編者按：絕大多數(shù)抗癌藥物劑量都是從最大耐受劑量開始，如果患者難以耐受，那么逐步減量，直至患者耐受或者停藥。從大劑量開始的好處是迅速殺死癌細胞，壞處是患者難以堅持治療，尤其對于術(shù)后短期復(fù)發(fā)風險較低、長期復(fù)發(fā)風險較高、需要長期治療的早期癌癥患者。激素受體陽性HER2陰性早期乳腺癌確診后數(shù)十年內(nèi)都有遠處復(fù)發(fā)風險，某些臨床和病理特征預(yù)示復(fù)發(fā)風險較高，包括腋窩淋巴結(jié)轉(zhuǎn)移、腫瘤較大和腫瘤分級較高。對于高風險患者，包括高風險淋巴結(jié)陽性患者，大約30%可能出現(xiàn)病變復(fù)發(fā)，大多為遠處轉(zhuǎn)移。對于復(fù)發(fā)風險較高患者，標準術(shù)后內(nèi)分泌治療添加入CDK4/6抑制劑（阿貝西利或瑞波西利）可顯著改善無浸潤病變生存。monarchE研究已經(jīng)證實，對于激素受體陽性HER2陰性高風險淋巴結(jié)陽性早期乳腺癌患者，標準術(shù)后內(nèi)分泌治療加用2年阿貝西利（每天2次口服150毫克）與單用內(nèi)分泌治療相比，可顯著改善中位無浸潤病變生存、遠處無復(fù)發(fā)生存甚至總生存。不過，阿貝西利可能引起副作用，使治療復(fù)雜化。不良事件（腹瀉、中性粒細胞減少或疲勞最常見）分別導(dǎo)致61.7%和43.4%的monarchE研究參與者暫?；驕p少阿貝西利劑量。2或3級不良事件主要發(fā)生于治療的前12周，腹瀉發(fā)生時間中位8天。此外，18.5%的參與者由于不良事件而提前停用阿貝西利，治療第1個月的停藥率最高。因此，確定降低毒性和提高術(shù)后阿貝西利治療依從性的策略至關(guān)重要，尤其開始治療的最初幾周。既往研究表明，早期劑量遞增方案可能降低口服抗癌治療早期毒性。對于HER2陽性早期乳腺癌患者，劑量遞增策略成功減少術(shù)后治療有臨床意義的不良事件，例如ExteNET研究奈拉替尼組患者3級腹瀉發(fā)生率達40%，由于腹瀉停止治療達17%，其中3級腹瀉達7.5%，多隊列CONTROL研究奈拉替尼劑量遞增方案將3級腹瀉發(fā)生率降至15%，僅3%的參與者由于腹瀉停用奈拉替尼。此外，DESIREE研究依維莫司劑量遞增策略降低有臨床意義的不良事件發(fā)生率，并提高晚期乳腺癌患者的治療依從性。 2025年10月17日，歐洲腫瘤內(nèi)科學(xué)會官方期刊《腫瘤學(xué)年鑒》在線發(fā)表美國哈佛大學(xué)醫(yī)學(xué)院德納法伯癌癥研究院、德納法伯布萊根癌癥中心、新英格蘭癌癥醫(yī)院、貝斯以色列女執(zhí)事醫(yī)療中心、貝內(nèi)特癌癥中心、波士頓醫(yī)療中心、北極光醫(yī)療中心、意大利米蘭大學(xué)歐洲腫瘤研究院的TRADE研究報告，首次前瞻嘗試淋巴結(jié)陽性早期激素受體陽性HER2陰性乳腺癌患者術(shù)后阿貝西利短期劑量遞增策略能否改善耐受性、降低停藥率并提高治療初期劑量達標率。- TRADE (NCT06001762): Dose Escalation Tolerability of Abemaciclib in HR+ HER2- Early Stage Breast Cancer
- Official Title: The TRADE Study: A Phase 2 Trial to Assess the ToleRability of Abemaciclib Dose Escalation in Patients With Early-Stage HR-positive and HER2-negative Breast Cancer
該多中心單組二期臨床研究于2023年10月至2024年9月在12個研究中心入組淋巴結(jié)陽性激素受體陽性HER2陰性乳腺癌且術(shù)后適合阿貝西利聯(lián)合內(nèi)分泌治療患者90例，阿貝西利開始劑量為每天2次50毫克連續(xù)2周，隨后每天2次100毫克連續(xù)2周，最后每天2次150毫克。劑量遞增前提為未發(fā)生3至4級或持續(xù)2級毒性反應(yīng)。主要終點為12周時阿貝西利由于任何原因停藥或無法達到或維持目標劑量的綜合不良事件發(fā)生率。 結(jié)果，主要終點中位隨訪32.1周，其中1例患者完成術(shù)后阿貝西利治療12周前復(fù)發(fā)，其余89例患者12周時綜合不良事件發(fā)生率僅29.2%（90%置信區(qū)間：21.3%～38.2%）顯著低于monarchE研究歷史數(shù)值40%（P=0.023）。其中僅6例（6.7%）患者提前停藥、8例（9.0%）患者無法達到150毫克、12例（13.5%）患者從150毫克減量。大多數(shù)（70.8%）患者達到并堅持每天2次口服150毫克。 因此，該研究結(jié)果表明，術(shù)后阿貝西利劑量遞增策略可使超過70%的患者達到并堅持標準劑量，早期停藥率低于7%，12周時治療堅持率高于93%。在開始術(shù)后阿貝西利治療時，可以考慮采用此劑量遞增策略。Ann Oncol. 2025 Oct 17. IF: 65.4TRADE: A phase II trial to assess the tolerability of abemaciclib dose escalation in early-stage HR+/HER2- breast cancer.Mayer EL, Trapani D, Kim SE, Faggen M, Sinclair N, Sanz-Altamira P, Battelli C, Berwick S, Lo S, Acevedo J, Sinclair S, Malcolm A, Varella L, Sammons S, Schumer S, Poorvu PD, Wallace E, Pasternak E, Tayob N, Tolaney SM.Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Dana-Farber Brigham Cancer Center - Foxborough and Milford, MA, USA; New England Cancer Specialists, Westbrook, ME, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Bennett Cancer Center, Stamford Health, Stamford, CT, USA; Boston Medical Center, Boston, MA, USA; Northern Light Health, Brewer, ME, USA; European Institute of Oncology, IRCCS, Milan, Italy; University of Milan, Milan, Italy.- Adjuvant abemaciclib reduces risk of HR+ HER2- breast cancer recurrence; however, therapy can be complicated by toxicity.
- The TRADE study asks if abemaciclib dose escalation helps to reach target dose and reduce discontinuations at 12 weeks.
- Results show dose escalation significantly reduced the composite adverse event rate compared to historic control (p=0.023).
- With dose escalation, 70% of patients were able to reach target dose and almost 95% avoided drug discontinuation.
- Adjuvant abemaciclib dose escalation can be considered as a clinical strategy when initiating patients on this agent.
PURPOSE: Adjuvant abemaciclib with endocrine therapy (ET) improves clinical outcomes in patients with high-risk node-positive early-stage hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer, based on the monarchE trial. Patients may experience tolerability issues at the standard abemaciclib dose (150 mg twice daily [BID]), potentially leading to early treatment discontinuation, particularly within the initial weeks of therapy. TRADE is a prospective, single-arm, phase 2 study evaluating whether dose escalation of adjuvant abemaciclib improves drug tolerability.PATIENTS AND METHODS: Eligible patients had node-positive HR+/HER2- breast cancer and were candidates for adjuvant abemaciclib with ET. Participants initiated abemaciclib at 50 mg BID for two weeks, then escalated to 100 mg BID for two weeks, then escalated to the final dose level (150 mg BID). Dose escalation required the absence of ongoing grade 3-4 or persistent grade 2 toxicity. The primary endpoint, measured at 12 weeks, was a composite rate of abemaciclib discontinuation for any reason or inability to reach or maintain the target dose.RESULTS: In 89 evaluable patients, the initial dose escalation strategy significantly reduced the composite rate at 12 weeks versus a historical value of 40% from monarchE. In total, 26/89 participants (29.2%; 90% CI [21.3% - 38.2%]; p=0.023) met the endpoint: 6 (6.7%) for early discontinuation, 8 (9.0%) for inability to reach 150 mg, and 12 (13.5%) for dose reduction from 150 mg. The majority (70.8%) reached and maintained 150 mg BID dosing.CONCLUSION: Use of an adjuvant abemaciclib dose escalation strategy allowed more patients to reach and maintain target dosing at 12 weeks than observed in monarchE. Early discontinuation was infrequent, and 93.3% were continuing therapy at 12 weeks. This dosing strategy could be considered when initiating adjuvant abemaciclib.KEYWORDS: abemaciclib, HR-positive, HER2-negative, breast cancer, TRADE, dose escalationClinical trial registration: NCT06001762, clinicaltrials.govDOI: 10.1016/j.annonc.2025.09.141
|
