图兰朵：贝伐珠单抗＋紫杉醇对比贝伐珠单抗＋卡培他滨一线治疗HER2阴性转移性乳腺癌的随机非盲非劣效性Ⅲ期研究主要终点结果
前情提要：意大利歌剧《图兰朵》来自意大利语“Turandot”的音译，而此词本身就来自波斯语“Turandokht”，由“Turan”（中亚地名）和“dokht”（女儿）两个字组成，意即“图兰之女”。2008年，中欧肿瘤协作组（CECOG）将贝伐珠单抗＋紫杉醇对比贝伐珠单抗＋卡培他滨一线治疗HER2阴性转移性乳腺癌（capeciTabine and bevacizUmab. Randomised Against avastiN anD taxOl Trial）的随机非盲非劣效性Ⅲ期研究命名为：图兰朵（TURANDOT）。2013年，该研究在英国《柳叶刀肿瘤学分册》发表的中期分析未能确定总生存的非劣效性（分层风险比：1.04，97.5%重复置信区间：-∞～1.69）。
2016年8月5日，英国《柳叶刀肿瘤学分册》在线发表奥地利、匈牙利、以色列、波黑、拉脱维亚、捷克、波兰、罗马尼亚、德国的TURANDOT研究主要终点结果，比较了两种FDA批准的HER2阴性转移性乳腺癌含贝伐珠单抗治疗方案的有效性、安全性和生活质量，以证明贝伐珠单抗＋紫杉醇对比贝伐珠单抗＋卡培他滨一线治疗局部复发性或转移性乳腺癌总生存的非劣效性。
该研究患者入选条件为年龄≥18岁、东部肿瘤协作组（ECOG）体能状况评分0～2、HER2阴性、局部复发性或转移性乳腺癌、病灶可测或不可测量、既往未接受过针对局部复发性或转移性而进行的化疗，将患者进行分层，采用六格置换矩阵进行随机分组（1∶1），分为贝伐珠单抗＋紫杉醇组（贝伐珠单抗10mg/kg，第1、15天；紫杉醇90mg/m²，第1、8、15天；每4周重复）和贝伐珠单抗＋卡培他滨组（贝伐珠单抗15mg/kg，第1天；卡培他滨1000mg/m²，每天2次，第1～14天；每3周重复），直至疾病进展、出现难以耐受的毒性或退出研究。分层因素为雌激素或孕激素受体状态、国家、绝经情况。主要终点为按方案治疗患者贝伐珠单抗＋卡培他滨对比贝伐珠单抗＋紫杉醇出现总生存非劣效，采用分层Cox比例风险模型排除劣效性无效假设（风险比≥1.33）判断非劣效性。该研究在美国政府临床研究注册网站（ClinicalTrials.gov）注册号为：NCT00600340。
该研究于2008年9月10日～2010年8月30日对564例意向治疗患者进行随机分组，按方案治疗患者531例（贝伐珠单抗＋紫杉醇组266例、贝伐珠单抗＋卡培他滨组265例）。贝伐珠单抗＋紫杉醇组266例死亡183例（69%）、贝伐珠单抗＋卡培他滨组265例死亡201例（76%）之后，在意向治疗患者中进行总生存最终分析，中位总生存（95%置信区间）分别为30.2（25.6～32.6）个月和26.1（22.3～29.0）个月。分层风险比为1.02（97.5%重复置信区间：-∞～1.26，p=0.0070），表现出非劣效性。未分层Cox模型（风险比：1.13，97.5%重复置信区间：-∞～1.39，p=0.061）并不支持该分析结果。意向治疗分析与按方案治疗的分析结果一致。贝伐珠单抗＋紫杉醇组（284例）、贝伐珠单抗＋卡培他滨组（277例）最常见的≥3级不良反应分别为中性粒细胞减少（54例[19%]、5例[2%]）、手足综合征（1例[＜1%]、43例[16%]）、外周神经病变（39例[14%]、1例[＜1%]）、白细胞减少（20例[7%]、1例[＜1%]）、高血压（12例[4%]、16例[6%]），报告严重不良反应的患者分别有65例（23%）、68例（25%），研究者判定治疗相关性死亡患者分别有2例、0例。
因此，贝伐珠单抗＋卡培他滨对于HER2阴性局部复发性或转移性乳腺癌是有效的一线治疗选择，与贝伐珠单抗＋紫杉醇相比，耐受性好且不影响总生存。尽管贝伐珠单抗＋卡培他滨的无进展生存不如贝伐珠单抗＋紫杉醇，但仍建议医生应当根据总生存预测性风险因素、患者本人治疗选择意愿、治疗方案安全性进行综合考虑，选择个体化治疗方案。
对此，美国匹兹堡大学的血液学与肿瘤学专家发表同期述评：贝伐珠单抗在转移性乳腺癌中是否存在空间？
Lancet Oncol. 2016 Aug 5. [Epub ahead of print]
Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial.
Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators.
Medical University Vienna, Vienna, Austria; National Institute of Oncology, Budapest, Hungary; Tel Aviv University, Tel Aviv, Israel; University of Szeged, Szeged, Hungary; Paracelsus Medical University, Salzburg, Austria; Clinical Center of Sarajevo University, Sarajevo, Bosnia and Herzegovina; Rabin Medical Center, Petach Tikva, Israel; Riga Eastern Clinical University Hospital, Riga, Latvia; Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Postgraduate Medical Center, Warsaw, Poland; Oncomed Oncology Practice, Timisoara, Romania; Charles University Prague, Prague, Czech Republic; Cancer Institute I Chiricuta, Cluj-Napoca, Romania; Meir Medical Center, Kfar Saba, Israel; Semmelweis University Cancer Center, Budapest, Hungary; University of Medicine and Pharmacy 'Carol Davila', Bucharest, Romania; Prometris GmbH, Mannheim, Germany.
BACKGROUND: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1.04; 97.5% repeated CI [RCI] -∞ to 1.69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer.
METHODS: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m² on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m² twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1.33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340.
FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30.2 months (95% CI 25.6-32.6 months) versus 26.1 months (22.3-29.0), respectively. The stratified HR was 1.02 (97.5% RCI -∞ to 1.26; repeated p=0.0070), indicating non-inferiority. The unstratified Cox model (HR 1.13 [97.5% RCI -∞ to 1.39]; repeated p=0.061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group.
INTERPRETATION: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles.
FUNDING: Roche.
PMID: 27501767
PII: S1470-2045(16)30154-1
DOI: 10.1016/S1470-2045(16)30154-1
Lancet Oncol. 2016 Aug 5. [Epub ahead of print]
Is there room for bevacizumab in metastatic breast cancer?
Brufsky A.
Department of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Exciting advances in the therapy of metastatic breast cancer have occurred over the past decade. For example, median overall survival from first-line therapy in Her2-positive metastatic breast cancer exceeded 56 months in a recent trial of pertuzumab, traztuzumab, and docetaxel as first-line therapy. Additionally, median progression-free survival of oestrogen receptor-positive metastatic breast cancer now exceeds 24 months when letrozole and palbociclib is given as first-line therapy. Several novel compounds are currently being tested, with some, such as entinostat (a histone deacetylase inhibitor) and atezolizumab (a PD-L1 inhibitor) currently in phase 3 trials.
In this new era, where does this leave the development of older therapeutics for metastatic breast cancer, such as bevacizumab? The addition of bevacizumab to cytotoxic chemotherapy for metastatic breast cancer was first proposed more than a decade ago, and initial excitement over improvements in progression-free survival with bevacizumab was tempered by an absence of overall survival benefit. However, in the recent IMELDA trial, when bevacizumab was added to capecitabine as therapy for metastatic breast cancer in a prolonged maintenance phase after initial response to docetaxel and bevacizumab, median overall survival was increased to 39 months (95% CI 32.3-not reached) from 23.7 months (18.5-31.7) with capecitabine maintenance alone.
Thus, substantial uncertainty remains over the best use of bevacizumab for metastatic breast cancer, which is reflected in the regulatory status of bevacizumab. European authorities have approved its use in first-line therapy for metastatic breast cancer, but the US Food and Drug Administration has not.
The TURNADOT trial by Christoph Zielinski and colleagues, published in The Lancet Oncology, is an opportunity to clarify some of this uncertainty. TURANDOT attempted to expand the choice of a less toxic systemic chemotherapy partner for bevacizumab by testing bevacizumab plus capecitabine against bevacizumab plus paclitaxel as first-line therapy for Her2-negative metastatic breast cancer. The primary objective was non-inferiority of overall survival for the bevacizumab plus capecitabine group. A previous interim analysis9 had shown superiority for bevacizumab plus paclitaxel over bevacizumab plus capecitabine with a progression-free survival of 11.0 months (95% CI 10.4-12.9) versus 8.1 months (7.1-9.2), with a hazard ratio (HR) of 1.36 (95 CI% 1.09-1.68, p=0.0052).
564 patients were included in the final updated intent-to-treat overall survival analysis, with 531 treated per protocol. At a median duration of follow-up of 54.3 months (IQR 50.2-61.7), median overall survival was 30.2 months (95% CI 25.6-32.6) with bevacizumab plus paclitaxel. The median duration of follow-up was 55.7 months (IQR 50.5-64.4) in the bevacizumab plus capecitabine group with a median overall survival of 26.1 months (22.3-29.0). The stratified HR was 1.02 (97.5% repeated CI [RCI] -∞ to 1.26; p=0.0070) between groups, indicating non-inferiority of bevacizumab plus capecitabine to bevacizumab plus paclitaxel. However, several additional sensitivity analyses, using unstratified HR for overall survival, did not support non-inferiority of bevacizumab plus capecitabine. Interestingly, in an exploratory Cox model of prognostic factors for survival, bevacizumab plus capecitabine was superior in post-menopausal women, and in patients with a body surface area less than 1.8 m². These exploratory observations are intriguing, and hopefully will be the subject of further study.
A noteworthy aspect of TURNADOT was post study therapy at progression. It seems that about 40% of participants in each group received the opposite systemic therapy without bevacizumab at progression (paclitaxel in the capecitabine group, and vice-versa). This might be a potential reason for the apparent non-inferiority in overall survival in this study where progression-free survival was superior with bevacizumab plus paclitaxel. Preclinical data suggest that discontinuation of bevacizumab results in rapid re-establishment of neoangiogenesis. Furthermore, preclinical data also suggest that bevacizumab normalises tumour vasculature and reduces tumour oncotic pressure, allowing for greater chemotherapy delivery. Would bevacizumab continued during second-line therapy and beyond have resulted in a potential overall survival benefit to bevacizumab plus paclitaxel in TURANDOT? We cannot answer this, although several clinical trials are currently in progress to address this question.
Thus, bevacizumab still does have a substantial role in the management of metastatic breast cancer. Bevacizumab is a reasonable option as first-line therapy in combination with paclitaxel, and as the TURNADOT results suggest, bevacizumab is also a reasonable first-line therapy in combination with capecitabine. Data from the IMELDA trial pose the intriguing hypothesis that bevacizumab might have significant benefit when part of an extended maintenance regimen in metastatic breast cancer. The challenge for the next few years, as more drugs with exciting activity and novel mechanism are introduced for the treatment of metastatic breast cancer, will be how best to integrate bevacizimab into a comprehensive management strategy for this disease.
PMID: 27501769
PII: S1470-2045(16)30295-9
DOI: 10.1016/S1470-2045(16)30295-9