Xiaojia Wang

Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer

Apatinib is an oral, highly potent tyrosine‐kinase inhibitor targeting VEGFR2. Phase I study showed the recommended dose of 750 mg/day with substantial antitumor activity. This phase II study aims to evaluate the optimum dose level for the efficacy and safety of apatinib monotherapy in heavily pretreated patients with metastatic triple negative breast cancer (mTNBC) in China. Phase IIa was first performed among 25 patients previously treated with anthracycline and/or taxane. All patients received apatinib 750 mg/day p.o. in a 4‐week cycle. Subsequently, a phase IIb study of 59 patients was activated, with the endpoint progression‐free survival (PFS). The dosage of drug for the Phase IIb was determined according to safety, tolerability and efficacy from the phase IIa study. As a result of toxicity associated with the 750 mg dose in phase IIa, the recommended initial dose of apatinib in the phase IIb was 500 mg/day. In phase IIb, grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%) and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand–foot syndrome, proteinuria, hypertension, and increased ALT. In the 56 evaluable patients, overall response rate and clinical benefit rate (CBR) were 10.7 and 25.0%, respectively. Median PFS and overall survival were 3.3 (95% CI 1.7–5.0) and 10.6 (95% CI 5.6–15.7) months, respectively. Our results indicate that apatinib dose of 500 mg rather than 750 mg is the recommended starting dose for the heavily pretreated mTNBC patients with measurable rate of partial response and PFS.

Disparities of Trastuzumab Use in Resource‐Limited or Resource‐Abundant Regions and Its Survival Benefit on HER2 Positive Breast Cancer: A Real‐World Study from China

BACKGROUND Trastuzumab is a key component of therapy for human epidermal growth receptor 2 (HER2) positive breast cancer. Because real-world data are lacking, the present research was conducted to evaluate the actual use of and the effectiveness of trastuzumab in the real world in China. METHODS Inpatients with HER2 positive invasive breast cancer from 13 hospitals in Eastern China (2010-2015, n = 1,139) were included in this study. We aimed to assess the actual use of trastuzumab and to evaluate potential efficacy from trastuzumab in real-world research. RESULTS Of 1,017 patients with early stage breast cancer (EBC), 40.5% (412/1,017) received trastuzumab therapy. Patients with EBC in resource-abundant regions (gross domestic product per capita >

Fulvestrant 500 mg vs 250 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer: a randomized, double-blind registrational trial in China

15,000 and trastuzumab included in Medicare) are more likely to receive trastuzumab than those in resource-limited regions (37.3% vs. 13.0%, p < .05). After metastasis, 50.8% (366/720) patients received trastuzumab as their first-line therapy. More than 10% of patients with metastatic breast cancer (MBC) continued trastuzumab therapy after twice progression in resource-abundant regions, whereas more than 40% of patients never received any trastuzumab therapy during the whole course of therapy in resource-limited regions. Overall, the improvement in survival for trastuzumab versus non-trastuzumab was substantial in EBC (hazard ratio [HR] = 0.609, 95% confidence interval [CI]: 0.505-0.744) and in MBC (HR = 0.541, 95% CI: 0.418-0.606). This association was greater for patients with MBC who had never received trastuzumab (HR = 0.493, 95% CI: 0.372-0.576) than for those who had received adequate trastuzumab therapy in EBC stage (HR = 0.878, 95% CI: 0.506-1.431). CONCLUSION This study showed great disparities in trastuzumab use in different regions and different treatment stages. Both EBC and MBC patients can benefit from trastuzumab, as the survival data show; however, when trastuzumab is adequate in the early stage, a further trastuzumab-based therapy in first-line treatment of MBC will be ineffective, especially for those with short disease-free survival, and a second line of anti-HER2 therapy will be recommended. (Research number: CSCO-BC RWS 15001). IMPLICATIONS FOR PRACTICE This article explores the disparities in the rates of trastuzumab use due to the inequitable allocation of medical resources in China. The irrational use can be found both in resource-abundant regions and in resource-limited regions. Although trastuzumab-based therapy improved survival, the actual use of trastuzumab in the early stage of breast cancer may influence the subsequent therapeutic effect after metastasis. These findings from real-world research could help to optimize HER2 therapy after metastasis, especially in regions with limited access to these expensive targeted drugs.

National consensus in China on diagnosis and treatment of patients with advanced breast cancer

The international CONFIRM study showed that fulvestrant 500 mg improved progression-free survival (PFS) vs fulvestrant 250 mg in postmenopausal women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer (LA/MBC). In this randomized, double-blind study, postmenopausal Chinese women with ER-positive LA/MBC and progression after endocrine therapy received fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or fulvestrant 250 mg (every 28 days). Consistency with the international study was assumed if the hazard ratio (HR) for comparison of PFS (primary endpoint) was < 1 (stratified log-rank test). The study was not powered to assess between-group differences. In total, 221 patients were randomized (fulvestrant 500 mg: n = 111; fulvestrant 250 mg: n = 110). Baseline characteristics were balanced. Median PFS was 8.0 months with fulvestrant 500 mg vs 4.0 months with 250 mg (HR = 0.75; 95% confidence interval [CI] 0.54−1.03; P = 0.078). PFS (HR; 95% CI) favored fulvestrant 500 mg in post-antiestrogen (0.86; 0.54−1.37) and post-aromatase inhibitor (0.65; 0.42−1.03) settings. No new safety considerations were observed. These results are consistent with the international CONFIRM study, supporting the superior clinical benefit of fulvestrant 500 mg in women with ER-positive LA/MBC experiencing progression following prior endocrine therapy.

Outcomes of re-treatment with first-line trastuzumab plus a taxane in HER2 positive metastatic breast cancer patients after (neo)adjuvant trastuzumab: A prospective multicenter study

The recently available guidelines on the management of advanced breast cancer (ABC) organized by Chinese Anti-Cancer Association, Committee of Breast Cancer Society (CACA-CBCS) do not elucidate ABC in details. To instruct clinicians in treatment of ABC, a Chinese expert consensus meeting on diagnosis and treatment of ABC was held in June 2014 and a consensus is developed. The following consensus provides the level of evidence and supporting documents for each recommendation, and introduces research topics to be urgently addressed. Notably, the consensus on diagnosis and treatment of ABC in China is developed to be applied nationwide. In different areas, multidisciplinary treatment (MDT) tailored to the each patient and the disease itself should be applied based on the basic principles of modern oncology.

Abstract P3-10-02: Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer

Trastuzumab is the backbone of HER2-positive early breast cancer (eBC) and metastatic breast cancer (mBC) treatment, but limited data exist as to re-treatment in relapsed patients. In this prospective, single arm, multicenter trial, we assessed efficacy and safety of trastuzumab and taxane combination in Chinese patients with HER2-positive mBC relapsed after prior (neo)adjuvant trastuzumab. Patients with previous (neo)adjuvant trastuzumab treatment for≥9 weeks and a relapse-free interval ≥6 months were assigned to trastuzumab treatment with paclitaxel or docetaxel. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), time to progression (TTP), overall survival (OS) and safety profile. Thirty-two patients were enrolled and treated for a median duration of 33.5 weeks. The median PFS was 9.9 months (95% CI, 6.28 - 13.63 months). The ORR was 81.3% (95% CI, 63.6% - 92.8%) and CBR (CR+PR+SD≥6months) was 81.3% (95% CI, 63.6% - 92.8%). The median DOR was 9.8 months (95% CI, 5.82 - 11.60 months) and median TTP was 9.9 months (95% CI, 6.28-13.63 months). OS median follow-up time was 20.1 months and 25% OS time was 25.5 months. The safety profile was acceptable with common adverse events including leukopenia (59.4%), neutropenia (56.3%), hypoaesthesia (34.4%) and granulocytopenia (31.3%). In conclusion, re-treatment with trastuzumab plus a taxane as first-line therapy is an effective regimen for patients with HER2-positive mBC relapsed after (neo)adjuvant trastuzumab. The safety profile was good and the adverse reactions were tolerable and manageable.

Abstract P1-13-07: A phase III study of fulvestrant 500 mg versus 250 mg in postmenopausal Chinese women with advanced breast cancer and disease progression following failure on prior antiestrogen or aromatase inhibitor therapy: Supporting superior clinical benefit for the

Background: There is still no standard chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Our previous phase II pilot trial with first-line gemcitabine and cisplatin combination (GP) in patients with mTNBC (clinicaltrials.gov Identifier: NCT00601159) showed a median progression-free survival (PFS) of 6.2 months. In this Chinese Breast Cancer Study Group (CBCSG) 006 trial (clinicaltrials.gov Identifier: NCT01287624) we explored in a randomized trial the role of the less costly GP regimen versus the standard GT [Gemcitibine + paclitaxel] chemotherapy for the metastatic breast cancer as a first line treatment for mTNBC. Trial objectives: progression free survival [PFS]; overall survival [OS]; and toxicity. Methods: In the trial with a hybrid trial design incorporating a formal test of superiority as well as noninferiority, mTNBC patients with no previous chemotherapy for metastatic disease were randomly assigned to receive either GP regimen (G/P: 1250 mg/m2 d1,8/ 75 mg/m2 d1) or the GT regimen (same G; T: 175 mg/m2 d1). Results: Between Jan. 2011 and Nov., 2013, 236 patients were randomized [118 patients / arm], and all received at least one dose of assigned chemotherapy. As of Mar. 20, 2014, the intent-to-treat analysis showed 201 recurrences and 97 deaths. Objective response rates of GP vs GT were 67.9% vs. 50.4% (P= 0.008), with median PFS of 232 vs. 194 days (HR=0.692, 95% CI 0.523-0.915; P= 0.009). Overall survival of patients from the GP vs. the GT arms was median 672 vs. 556 days (HR=0.902, 95% CI 0.605-1.344; P= 0.611). Significant differences in grade 3/4 adverse events were seen for nausea, vomiting, anemia and thrombocytopenia [GP vs. GT, 6.8 vs. 0.8%; 11.0 vs. 0.8%; 33.1 vs. 51.0%; and 32.2 vs. 2.5%, respectively]. In addition, assessment of adverse events of any grade showed the GP regimen had more anorexia, constipation, hypomagnesemia and hypokalemia, while GT regimen had significantly more alopecia and peripheral neuropathy. The delivered relative dose intensity was > 90% for all three drugs, with the total number of delivered cycles of chemotherapy in GP and GT arms being 654 and 648 [average 5.54 and 5.49 /patient], respectively. Conclusions: 1.The Gemcitabine + Platinum is superior to Gemcitabine + Paclitaxel in terms of objective response rates and duration of PFS. 2.While grade 3 / 4 nausea & vomiting, and anemia, were heavier for the GP combination, the delivery of chemotherapy and average number of cycles delivered were comparable between the two arms. 3.Overall survival data will be updated on the conference to indicate the long-term effect of the somehow more toxic GP regimen, which shows nevertheless superiority of response rates and of the PFS over the more costly GT regimen. Citation Format: Xichun Hu, Binghe Xu, Li Cai, Zhonghua Wang, Biyun Wang, Jian Zhang, Yuee Teng, Zhongsheng Tong, Yueyin Pan, Yongmei Yin, Changping Wu, Zefei Jiang, Xiaojia Wang, Guyin Lou, Donggeng Liu, Jifeng Feng, Jianfeng Luo, Jiong Wu, Zhimin Shao, Joseph Ragaz. Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-02.

[Effects of auto-tumor infiltrating lymphocytes induced by interleukin (IL)-12 with IL-2 on patients of primary hepatic carcinoma].

Background: In the international Phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study, fulvestrant 500 mg was associated with significantly longer progression-free survival (PFS) over the 250 mg dose (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.68, 0.94; p=0.006) in postmenopausal women with advanced breast cancer (ABC) following failure on prior endocrine therapy. There were no clinically meaningful differences between the treatment groups in terms of the incidence or severity of adverse events. The present study was designed to compare the efficacy and safety of fulvestrant 500 mg versus 250 mg in a Chinese population for registration purposes. Methods: This was a Phase III randomized, double-blind study in a Chinese population (ClinicalTrials.gov: NCT01300351). Postmenopausal women with estrogen receptor positive (ER+) ABC following failure on prior endocrine (antiestrogen [AO] or aromatase inhibitor [AI]) therapy were randomized 1:1 to fulvestrant 500 mg or 250 mg. Patients (pts) were stratified by post-AO/post-AI status and enrollment of post-AI pts was capped at 45%. Primary study endpoint was PFS. Consistency with the global CONFIRM study was to be concluded if the HR for the treatment comparison of PFS was Results: 221 pts were randomized to fulvestrant 500 mg (n=111) or fulvestrant 250 mg (n=110). 121 pts were in the post-AO subgroup and 100 pts were in the post-AI subgroup. Demographic and baseline characteristics were balanced between fulvestrant 500 mg and fulvestrant 250 mg and comparable with those in the global CONFIRM study. 98% (119/121) in the post-AO subgroup and 92% (92/100) in the post-AI subgroup had adjuvant endocrine therapy, while only 12% (14/121) in the post-AO subgroup and 51% (51/100) in the post-AI subgroup used salvage endocrine therapy. At the time of the primary analysis, 152 progression events (69%) had occurred (post-AO 59% [71/121]; post-AI 81% [81/100]). Median PFS was 8.0 months (m) in the fulvestrant 500 mg group vs 4.0 m in the 250 mg group (HR 0.75; 95% CI 0.54, 1.03; p=0.078); the predefined criterion for consistency with the global CONFIRM study was met. In a predefined subgroup analysis of PFS, the HR for fulvestrant 500 mg vs 250 mg was Conclusions: Data from the present study support the superior clinical benefit of fulvestrant 500 mg vs 250 mg demonstrated in the global CONFIRM study, in postmenopausal Chinese women with ER+ ABC. Hazard ratios favoring fulvestrant 500 mg were observed in both the post-AO and post-AI settings. Citation Format: Zefei Jiang, Qingyuan Zhang, Zhimin Shao, Kunwei Shen, Li Li, Jifeng Feng, Zhongseng Tong, Kangsheng Gu, Xiaojia Wang, Binghe Xu, Guofang Sun, Huifang Chen, Yuri Rukazenkov. A phase III study of fulvestrant 500 mg versus 250 mg in postmenopausal Chinese women with advanced breast cancer and disease progression following failure on prior antiestrogen or aromatase inhibitor therapy: Supporting superior clinical benefit for the [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-07.