PFS Benefit Found With Added Trastuzumab in Uterine Serous Carcinoma

Alessandro D. Santin, MD

When trastuzumab (Herceptin) was added to chemotherapy, a more than 50% improvement in progression-free survival (PFS) was observed compared with chemotherapy alone in patients with HER2-positive uterine serous carcinoma (USC), according to findings from a small randomized trial. 

An increase in median PFS was found with carboplatin and paclitaxel from 8.0 months to 12.6 months with the addition of trastuzumab to the same chemotherapy regimen. There was almost a twofold increase for medial PFS in patients with more advanced disease from 9.3 months with chemotherapy to 17.9 months with chemotherapy plus trastuzumab.

Preliminary survival analysis demonstrated a trend in favor of the trastuzumab arm. According to the results shared at the 2018 Society of Gyneocologic Oncology Annual Meeting, there was an increase in survival for patients with more advanced-stage disease and those who received the combination as initial systemic therapy.

“The addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival in both advanced and recurrent uterine serous carcinoma,” said Alessandro D. Santin, MD, a professor of obstetrics, gynecology, and reproductive sciences at Yale School of Medicine. “These encouraging results deserve further investigation to determine the impact of HER2/neu-targeted treatment on overall survival in women with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.”

A rare but aggressive form of endometrial cancer, USC accounts for 10% or fewer new cases. However, 40% of endometrial cancer-related deaths occur each year. Most patients have extrauterine spread at the time of their diagnosis. Activity with chemotherapy and radiation therapy has been found, but there is only about 40% 5-year survival across all stages at diagnosis.

Santin exlpained that USC has a distinct molecular makeup compared to endometroid carcinoma, which is more common. Characterized by high genomic instability, USC is noted to also have low mutational burden, and alterations inTP53. Dysregulation ofHER2/neualso may occur in more than a fourth of the tumors in USC, andHER2/neuoverexpression has been found in as many as 60% of patients with USC.

Trastuzumab was evaluated by The Gynecologic Oncology Group (GOG) as a single agent in patients with advanced or recurrent endometrial cancer withHER2/neuoverexpression (GOG 1818). However, the patient-accrual target was not reached in this study, and trastuzumab was considered inactive inHER2+endometrial carcinoma.

“However, the final analysis of GOG 1818 was flawed in that 47% of the study subjects treated with trastuzumab ultimately did not have tumoralHER/2neugene amplification. Additionally, there was no limit on the number of prior lines of chemotherapy, much of the cohort had bulky, measurable, and heavily pretreated recurrent disease," said Santin

Since the completion of GOG 1818, findings from USC provide evidence to explain the trial’s negative outcome, Santin added. unlike breast cancer, USC is highly heterogeneous inHER2/neuexpression and the mutations in thePIK3CApathway may appear in up to 60% ofHER2/neu-amplified US, representing a major mechanism of resistance to trastuzumab.

Investigators from 11 centers in the United States conducted a randomized phase II trial with the expectation of determining the benefit in adding trastuzumab to carboplatin-paclitaxel chemotherapy in women withHER2/neu+ USC. The primary endpoint of PFS and secondary objectives of the trial included objective response rate, overall survival, and safety.

There was an initial accrual goal of 100 patients. Researchers hoped this would give the trial the statistical power to demonstrate improvement in median PFS from 6 months with chemotherapy alone to 10.5 months with the addition of trastuzumab (HR, 0.57). However, the accrual proceeded slower than anticipated, which subsequently closed the trial with 61 patients, 58 of whom were evaluable for the primary endpoint.

Eligible patients had FIGO stage III/IV or recurrent USC. TheHER2/neuoverexpression was defined as 3+ by immunohistochemistry or 2+ by fluorescence in situ hybridization. Enrollment occurred within 8 weeks of surgery or diagnosis of recurrent disease and there could not be more than three prior lines of chemotherapy in the case of recurrent disease. Patients also had a treatment-free interval >6 months from the last carboplatin-paclitaxel regimen for patients with recurrent disease.

The study population comprised 41 patients with advanced disease and 17 had recurrent disease. The median number of prior lines of therapy was one and did not differ between the treatment arms.

The addition of trastuzumab was found to have reduced the hazard ratio for progression or death by 56% (HR, 0.44; 90% CI, 0.26-0.76;P= .005) after analysis of the 58 patients. Among the 41 patients with advanced disease, there was a median PFS of 17.9 months with trastuzumab versus 9.1 months in patients that recieved chemotherapy alone (HR, 0.40; 90% CI, 0.20-0.80;P= .013).

Patients with recurrent disease, though a smaller group, also demonstrated benefit from trastuzumab, showing a median PFS of 9.2 months with the anti-HER2 drug and 6.0 months for chemotherapy alone (HR, 0.14; 90% CI, 0.04-0.53;P= .003).

Among this group, 2 patients treated with chemotherapy alone had complete responses, while 4 had partial responses, 1 had stable disease, and 1 had progressive disease. Patients randomized to the trastuzumab arm demonstrated 1 complete response, 3 partial responses, and 5 who had stable disease. There was a clinical benefit rate (response plus stable disease) of 87.5% in the control arm and 100% among patients randomized to trastuzumab.

The safety analysis included all but 1 patient from the trial. Toxicities did not differ significantly between treatment arms. There was 1 case of fatal thromboembolism in the control arm.

Of the 58 (23 deaths) patients, the preliminary survival analysis showed a median duration of 15.4 months, yielding 1-sidedP-values of .050 for patients with advanced USC and .097 for the patients with recurrent disease. Sensitivity analysis yielded a 1-sided P-value of .0231.

“The preliminary overall survival data suggest that the greatest benefit of trastuzumab may be in the upfront setting in those with the most advanced disease,” said Santin. “A statistically more robust analysis of trastuzumab’s effect on overall survival will be conducted once the number of deaths reaches 30.”

Reference:

Fader AN, Roque DM, Siegel E, 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. Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Abstract 22: