Donggeng Liu

Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1) : a phase 3, randomised, double-blind, multicentre trial

BACKGROUNDnmTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer.nnnMETHODSnIn this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m(2) on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395.nnnFINDINGSnBetween Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4-46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55-17·91) with everolimus versus 14·49 months (12·29-17·08) with placebo (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95-24·08) versus 13·08 months (10·05-16·56) with placebo (hazard ratio 0·66, 95% CI 0·48-0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group.nnnINTERPRETATIONnAlthough progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial.nnnFUNDINGnNovartis Pharmaceuticals.

Guidelines on the diagnosis and treatment of breast cancer (2011 edition)

As the most common malignancy among women, breast cancer seriously endangers the physical and mental health of women. So far, the application of multidisciplinary treatment has made breast cancer one of the most treatment-responsive solid tumors.

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

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.

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

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.

Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1

BackgroundThe current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in the Asian subset of patients in the BOLERO-1 trial.MethodsPostmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR–) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety.ResultsIn the Asian subset, median PFS was similar in the everolimus (nu2009=u2009198) and placebo (nu2009=u2009105) arms in the full analysis set (hazard ratiou2009=u20090.82 (95% CI 0.61–1.11)). In the HR– subpopulation, everolimus prolonged median PFS by 10.97xa0months vs placebo (25.46 vs 14.49xa0months; hazard ratiou2009=u20090.48 (95% CI 0.29–0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm.ConclusionsThe efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population.Trial registrationClinicalTrials.gov, NCT00876395. Registered on 2 April 2009.

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

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.

Abstract S6-01: Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1

Background: Everolimus (EVE), an inhibitor of mammalian target of rapamycin (mTOR), is a protein kinase central to a number of signaling pathways regulating cell growth and proliferation. In early studies, EVE showed antitumor activity in breast cancer and synergy with both trastuzumab (TRAS) and paclitaxel. The international BOLERO-1 study is being conducted to evaluate the addition of EVE to TRAS plus paclitaxel as first-line therapy for HER2+ advanced breast cancer. Methods: In this phase 3 randomized trial, 719 adult women with HER2+ advanced breast cancer who had not received prior TRAS or chemotherapy in the advanced setting were randomized 2:1 to receive either EVE or placebo (10 mg) in combination with weekly paclitaxel and TRAS. The two primary objectives were to compare the progression-free survivals (PFS) of everolimus/trastuzumab/paclitaxel and trastuzumab/paclitaxel/placebo in both the full population and in the Hormone Receptor negative (HR-) subpopulation. Secondary endpoints included survival, response rate, and safety. The final analysis was performed after 420 PFS events were observed in the full population. Results: In the full population, the median age was 53 years, 70.4% had visceral metastases, 56.1% had ER and/or PgR +ve disease, and 43.3% had ≥ 3 metastatic sites. Previous adjuvant therapy included TRAS (11.4%) and taxane (24.7%). Conclusions: The data from the final analysis will be available in October 2014. PFS, safety, and secondary efficacy endpoints will be presented at SABCS 2014. (Funded by Novartis; BOLERO-1 ClinicalTrials.gov number, NCT00876395.) Citation Format: Sara A Hurvitz, Fabrice Andre, Zefei Jiang, Zhimin Shao, Silvia P Neciosup, Max S Mano, Ling-Min Tseng, Qingyuan Zhang, Kunwei Shen, Donggeng Liu, Lydia M Dreosti, Jifeng Feng, Howard A Burris, Masakazu Toi, Marc E Buyse, David Cabaribere, Mary-Ann Lindsay, Tiffany Kunz, Shantha Rao, Lida B Pacaud, Tetiana Taran, Dennis Slamon. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1 [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 S6-01.