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 AE 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 medianfollow-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 ¼ 0.46; 90% CI, 0.28-0.76; P ¼ 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 ¼ 0.44; 90% CI, 0.23-0.83; P ¼ 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR ¼ 0.12; 90% CI, 0.03-0.48; P ¼ 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR ¼ 0.58; 90% CI, 0.34-0.99; P ¼ 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 ¼ 0.49; 90% CI, 0.25-0.97; P ¼ 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.

Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis

“…Most recently, with the publication of PORTEC‐3 data evaluating the response of high‐risk ECs to adjuvant radiation with or without chemotherapy by molecular subtype, 20 the powerful predictive potential of molecular subgroups is apparent and dictates application into clinical care. Although drawn from retrospective series, there is evidence of improved outcomes for EC patients with abnormal p53 (p53abn) with the administration of chemotherapy 20 and targeted agents 43‐46 ; there is a suggestion of an improved response to radiation 47 and immune blockade 48‐50 with no apparent benefit of conventional chemotherapy in MMRd ECs 20 , as well as the possibility of de‐escalated therapy or no additional therapy for POLE mut ECs 20,51,52 . With the 5‐year recurrence‐free survival and overall survival rates both at 98% for patients with POLE mut ECs in PORTEC3 (high‐risk ECs by ESMO risk stratification; data unavailable at the time of assembly of this cohort), was any adjuvant therapy needed for these women?…”

Adjuvant brachytherapy for FIGO stage I serous or clear cell endometrial cancer

“…Currently, the role of targeted therapeutic agents, in early and late stage uterine serous cancers that express human epidermal growth factor 2 (HER2), is being studied, with favorable outcomes. 29 30 However, despite the move into molecular profiling, at this time, this is not readily available at all treatment centers. PORTEC-4 31 is currently accruing and will randomize women with early-stage endometrial cancer to adjuvant therapy based on integrated molecular risk profile versus vaginal brachytherapy alone; however, women with high-risk histologies will not be enrolled in this study.…”

HER2 Status in High-Risk Endometrial Cancers (PORTEC-3): Relationship with Histotype, Molecular Classification, and Clinical Outcomes

“…Nevertheless, existing evidence points towards a correlation between HER2 protein overexpression and/or ERBB2 amplification in EC with serous histology (SEC), with reported frequencies ranging between 29-49% [18][19][20][21]. Recently, a phase II clinical trial comparing adjuvant carboplatinpaclitaxel with and without trastuzumab in 58 patients with advanced and recurrent HER2-overexpressing SEC showed increased progression-free survival in favor of the combined chemotherapy-trastuzumab treatment arm [22,23]. These findings encourage further investigation of the efficacy of trastuzumab in combination with chemotherapeutic agents in HER2-overexpressing/amplified EC.…”