September 15 2022
Written by Britt K. Erickson, MD, University of Minnesota
NRG-GY026:Phase II/III study of paclitaxel/carboplatin combined with either trastuzumab and hyaluronidase-oysk (Herceptin HYLECTA) or pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma
Although representing only 10% of all endometrial cancer cases, serous carcinomas account for a disproportionate and alarming 40% of all endometrial cancer deaths (Hamilton, 2006). The incidence of endometrial cancer and deaths caused by endometrial cancer are increasing, and this is driven primarily by an increase in the incidence of non-endometrioid histology (Clark, 2022).Currently, adjuvant chemotherapy with carboplatin and paclitaxel remains the standard of care for most cases of early and advanced stage uterine serous and carcinosarcoma (Miller 2020; Powell 2022).However, even with adjuvant therapy, many patients recur and ultimately die from disease. Innovative and targeted strategies are needed to improve outcomes for patients with these high-risk histologic subtypes of endometrial cancer.
The oncogenic potential of HER2 is widely recognized and overexpression has been shown to play an important role in the development and progression of certain aggressive types of breast and gastric cancers. The utility of HER2 as a both prognostic and therapeutic biomarker in endometrial cancer is emerging (Erickson 2020). A significant proportion of uterine serous and carcinosarcomas demonstrate HER2 amplification or overexpression. Phase II data has demonstrated a benefit from adding trastuzumab (a monoclonal antibody directed at HER2)in HER2 positive advanced and recurrent uterine serous carcinoma, with the greatest benefit seen in patients with chemo-naïve disease (Fader, 2020).Clinical trials in HER2 positive breast cancer have demonstrated that the addition of pertuzumab, a different monoclonal antibody that binds to a separate HER2 dimerization domain, to trastuzumab and chemotherapy further improves survival (Swain, 2015).
NRG-GY026 is a randomized phase II/III study evaluating the efficacy of trastuzumab or hyaluronidase-oysk (HERCEPTIN HYLECTA) and pertuzumab, trastuzumab or hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive endometrial serous carcinoma or carcinosarcoma. Patients will be eligible if they have chemo-naïve, non-recurrent stage 1A-IVB uterine serous or carcinosarcoma that is found to be HER2 positive. The formulations of HERCEPTIN HYLECTA and PHESGO are subcutaneous, thus allowing for more convenient administration. The trial opened in August of 2022. The trial seeks to demonstrate prospectively whether the addition of single or dual HER2 targeting therapy improves progression free and overall survival in patients with this high risk endometrial cancer subtype.
Clarke MA, DevesaSS, HammerA, et al. Racial and Ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype. JAMA Oncology. 2022;8(6):895-903
Erickson BK, Najjar O, Klein M, et al. Human Epidermal Growth Factor 2 (HER2) in Early Stage Uterine Serous Carcinoma: A Multi-Institutional Cohort. Gynecol Oncol. 2020
Fader AN, Roque DM, Siegel E, Buza N et al. Randomized phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinosarcomas that overexpress HER2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res. 2020 Aug 1;26(15):3928-3935
Hamilton CA, Cheung MK, Osann K, et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br. J. Cancer. 2006;94:642.
Miller D, Filiaci V, Fleming G, et al. Randomized phase Ill noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. Gynecol. Oncol. 2012. p. 771.
Powell MA, Filiaci VL,Hensley ML et al. Randomized phase II trial of paclitaxel and carboplatin versus paclitaxel and ifosfamide in patients with carcinosarcoma of the uterus or ovary: an NRG oncology trial. J Clin Oncol. 2022 Mar 20;40(9):968-977.
Swain SM, Baselga J, Kim S-B, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Eng J Med 2015; 372:724-734.