Trastuzumab Combo Paves Way for Novel Regimens in HER2+ Uterine Serous Carcinoma

Amanda Nickles Fader, MD

Available treatments for women with uterine serous carcinoma represent a significant unmet clinical need, said Amanda Nickles Fader, MD. For patients who overexpress HER2/neu, the addition of trastuzumab (Herceptin) to standard chemotherapy could provide a novel regimen with improved outcomes.

"Uterine serous carcinoma is a very rare subtype of uterine cancer, representing only about 5% to 10% of all uterine malignancies," explained Fader. "However, the disease accounts for about 40% of all uterine cancer deaths. It is an important group of women who we need to study to move the needle toward improved survival."

Updated findings from a phase II trial (NCT01367002), which were made available as part of the virtual platform for the 2020 SGO Annual Meeting, demonstrated a statistically significant improvement in survival with the addition of trastuzumab to carboplatin/paclitaxel versus chemotherapy alone for women with advanced or recurrent, HER2-positive uterine serous carcinoma.

The median overall survival (OS) was 29.6 months in the trastuzumab arm compared with 24.4 months in the chemotherapy-alone arm (HR, 0.58; 90% CI, 0.34-0.99; P = .046).

Notably, the OS benefit was extended among patients with newly diagnosed stage III/IV disease who received the combination of trastuzumab and chemotherapy up front. In these patients, the median OS had not yet been reached versus 25.4 months in those who received chemotherapy alone (HR, 0.49; 90% CI, 0.25-0.97; P = .041).

No significant improvement in OS was reported with the addition of trastuzumab to chemotherapy in patients with recurrent uterine serous carcinoma.

In an interview with OncLive, Fader, an associate professor of gynecology and obstetrics, vice chair of Gynecologic Surgical Operations, director of the Kelly Gynecologic Oncology Service, director of the Center for Rare Gynecologic Cancers at The Johns Hopkins Hospital, and director of the F.J. Montz Fellowship Program in Gynecologic Oncology at Johns Hopkins Medicine, discussed the rationale for the phase II study and explained how the findings could open the door to other treatment options for women with uterine serous carcinoma.

OncLive: Why is HER2/neu a good target in uterine serous carcinoma?

Fader: HER2/neu is a growth factor receptor (GFR) that is present in many human cells. [HER2/neu] is evident in many human cancers and is quite common in breast cancer, where it was first identified.

About 10% of women have HER2/neu overexpression in their tumors. As such, these patients are candidates for trastuzumab.

The addition of trastuzumab to [standard chemotherapy in] women whose tumors overexpress HER2 leads to improved outcomes and survival.

What is interesting is that in select uterine cancers, including uterine serous carcinoma, HER2/neu is also very commonly overexpressed. In fact, in uterine serous carcinoma, which is the tumor type that we studied in this randomized phase II trial, HER2/neu was overexpressed in up to 25% to 30% of cases. Even though uterine serous carcinoma is a rarer tumor subtype than breast cancer, HER2/neu is proportionally present in more cases.

We wanted to study the impact of adding trastuzumab, which is a monoclonal antibody, to standard chemotherapy in women with HER2-positive uterine serous carcinoma to determine whether it would improve outcomes.

Could you shed light on the current unmet need in this space?

While the incidence of many solid tumors, as well as mortality [from cancer] around the world, is either decreasing or plateauing, uterine cancer rates and mortality is on the rise. As such, it is important that we study uterine cancer to determine why this is happening. Why is the global phenomenon occurring? What types of uterine cancers are associated with the poorest prognosis? Uterine serous carcinoma represents one of those subtypes with historically poor prognosis.

As stated earlier, uterine serous carcinoma can overexpress the HER2/neu GFR in up to 25% to 30% of cases. When we look at outcomes in women with uterine serous carcinoma who are treated with standard therapies such as surgery followed by chemotherapy, individuals with early-stage disease can do OK, but even in that subgroup quite a few women experience recurrence, disease progression, and eventual death. For women with advanced-stage disease, that number is much higher.

What was the rationale for evaluating trastuzumab in combination with carboplatin/paclitaxel in this patient population?

Trastuzumab has been well studied in breast cancer and other types of HER2-positive tumors. We think that trastuzumab, and monoclonal antibodies in general, work better when they are used in concert with other therapies, including conventional cytotoxic chemotherapy.

From the phase III GOG-209 trial, we know that carboplatin/paclitaxel is 1 of the best chemotherapy regimens we have for the treatment of patients with advanced or recurrent uterine cancers. We were building upon that backbone [when designing this trial].

How was the trial designed, and what were the primary end points of the study?

This is a randomized, phase II trial that had a 2-arm design. One arm enrolled women with advanced-stage primary uterine serous carcinoma who had stage III or IV disease, were newly diagnosed, and [had] just had surgery. The other arm enrolled women with recurrent disease who were remote from having received primary treatment. All women had to have HER2 overexpression in their tumors.

Patients were randomized to receive standard chemotherapy with carboplatin/paclitaxel or carboplatin/paclitaxel plus trastuzumab. The primary end point was progression-free survival (PFS) with secondary endpoints for toxicity and OS. [The goal of the study was to] determine whether the addition of trastuzumab would improve outcomes for these women.

What were the preliminary results of the trial?

The preliminary results were published in the Journal of Clinical Oncology a few of years ago and were previously presented at the 2017 SGO Annual Meeting. Those findings stated that the subgroup of women treated with chemotherapy plus trastuzumab had significantly improved PFS. Particularly, chemotherapy-naïve women with stage III/IV disease who received the combination up front did the best. However, we did see a statistically significant improvement in PFS in [the up front and recurrent settings].

When those data were presented, we did not have enough events to calculate a mature OS estimation. Therefore, OS was not reported in that first manuscript.

We also identified that there were no significant differences in toxicity between the 2 subgroups. This was important because the addition of any targeted therapy can increase toxicity for patients.

What did the updated survival data from this study show?

We were excited to see mature OS data. We recalculated the PFS after a median follow-up of almost 88 months. We showed that the PFS was still significantly improved in the cohort of patients who were treated with chemotherapy plus trastuzumab. Overall, this was almost a 5-month improvement in the overall cohort.

[As in the initial analysis], the biggest difference we saw [in outcomes] was in the women who were treated [with trastuzumab/chemotherapy] up front [versus in the recurrent setting]. The median PFS was 17.7 months in the trastuzumab group versus 9.3 months in the chemotherapy-alone group. That was interesting to see.

We also saw a significantly improved OS difference. The median OS was 29.6 months in the trastuzumab arm compared with 24.4 months in the chemotherapy-alone arm.

Again, the benefit was particularly striking in the subgroup of patients with stage III/IV disease who were treated upfront. In that subgroup, the median OS in the trastuzumab-treated arm has not yet been reached.

In 2019, the National Comprehensive Cancer Network guidelines for uterine cancer recognized the trastuzumab/chemotherapy as a preferred treatment regimen in this cohort of patients with HER2-overexpressing uterine serous carcinoma.

What did the OS analysis demonstrate in patients with recurrent disease?

Interestingly, we did not observe a survival benefit in patients with recurrent disease. We have to take this with a grain of salt because this cohort included 58 evaluable patients, which is not that many. That comes with the territory in rare tumor trials; you are going to have fewer patients that require smaller, more innovative, adaptive study designs in order to determine the optimal treatment.

We do have another large trial planned within the NRG Oncology Group that is currently under development. That trial will hopefully validate these results and allow us to further explore alternative HER2-directed therapies in addition to trastuzumab for patients with uterine serous carcinoma.

What might the OS disparity between women with newly diagnosed disease and women with recurrent disease be attributed to?

The reason we are seeing a more striking difference in the upfront setting compared with the recurrent setting is because most women with uterine serous carcinoma are treated up front with chemotherapy, most likely carboplatin/paclitaxel. The women who recur are already somewhat pretreated. It is possible that their tumors developed resistance to this cytotoxic regimen when they recur. We know that carboplatin/paclitaxel is not as effective in the recurrent setting as it is upfront.

It could be because the patient's tumor develops resistant cancer clones, that their bone marrow is more heavily pretreated, or that platinum-based resistance develops. There are many therapies that are postulated to be the reason that this occurs. However, it appears that the addition of trastuzumab in the recurrent setting may not be potent enough to overcome the potential resistance to cytotoxic chemotherapy.

Could this regimen be used in earlier lines of therapy?

Yes, we believe that these data do support using this regimen in the up-front setting to get the best result for patients with HER2-overexpressing uterine serous carcinoma.

Are there any remaining questions with this research? What next steps are planned?

There are many remaining research questions regarding this trial, and it seems like [the trial created] more questions than it answered. There are a variety of anti-HER2 therapies on the market now, many of which have already been explored in breast cancer, gastric cancer, and other tumor types. We are very excited to explore some of those in patients with uterine serous carcinoma.

I can't say much about the NRG trial other than [it is a trial in progress] that we are excited about. It is likely going to have 3 arms in which we will explore different anti-HER2 therapies in other HER2-positive uterine cancers beyond uterine serous carcinoma.

We're trying to [evaluate the benefit of anti-HER2 therapy] agnostic of tumor type because we think it is an important target to explore.

What is the key takeaway from this study?

The updated survival analysis is very promising, and it suggests that we should be testing all of our patients with uterine serous carcinoma for HER2. We now have an actionable target. When we utilize trastuzumab in women with advanced disease especially, we see short- and long-term survival improvement.

We wish to continue to add to these data to further validate them, but for the time being, these are the best data we have from the only randomized trial we've seen. This is valuable clinical information that [should] be acted upon until we have further trial data.

Are there any other promising approaches under investigation for this patient population you wanted to highlight?

There are many anti-HER2 therapies that are emerging, including other small molecule monoclonal antibody TKIs like lapatinib (Tykerb). Ado-trastuzumab emtansine (TDM-1; Kadcyla) and other antibody-drug conjugates (ADCs) are an exciting area of exploration.

We are currently only treating patients who have very high HER2 expression. However, the level of HER2 expression may not matter as much with some of these novel targeted agents, including ADCs. We may be able to see benefit in patients who have lower HER2 expression and therefore provide therapy for more women.

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.