMMR recurrent or advanced endometrial cancer. The confirmed ORR was 42.3% in this cohort, with a 12.7% complete response rate and a 29.6% partial response rate. The median DOR was not reached, with 93.3% of patients having a response lasting at least 6 months.¹⁴ The RUBY trial will determine whether outcomes can be improved by adding dostarlimab to paclitaxel and carboplatin. Investigators are expected to enroll more than 700 patients with an anticipated completion date of February 2026.

NRG-GY018 will evaluate the addition of pembrolizumab to paclitaxel and carboplatin in patients with stage III or IV or recurrent endometrial cancer.¹² The trial investigators are planning to enroll more than 800 patients, and the study’s estimated completion date is June 2023. Of note, investigators will also assess concordance between institutional MMR immunohistochemistry (IHC) testing and centralized MMR IHC, effect of pembrolizumab on PFS and OS by PD-L1–IHC status, and association between PD-L1 IHC and MMR status, as secondary outcome measures.

Further, the AtTEnd is assessing the addition of atezolizumab (Tecentriq) to paclitaxel and carboplatin in women with advanced or recurrent endometrial cancer with dual primary end points of PFS and OS.¹³ Investigators plan to enroll 550 participants with an estimated completion date of December 2023.

DUO-E Trial

“[Investigators are] also looking at a carboplatin-paclitaxel backbone with durvalumab (Imfinzi) followed by durvalumab maintenance plus or minus olaparib [after first-line treatment of advanced or recurrent endometrial cancer],” O’Malley said. DUO-E is a randomized, double-blind, placebo-controlled trial that is anticipated to enroll approximately 700 patients.¹⁵ The primary outcome measure is PFS. The estimated study completion date is March 2025.

In addition to DUO-E, Monk noted that part 2 of the RUBY trial and the RAINBO trials program will also examine the use of PARP inhibitors, which will help to answer the question of whether these agents may play a role in treating patients with endometrial cancer. Lorusso said she suspects these agents will eventually play a greater role, particularly for patients with TP53 mutations. “We will see the results of these trials, and then we will better define when to use them in the algorithm of treatment—if we should use them in the adjuvant setting or in the first-line metastatic setting,” she said.

ENGOT-EN5/SIENDO Trial

ENGOT-EN5/SIENDO (NCT03555422) is a randomized trial evaluating maintenance with selinexor or placebo after platinum and taxane chemotherapy in women with advanced or recurrent endometrial cancer who achieved a complete response or partial response following this treatment.16 “Selinexor is a novel oral selective inhibitor of nuclear export,” Makker said. “Essentially, this agent forces the nuclear retention and activation of tumor-suppressor proteins.” She noted that the agent is already approved as a treatment for patients with relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma.17 “[Selinexor] has shown activity across a number of other hematologic malignancies and solid tumors. It has shown some efficacy treating endometrial cancers that have been previously treated,” she said.

ENGOT-EN5/SIENDO is anticipated to enroll 248 participants, and the estimated study completion date is March 2023.¹⁶ The primary outcome measure is investigator- assessed PFS.

Novel Targets of Interest

“There’s emerging evidence that WEE1 inhibition might be effective in treating serous cancer,” Monk said. One agent targeting this pathway is adavosertib, which O’Malley said showed promising results in a small study that included 34 patients.¹⁸ “[There was a] response rate of 29%, with a duration of response of 9 months,” he said. “[Individuals] had to have 1 regimen of prior systemic chemotherapy, but it’s very interesting because this was an extremely heavily pretreated group of patients with [a median of] 3 prior regimens—3 prior regimens with a response rate of 29% in these patients with serous cancers. That’s a very impressive response.”

Another novel approach the panelists discussed is the combination of an aromatase inhibitor with a CDK4/6 inhibitor, which was explored in the phase 2 ENGOT-EN3-NSGO/ PALEO trial (NCT02730429).¹⁹ “There was a strong proof of concept suggesting that when we combine the aromatase inhibitor—in this case, letrozole—with palbociclib [Ibrance], a CDK4/6 inhibitor,” Lorusso said.

“We were able to increase response rates and PFS with respect to letrozole alone. Particularly, [data from] the subgroup analysis suggests that the benefit is higher in patients who were pretreated with hormonal treatment. We are designing the phase 3 confirmatory trial, and if these results are to be confirmed in the future, we may have this combination to treat all receptor-positive tumors,” she said.

She noted that a large percentage of patients had to discontinue treatment because of toxicity, but that the trial participants were older and had several comorbidities, which was a contributing factor that is being taken into consideration for the phase 3 trial. Additionally, although aromatase inhibitors plus CDK4/6 inhibitors have been shown to shrink tumors in breast cancer, this is not the case with endometrial cancer. Instead, this combination appears to keep disease stable.

References

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2. de Boer SM, Powell ME, Mileshkin L, et al; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): f inal results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(3):295-309. doi:10.1016/S1470-2045(18)30079-2
3. León-Castillo A, de Boer SM, Powell ME, et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy. J Clin Oncol. 2020;38(29):3388-3397. doi:10.1200/ JCO.20.00549
4. van den Heerik ASVM, Horeweg N, Nout RA, et al. PORTEC4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer. Int J Gynecol Cancer. 2020;30(12):20022007. doi:10.1136/ijgc-2020-001929
5. NCRI Gynaecological Group Annual Report 2019-20. National Cancer Research Institute. Accessed June 11, 2021. https:// bit.ly/2TmDiHU
6. Study of pembrolizumab (MK-3475) in combination with adjuvant chemotherapy with or without radiotherapy in participants with newly diagnosed endometrial cancer after surgery with curative intent. ClinicalTrials.gov. Updated June 7, 2021. Accessed June 11, 2021. https://clinicaltrials.gov/ ct2/show/NCT04634877
7. Lenvatinib in combination with pembrolizumab versus treatment of physician’s choice in participants with advanced endometrial cancer. ClinicalTrials.gov. Updated March 18, 2021. Accessed June 11, 2021. https://www.clinicaltrials. gov/ct2/show/NCT03517449
8. Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician’s choice in patients with advanced endometrial cancer. Presented at: Society of Gynecologic Oncology 2021 Annual Meeting on Women’s Cancer;March 19-25, 2021; Virtual. Abstract 11512. Accessed June 16, 2021. https://157slyoyo4y17zpa538hczs1-wpengine. netdna-ssl.com/wp-content/uploads/2021/01/FRIDAY_2021-Virtual-Annual-Meeting-on-Womens-Cancer.pdf
9. Keytruda (pembrolizumab) plus Lenvima (lenvatinib) significantly improved progression-free survival and overall survival versus chemotherapy in patients with advanced endometrial cancer following prior platinum-based chemotherapy in phase 3 study. News release. Merck. March 19, 2021. Accessed June 11, 2021. https://bwnews.pr/2ROalUF
10. Merck and Eisai receive priority review from FDA for Keytruda (pembrolizumab) plus Lenvima (lenvatinib) applications for advanced renal cell carcinoma and for advanced endometrial carcinoma. News release. Merck and Eisai Inc. May 6, 2021. Accessed June 16, 2021. https://bwnews.pr/3b9CzzA
11. A study to evaluate dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in participants with recurrent or primary advanced endometrial cancer (RUBY). ClinicalTrials.gov. Updated April 20, 2021. Accessed June 12, 2021. https://clinicaltrials.gov/ct2/show/NCT03981796
12. Testing the addition of the immunotherapy drug pembrolizumab to the usual chemotherapy treatment (paclitaxel and carboplatin) in stage III-IV or recurrent endometrial cancer. ClinicalTrials.gov. Updated June 11, 2021. Accessed June 12, 2021. https://clinicaltrials.gov/ct2/show/NCT03914612
13. Atezolizumab trial in endometrial cancer - AtTEnd (AtTEnd). ClinicalTrials.gov. Updated June 11, 2021. Accessed June 12, 2021. https://clinicaltrials.gov/ct2/show/NCT03603184
14. FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. April 22, 2021. Accessed June 12, 2021. https://bit.ly/3wmNpeb
15. Durvalumab with or without olaparib as maintenance therapy after first-line treatment of advanced and recurrent endometrial cancer (DUO-E). ClinicalTrials.gov. Updated June 10, 2021. Accessed June 12, 2021. https://clinicaltrials.gov/ct2/ show/NCT04269200
16. Maintenance with selinexor/placebo after combination chemotherapy in participants with endometrial cancer [SIENDO] (ENGOT-EN5). ClinicalTrials.gov. Updated May 26, 2021. Accessed June 12, 2021. https://clinicaltrials.gov/ct2/ show/NCT03555422
17. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. FDA. June 22, 2020. Accessed June 16, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-relapsedrefractory-diffuse-large-b-cell-lymphoma
18. Liu JF, Xiong N, Campos SM, et al. A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma. J Clin Oncol. 2020;38(15):6009. doi:10.1200/ JCO.2020.38.15_suppl.6009
19. Liu JF, Xiong N, Campos SM, et al. A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma. J Clin Oncol. 2020;38(15):6009. doi:10.1200/ JCO.2020.38.15_suppl.6009