Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis

Abstract

Purpose: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.

Patients and methods: Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.

Results: Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97; P = 0.041). Toxicity was not different between arms.

Conclusions: Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.

Figure 1:

CONSORT diagram.

Figure 2.

Updated progression-free survival analyses continue to support the addition of trastuzumab to the treatment of advanced/recurrent uterine serous carcinoma (USC). Left: Median PFS was 8.0 months in patients who received CP and 12.9 months in patients who received CP+T (HR 0.46, 90% CI 0.28–0.76, p=0.005). Benefit from the addition of trastuzumab was greatest in those undergoing primary treatment. Right, top: Median PFS was 9.3 (CP) versus 17.7 (CP+T) months among 41 stage III-IV pts undergoing primary treatment (HR 0.44, 90%CI 0.23–0.83, p=0.015). Right, bottom: Median PFS 7.0 (CP) versus 9.2 (CP+T) months among 17 patients with recurrent disease (HR 0.12, 90%CI 0.03–0.48, p=0.004)

Figure 3.

In a subset analysis of patients restricted to stage IIIC/IV disease, the addition of trastuzumab (n=17) continued to provide both (left) progression-free survival benefit over control (n=19) (9.0 versus 14.8 months, HR 0.393, 90% CI 0.203–0.758, p=0.0078) and (right) overall survival benefit over control (21.1 versus 31.9 months, HR 0.440 90% CI 0.219–0.882 p=0.0230).

Figure 4.

Addition of trastuzumab improves overall survival in advanced uterine serous carcinoma (USC). Left: Among all patients, OS was 24.4 (CP) versus 29.6 (CP+T) months (HR 0.581, 90% CI 0.339–0.994, p=0.0462). Right-top: Benefit was greatest in those undergoing primary therapy with advanced disease (OS 25.4 months versus not reached, HR 0.492, 90% CI 0.249 – 0.974, p=0.0406). Right-bottom: Benefit was not apparent in the recurrent setting (22.5 versus 25.0 months, HR 0.864, 90% CI 0.355–2.100, p=0.3929).