SGO communique: Newly approved and investigational therapies for endometrial cancer

In 2023, we have seen a record number of exciting developments in endometrial cancer research and clinical trials. Several new National Comprehensive Cancer Network (NCCN)-endorsed or Food and Drug Administration (FDA)-approved therapeutic combinations for endometrial cancer are now available. In addition, an advanced understanding of the pathogenesis and diversity of endometrial cancers has prompted the updated International Federation of Obstetrics and Gynecology (FIGO) staging for endometrial cancer, published early this year¹.

The SGO Clinical Practice Committee is actively working to update the previous evidence-based review on endometrial cancer^2,3. In the meantime, we have composed a rapid communication to ensure SGO members are current on newly approved and investigational therapies for endometrial cancer.

Immunotherapy

Dostarlimab-gxly approved for dMMR/MSI-H advanced and recurrent endometrial cancer

The RUBY investigators demonstrated that adding dostarlimab-gxly to carboplatin and paclitaxel (CP) in patients with advanced or recurrent endometrial cancer improved progression-free survival (PFS)⁴. In patients with mismatch-repair deficient (dMMR) tumors, the median PFS was 30.3 months for the dostarlimab arm versus (vs.) 7.7 months with placebo (Hazard Ratio (HR)=0.29, p <0.0001).

This prompted the July 31, 2023, FDA approval of dostarlimab-gxly with CP and as maintenance for patients with dMMR or microsatellite instability-high (MSI-H) advanced or recurrent endometrial cancer⁵. The recommended dose of dostarlimab-gxly is 500 mg intravenously every three weeks with CP for six cycles, followed by 1000 mg as maintenance every six weeks until disease progression, unacceptable toxicity, or up to three years. The most common adverse effects of dostarlimab-gxly in combination with CP were rash, diarrhea, hypothyroidism and hypertension. Immune-mediated adverse reactions occurring with maintenance dostarlmab-dxly include pneumonitis, colitis, hepatitis, hypothyroidism, nephritis and skin adverse reactions.

The NCCN lists carboplatin/paclitaxel/dostarlimab-gxly as a category one regimen for patients with stage III-IV tumors⁶. The GINECO-EN105b/ENGOT-en13 trial is currently underway to compare dostarlimab alone to CP in patients with advanced or recurrent dMMR/MSI-H.

Pembrolizumab NCCN compendia listed for stage III-IV endometrial cancer

The GY018 investigators demonstrated a benefit with the addition of pembrolizumab to CP in patients with advanced or recurrent endometrial cancer⁷. In this trial, patients with III or IVA disease were required to have measurable disease. They reported improved PFS in patients with dMMR endometrial cancer, with 12-month PFS rates of 74% with pembrolizumab compared to 38% with placebo (HR 0.30, p<0.001). In this trial, pembrolizumab was administered as 200 mg IV every three weeks with CP, followed by maintenance treatment with 400 mg IV every six weeks. The most common immune-mediated adverse reactions included infusion reactions, hyper/hypothyroidism, colitis and pneumonitis. Pembrolizumab is currently only FDA-approved for patients with dMMR and/or MSI-H recurrent endometrial cancer, and in combination with lenvatinib for recurrent disease. The NCCN currently lists pembrolizumab with CP as a category one regimen for patients with stage III-IV endometrial cancer except for patients with carcinosarcoma; this includes those measurable stage III or IVA disease or stage IVB without measurable disease⁸.

The MK-3475-C93/​KEYNOTE-C93/​GOG-3064/​ENGOT-en15 trial is currently underway to compare pembrolizumab alone versus platinum-doublet chemotherapy in patients with dMMR advanced or recurrent endometrial cancer.

Atezolizumab is not FDA approved or NCCN compendia listed for endometrial cancer

At the recent annual meeting of the European Society of Medical Oncology (ESMO), Nicoletta Colombo, MD, PhD, presented the findings from the ENGOT-en7/MaNGO/AtTEnd trial. Atezolizumab was combined with carboplatin and paclitaxel in patients with advanced and recurrent endometrial cancer, including patients with carcinosarcoma histology. In the experimental group, atezolizumub was continued as maintenance therapy following six cycles of chemotherapy and atezolizumab. There was an improvement in PFS in all patients, both in those with dMMR (HR 0.36) and in the entire cohort (HR 0.74; 95% Confidence Interval (CI) 0.61-0.91). Currently, atezolizumab is not NCCN compendia listed or approved by the FDA.

IO combinations

Combination with agents targeting DNA damage repair

The DUO-E trial compared the addition of durvalumab, another PD-L1 inhibitor, with chemotherapy with and without maintenance olaparib. In this phase III trial, both durvalumab and durvalumab plus olaparib demonstrated improved PFS_18m rates compared to the control arm (67.9% vs. 62.7% vs. 43.4%) in the dMMR cohort. The addition of olaparib did not substantially improve PFS outcomes in patients with dMMR endometrial cancer. Conversely, the addition of olaparib to durvalumab enhanced median PFS (15 vs. 9.9 vs. 9.7 months) compared to durvalumab alone [HR=0.57 (0.44–0.73)] and control [HR=0.76 (0.59–0.99)] arms for patients with pMMR cancers.

At ESMO 2023, Shannon N. Westin, MD, MPH, presented findings that the PD-L1 biomarker may predict durvalumab efficacy. In patients with PD-L1+ cancers, treatment with durvalumab plus olaparib improved PFS (PFS_18m, 54.9% vs. 40.2% vs. 38.6%) compared to durvalumab alone [HR=0.67 (0.49–0.91)] and control [HR=0.42 (0.31–0.57)] arms. Combination maintenance durvalumab and olaparib were associated with higher grade >3 adverse events (41.1% vs. 16.4% vs. 16.6%) and discontinuation rates (14.1% vs. 6.0% vs. 4.1%) compared to durvalumab alone and control arms, respectively.

Combination with agents targeting angiogenesis

The combination of lenvatinib and lenvatinib is FDA-approved for recurrent endometrial cancer⁸. The ENGOT-en9/LEAP-011 study is currently underway to compare lenvatinib and pembrolizumab to CP in patients with newly diagnosed or recurrent endometrial cancer.

TP53 as biomarker for therapy 

The Cancer Genome Atlas (TCGA) identified one of four subtypes of endometrial cancer with ubiquitous TP53 mutations. Such tumors carry the poorest prognosis of the identified molecular sub-types. The revised understanding of endometrial cancers based on molecular subtypes has allowed for additional analyses of previously completed trials.

In the GOG 86P phase II trial of chemotherapy combined with bevacizumab or temsirolimus, patients with a tumor demonstrating p53 oxer-expression on IHC and TP53 missense mutations had a 54% improvement in PFS9. This was concordant when patients with POLE mutations and dMMR tumors were removed from the analysis.

At ESMO 2023, Mansoor Mirza, MD, presented updated data from the RUBY trial based on molecular classification. Nearly a quarter (22%) of the cohort had cancers harboring a TP53 mutation. Updated survival data demonstrated significant improvement in PFS at 24 months as well as OS in the patients with dMMR/MSI-H [tumors PFS_24m, 57.0% vs. 10.2%; HR=0.31 (0.17-0.56); OS_24m, 78% vs. 55.3%; HR=0.40 (0.17-0.95)] and those with TP53 mutations [PFS_24m, 32.4% vs. 17.8%; HR=0.55 (0.30-0.99); OS_24m, 70.8% vs. 33.2%; HR=0.41 (0.2-0.82)]. This is welcome news given the poor prognosis associated with TP53 mutated tumors.

Selinexor

The ENGOT-EN5/GOG-3055/SIENDO phase III trial evaluated maintenance selinexor in patients with endometrial cancer following complete or partial response to CP¹⁰. Selinexor inhibits XP-01 which leads to nuclear accumulation and functional reactivation of tumor suppressor proteins such as p53 and is currently FDA-approved for relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma. In patients with TP53wt tumors, the median PFS was 13.7 months with selinexor compared with 3.7 months in the placebo cohort. Selinexor is currently undergoing investigation in the phase III ENGOT-EN20/GOG-3083/XPORT-EC-042 trial in patients with TP53wt tumors.

Anti-Her2 therapy

Funda Meric-Bernstam, MD, presented the DESTINY-PanTumor02 trial this past summer at the American Society of Clinical Oncology meeting. This was an open-label, multicenter study investigating the anti-tumor activity of trastuzumab-deruxtecan (T-DXd), an antibody-drug conjugate, in patients with HER2-expressing tumors. In the 40 patients with endometrial cancer with HER-2 expression (IHC 3+ or 2+), 80.0% had a disease control rate at 12 weeks.

Tadaaki Nishikawa, MD, PhD, et al. recently published the STATICE trial, a phase II trial of T-DXd in advanced or recurrent HER2-expressing uterine carcinosarcoma¹¹. Patients were classified as HER2-high (IHC 3 or 2+) or HER2-low (IHC 1+) regardless of FISH status. The overall response rates in the HER2-high and HER2-low groups were 54.5% and 70.0% respectively. There was no significant difference in the duration of response, PFS and OS between the HER2-high and -low groups.

Currently, fam-trastuzumab deructecan-nxki is listed as an option for recurrent disease in patients with ICH 3+ or 2+ endometrial cancer. We look forward to the results of NRG-GY026, a phase II/III trial of CP alone or combined with trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in Her2 positive Stage I-IV serous endometrial carcinoma or carcinosarcoma.

Hormonal therapies 

Earlier this year, Panagiotis Konstantinopoulos, MD, PhD, et al. published the findings of a phase II, two-stage study of letrozole and abemaciclib¹². Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6, critical regulators of cell cycle progression and a key mediator of resistance to hormonal therapy. In patients with recurrent, estrogen-receptor positive endometrial cancer, the objective response rate was 30.0%. This is currently being investigated in the Abemaciclib and Letrozole to Treat Endometrial multicenter trial (GOG-3039). The NCCN currently lists letrozole/ribociclib and letrozole/abemaciclib as treatment options for ER-positive, recurrent or metastatic endometrial cancer⁷.

Summary

The treatment options for our patients with endometrial cancer are becoming increasingly individualized and diverse. SGO members can serve as a resource for their patients and the medical community to advise on the options. We hope that this interim information will aid our SGO membership.

For questions or further guidance, please email sgo@sgo.org.

This communique was provided by the SGO Clinical Practice Committee.

References

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2. Hamilton CA, Pothuri B, Arend RC, Backes FJ, Gehrig PA, Soliman PT, Thompson JS, Urban RR, Burke WM. Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations. Gynecol Oncol. 2021 Mar;160(3):817-826. doi: 10.1016/j.ygyno.2020.12.021. Epub 2021 Jan 27. PMID: 33516529.
3. SGO Clinical Practice Endometrial Cancer Working Group; Burke WM, Orr J, Leitao M, Salom E, Gehrig P, Olawaiye AB, Brewer M, Boruta D, Herzog TJ, Shahin FA; Society of Gynecologic Oncology Clinical Practice Committee. Endometrial cancer: a review and current management strategies: part II. Gynecol Oncol. 2014 Aug;134(2):393-402. doi: 10.1016/j.ygyno.2014.06.003. Epub 2014 Jun 11. PMID: 24929052.
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5. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-dostarlimab-gxly-chemotherapy-endometrial-cancer
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7. National Comprehensive Cancer Network. Uterine neoplasms (Version 1.2024.2023). www.nccn.org/professionals/physician_gls/pdf/uterine.pdf Accessed November 2,2023.
8. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pembrolizumab-and-lenvatinib-advanced-endometrial-carcinoma
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10. Vergote I, Pérez-Fidalgo JA, Hamilton EP, Valabrega G, Gorp TV, Sehouli J, Cibula D, Levy T, Welch S, Richardson DL, Guerra EM, Scambia G, Henry S, Wimberger P, Miller DS, Klat J, Martínez-Garcia J, Raspagliesi F, Pothuri B, Romero I, Bergamini A, Slomovitz B, Schochter F, Høgdall E, Fariñas-Madrid L, Monk BJ, Michel D, Kauffman MG, Shacham S, Mirza MR, Makker V; ENGOT-EN5/GOG-3055/SIENDO Investigators. Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer. J Clin Oncol. 2023 Sep 5:JCO2202906. doi: 10.1200/JCO.22.02906. Epub ahead of print. PMID: 37669480.
11. Nishikawa T, Hasegawa K, Matsumoto K, Mori M, Hirashima Y, Takehara K, Ariyoshi K, Kato T, Yagishita S, Hamada A, Kawasaki M, Kawashima S, Tomatsuri S, Nagasaka Y, Yoshida H, Machida R, Hirakawa A, Nakamura K, Yonemori K. Trastuzumab Deruxtecan for Human Epidermal Growth Factor Receptor 2-Expressing Advanced or Recurrent Uterine Carcinosarcoma (NCCH1615): The STATICE Trial. J Clin Oncol. 2023 May 20;41(15):2789-2799. doi: 10.1200/JCO.22.02558. Epub 2023 Mar 28. PMID: 36977309; PMCID: PMC10414746.
12. Konstantinopoulos PA, Lee EK, Xiong N, Krasner C, Campos S, Kolin DL, Liu JF, Horowitz N, Wright AA, Bouberhan S, Penson RT, Yeku O, Bowes B, Needham H, Hayes M, Sawyer H, Polak M, Shea M, Cheng SC, Castro C, Matulonis UA. A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer. J Clin Oncol. 2023 Jan 20;41(3):599-608. doi: 10.1200/JCO.22.00628. Epub 2022 Sep 29. PMID: 36174113.