Addition of Trastuzumab to Chemo Boosts Survival in HER2+ Uterine Serous Carcinoma

Amanda Nickles Fader, MD, an associate professor of gynecology and obstetrics, vice chair of Gynecologic Surgical Operations, director of the Kelly Gynecologic Oncology Service, and director of the Center for Rare Gynecologic Cancers at Johns Hopkins Hospital

Amanda Nickles Fader, MD

The addition of trastuzumab (Herceptin) to carboplatin and paclitaxel resulted in a significant survival benefit in women with advanced or recurrent, HER2-positive uterine serous carcinoma, with the greatest benefit observed in those with stage III/IV disease who received the regimen up front, according to updated phase II data.1

The results, which were made available as part of the virtual platform for the SGO 2020 Annual Meeting, showed that the median overall survival (OS) was significantly higher in the trastuzumab/chemotherapy arm versus chemotherapy alone, at 29.6 months versus 24.4 months, respectively (HR, 0.58; 90% CI, 0.34-0.99; P = .046).

However, the OS benefit with trastuzumab was particularly striking in those with stage III/IV disease. Here, the median OS had not been reached in those who received the experimental regimen versus 25.4 months in those who were given the control regimen (HR, 0.49; 90% CI, 0.25-0.97; P =.041). Notably, no significant OS benefit with the monoclonal antibody was observed in those with recurrent disease.

Updated findings also showed that at a median follow-up of 25.9 months, the trastuzumab regimen resulted in a median progression-free survival (PFS) of 12.9 months compared with 8.0 months for carboplatin/paclitaxel alone among all evaluable patients (n = 58; HR, 0.46; 90% CI, 0.28-0.76; P =.005).

The trastuzumab combination also led to increased PFS benefit in those with stage III/IV disease who were undergoing primary treatment (n = 41), with a median 17.7 months versus 9.3 months with the control regimen (HR, 0.44; 90% CI, 0.23-0.83; P =.015). Among patients with recurrent disease (n = 17), the median PFS was 9.2 months with trastuzumab versus 7.0 months with the control (HR, 0.12; 90% CI, 0.03-0.48; P = .004).

“Uterine serous carcinoma can overexpress HER2/neu growth factor receptor in 25% to 30% of cases. When we look at women with [early-stage] disease who were just treated with standard therapy, such as surgery and then chemotherapy, they can do OK; however, even in that subgroup, there are quite a few who experience recurrence, disease progression, and death,” lead study author Amanda Nickles Fader, MD, told OncLive in an interview. “For women with advanced disease, that number is much higher. We have a really big clinical unmet need here. We need to help these women [by finding more effective strategies to] improve their survival.”

In the investigator-initiated, randomized phase II study, patients with primary stage/IV or recurrent, HER2/neu-positive uterine serous carcinoma were randomized 1:1 to receive intravenous carboplatin area under the curve 5 and paclitaxel at 175 mg/m2 for 3 hours every 21 days for 6 cycles, with or without trastuzumab at 8 mg/kg for the first dose and 6 mg/kg in subsequent cycles, until either disease progression or unacceptable toxicity. The primary end point was PFS; a secondary end point was safety.

“The rationale [for this combination] is that trastuzumab has been really well studied in combination with chemotherapy in breast cancer and other subtypes [with HER2 [positivity],” said Fader, who is an associate professor of gynecology and obstetrics, vice chair of Gynecologic Surgical Operations, director of the Kelly Gynecologic Oncology Service, and director of the Center for Rare Gynecologic Cancers at Johns Hopkins Hospital. “We believe that trastuzumab, and monoclonal antibodies in general, work better when they’re used in concert with other therapies, including conventional cytotoxics.”

Previously published data from the study showed a median PFS of 12.6 months versus 8.0 months in the trastuzumab arm versus the control arm, respectively (HR, 0.44; 90% CI, 0.26-0.76; P = .005) and a median PFS of 17.9 months versus 9.3 months, respectively, among 41 patients with stage III/IV disease receiving primary treatment (HR, 0.40; 90% CI, 0.20-0.80; P = .013).²

Among 17 patients with recurrent disease, the median PFS was 9.2 months versus 6.0 months with the trastuzumab regimen and the control regimen, respectively (HR, 0.14; 90% CI, 0.04-0.53; P =.003).

Sixty patients were evaluable for toxicity and 57 of them were reported to have had ≥1 Common Terminology Criteria for Adverse Events (CTCAE) while receiving treatment. The most common grade ≥3 toxicities that were reported were decreased neutrophil counts (13% with trastuzumab vs 18% with control), anemia (19% vs 7%, respectively), blood and lymphatic system disorders (16% vs 4%), and hypertension (16% vs 0%).

None of these toxicities differed significantly between arms. Although hypertension showed the largest difference (P = .055), the 5 events reported were scored by investigators as either unrelated (n = 2), unlikely (n = 2), or possibly (n = 1) treatment-related.

“The key takeaway from this study is that the updated survival analysis is very promising and suggests that we should be testing all our patients with uterine serous carcinoma for HER2 [overexpression] because we now have an actionable target,” said Fader. “When we utilize trastuzumab in women with advanced disease, we know that we see improved survival outcomes, both short- and long-term.”

Investigators hope to further validate these data; however, this marks the first randomized trial to show a significant survival difference for women with uterine serous carcinoma, according to Fader, so this research offers valuable clinical insight that can still be acted upon now until further trial data are reported.

References

1. Fader AN, Roque DM, Siegel ER, et al. Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress Her2/neu (NCT01367002): updated survival analysis. Data made available as part of the virtual platform for the SGO 2020 Annual Meeting. Abstract 12.
2. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol. 2018;36(suppl_20):2044-2051. doi: 10.1200/JCO.2017.76.5966