自然：一线或二线CDK4/6抑制剂
学术
健康
2024-11-28 13:05
上海
对于激素受体阳性晚期乳腺癌，内分泌治疗是主要的治疗方法，细胞有丝分裂周期蛋白依赖性激酶CDK4和6过度活跃是内分泌治疗耐药的主要原因。既往多项随机对照研究已经证实，CDK4/6抑制剂哌柏西利、阿贝西利、瑞波西利联合内分泌治疗与单用内分泌治疗相比，激素受体阳性晚期乳腺癌患者生存结局显著改善，无论一线治疗早期用药，还是推迟至二线治疗用药。不过，早期用药虽然可以减少内分泌治疗耐药，但是治疗时间更长、累积毒性更大。此外，单用内分泌治疗通常可以获得持久缓解，早期联合CDK4/6抑制剂可能降低随后对内分泌治疗的敏感性。CDK4/6抑制剂长期用药还给医疗资源带来沉重负担，包括就诊次数和药物费用。那么，究竟应该一线治疗早期用药，还是推迟至二线治疗用药？对于这个问题，过去缺乏随机对照研究证据。 2024年11月27日，全球自然科学三大旗舰期刊之首、创刊155周年的英国《自然》正刊在线发表荷兰癌症研究院、阿姆斯特丹大学医学中心、阿姆斯特丹癌症中心、鹿特丹大学医学中心癌症研究院、荷兰综合癌症组织、荷兰乳腺癌学会、荷兰乳腺癌研究协作组研究中心、莱茵州立医院、吕伐登医疗中心、安菲亚医院、伊萨拉医院、圣安东尼医院、弗朗西斯医院、米安德医疗中心、杰伦博世医院、盖尔医院、西北医院集团的SONIA（BOOG 2017-03）研究报告，首次对CDK4/6抑制剂一线或者二线治疗激素受体阳性晚期乳腺癌的有效性、安全性和经济性进行随机比较。该研究由研究者自己发起、荷兰医疗研究与发展组织和荷兰医疗保险资助，并非药企发起或资助，可能较少受到药企的影响，但是可能多多少少受到医保政策的影响。此外，英国《自然》正刊属于自然科学期刊，极少发表临床医学研究，此次破例，可能又是难以发表于临床医学期刊的反药企研究。- SONIA (NCT03425838): Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone (SONIA) Receptor Positive Advanced Breast Cancer
- Official Title: BOOG 2017-03: Endocrine Therapy Plus CDK 4/6 Inhibition in First- or Second-line for Hormone Receptor Positive Advanced Breast Cancer - the SONIA Study
该全国多中心非盲随机对照三期临床研究于2017年11月23日至2021年9月1日从荷兰全国74家医院入组激素敏感型晚期乳腺癌尚未开始治疗患者1050例，按1∶1的比例随机分为两组：- CDK4/6抑制剂一线治疗组524例：先用CDK4/6抑制剂＋芳香酶抑制剂，疾病进展后再用氟维司群（注：在目前的临床实践中，对于CDK4/6抑制剂一线治疗后进展的患者，通常不会单用氟维司群治疗，但是随机对照研究只能如此设计，而且2017年研究设计时其他治疗选择也不多）
- CDK4/6抑制剂二线治疗组526例：先用芳香酶抑制剂，疾病进展后再用CDK4/6抑制剂＋氟维司群
CDK4/6抑制剂类型：哌柏西利各479例、瑞波西利42例和44例、阿贝西利各3例。 主要终点为从随机分组至二线治疗后疾病进展或死亡的无进展生存时间。次要终点为毒性、总生存时间、生活质量和成本效益。每12周通过影像学评定疗效。内脏危象患者被该研究排除，因为此类患者一旦疾病进展，可能迅速迎来生存终点。该研究被设计为优效研究，而非非劣效研究，因为后者往往对强度较低的替代治疗方法施加不成比例的举证责任。 结果，经过中位37.3（95%置信区间：35.7～38.3）个月随访，CDK4/6抑制剂一线治疗与二线治疗相比：- 无进展生存：中位31.0个月比26.8个月（风险比：0.87，95%置信区间：0.74～1.03；P=0.10）
- 总生存：中位45.9个月比53.7个月（风险比：0.98，95%置信区间：0.80～1.20，P=0.83）
亚组分析表明，以下情况可能有利于CDK4/6抑制剂一线治疗：早期乳腺癌阶段未进行内分泌治疗或化疗、初诊已经转移、无内脏转移、仅骨转移、哌柏西利与阿贝西利相比、小叶癌、未绝经或围绝经与已绝经相比、此前未用过芳香化酶抑制剂或间隔超过24个月、PIK3CA突变。 因此，该研究结果表明，可能并非全部激素敏感型晚期乳腺癌患者都需要CDK4/6抑制剂一线治疗。 对此，美国德克萨斯大学MD安德森癌症中心发表同期评论：通过推迟CDK4/6抑制剂用药降低癌症治疗的毒性和成本。评论认为该三期临床研究报告具有至关重要的意义，因为其迫使我们重新思考是否应该始终首先采用最有效的疗法。更有攻击性和有效性（通常毒性更大且更昂贵）的疗法正被作为更早期疗法进行试验和批准，这是肿瘤治疗领域被加速的趋势之一。该研究作者和研究协作组值得赞扬，因为他们试验了该替代疗法：将更有效的治疗方法推迟到旧的标准内分泌治疗之后。
Nature. 2024 Nov 27. IF: 50.5Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer.Gabe S. Sonke, Annemiek van Ommen-Nijhof, Noor Wortelboer, Vincent van der Noort, Astrid C. P. Swinkels, Hedwig M. Blommestein, Cristina Guerrero Paez, Linda Mol, Aart Beeker, Karin Beelen, Lisanne C. Hamming, Joan B. Heijns, Aafke H. Honkoop, Paul C. de Jong, Quirine C. van Rossum-Schornagel, Christa van Schaik-van de Mheen, Jolien Tol, Cathrien S. Tromp-van Driel, Suzan Vrijaldenhoven, A. Elise van Leeuwen-Stok, Inge R. Konings, Agnes Jager; SONIA Study Consortium.Netherlands Cancer Institute, Amsterdam, The Netherlands; Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands; Erasmus University Rotterdam, Rotterdam, The Netherlands; Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands; Dutch Breast Cancer Society, Utrecht, The Netherlands; Dutch Breast Cancer Research Group, BOOG Study Center, Utrecht, The Netherlands; Spaarne Gasthuis, Hoofddorp, The Netherlands; Rijnstate Hospital, Arnhem, The Netherlands; Medical Center Leeuwarden, Leeuwarden, The Netherlands; Amphia, Breda, The Netherlands; Isala Clinics, Zwolle, The Netherlands; St Antonius Hospital, Nieuwegein, The Netherlands; Franciscus Gasthuis & Vlietland, Schiedam, The Netherlands; Meander Medical Center, Amersfoort, The Netherlands; Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands; Gelre Hospital, Apeldoorn, The Netherlands; Northwest Hospital Group, Alkmaar, The Netherlands.Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment. Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting. All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74-1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.DOI: 10.1038/s41586-024-08035-2
Nature. 2024 Nov 27. IF: 50.5Toxicity and costs of cancer treatment reduced by deferring CDK4/6 inhibitor use.The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.The SONIA study shows that early use of inhibitors that target both CDK4 and CDK6 (hereafter, CDK4/6) in metastatic breast cancer prolongs time on treatment but does not improve patient outcomes. Postponing innovative treatments to a later stage of the disease could thus safely reduce the time on treatment, the number of adverse effects for people with breast cancer and the burden on health-care resources.DOI: 10.1038/d41586-024-03838-9
