Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet. 2022 Aug 13;400(10351):512-521. doi: 10.1016/S0140-6736(22)01390-3.
The low expectation of clinical benefit from phase 1 cancer therapeutics trials might negatively affect patient and physician participation, study reimbursement, and slow the progress of oncology research. Advances in cancer drug development, meanwhile, might have favourably improved treatment responses; however, little comprehensive data exist describing the response and toxicity associated with phase 1 trials across solid tumours. The aim of the study is to evaluate the trend of toxicity and response in phase 1 trials for solid tumours over time.
We analysed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute-sponsored investigator-initiated phase 1 trials for solid tumours, from Jan 1, 2000, to May 31, 2019. We assessed risks of treatment-related death (grade 5 toxicity ratings possibly, probably, or definitely attributable to treatment), all on-treatment deaths (deaths during protocol treatment regardless of attribution), grade 3-4 toxicity, and proportion of overall response (complete response and partial response) and complete response rate in the study periods of 2000-05, 2006-12, and 2013-2019, and evaluated their trends over time. We also analysed cancer type-specific and investigational agent-specific response, and analysed the trend of response in each cancer type over time. Univariate associations of overall response rates with patients' baseline characteristics (age, sex, performance status, BMI, albumin concentration, and haemoglobin concentration), enrolment period, investigational agents, and trial design were assessed using risk ratio based on the modified Poisson regression model.
We analysed 465 protocols that enrolled 13 847 patients using 261 agents. 144 (31%) trials used a monotherapy and 321 (69%) used combination therapies. The overall treatment-related death rate was 0·7% (95% CI 0·5-0·8) across all periods. Risks of treatment-related deaths did not change over time (p=0·52). All on-treatment death risk during the study period was 8·0% (95% CI 7·6-8·5). The most common grade 3-4 adverse events were haematological; grade 3-4 neutropenia occurred in 2336 (16·9%) of 13 847 patients, lymphopenia in 1230 (8·9%), anaemia in 894 (6·5%), and thrombocytopenia in 979 (7·1%). The overall response rate for all trials during the study period was 12·2% (95% CI 11·5-12·8; 1133 of 9325 patients) and complete response rate was 2·7% (2·4-3·0; 249 of 9325). Overall response increased from 9·6% (95% CI 8·7-10·6) in 2000-05 to 18·0% (15·7-20·5) in 2013-19, and complete response rates from 2·5% (2·0-3·0) to 4·3% (3·2-5·7). Overall response rates for combination therapy were substantially higher than for monotherapy (15·8% [15·0-16·8] vs 3·5% [2·8-4·2]). The overall response by class of agents differed across diseases. Anti-angiogenesis agents were associated with higher overall response rate for bladder, colon, kidney and ovarian cancer. DNA repair inhibitors were associated with higher overall response rate in ovarian and pancreatic cancer. The rates of overall response over time differed markedly by disease; there were notable improvements in bladder, breast, and kidney cancer and melanoma, but no change in the low response of pancreatic and colon cancer.
During the past 20 years, the response rate in phase 1 trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision making is crucial for patients before participating in phase 1 trials. This study provides updated encouraging outcomes of modern phase 1 trials in solid tumours.
National Cancer Institute.
人们对癌症治疗药物临床试验的临床获益的期望较低，这可能会对患者和医生的参与、研究的报销以及肿瘤学研究的进展产生负面影响。与此同时，癌症药物开发方面的进展可能会使治疗反应得到显著改善；然而，几乎没有全面的数据描述实体肿瘤的 1 期临床试验的反应和毒性。本研究的目的是评估过去 20 年来实体肿瘤 1 期临床试验的毒性和反应趋势。
我们分析了从 2000 年 1 月 1 日至 2019 年 5 月 31 日，国家癌症研究所癌症治疗评估计划（Cancer Therapy Evaluation Program）资助的，由研究者发起的，针对实体肿瘤的 1 期临床试验的患者水平数据。我们评估了治疗相关死亡的风险（可能、很可能或几乎肯定与治疗有关的 5 级毒性评分）、所有治疗期间的死亡（无论归因如何，在方案治疗期间死亡）、3-4 级毒性和总反应率（完全缓解和部分缓解），以及它们在 2000-05 年、2006-12 年和 2013-2019 年研究期间的趋势，并评估了随时间的变化。我们还分析了癌症类型特异性和研究药物特异性反应，并分析了每个癌症类型随时间的反应趋势。使用基于修正泊松回归模型的风险比，评估了总反应率与患者基线特征（年龄、性别、表现状态、BMI、白蛋白浓度和血红蛋白浓度）、入组期、研究药物和试验设计之间的单变量关联。
我们分析了 465 项试验，共纳入了 13847 名患者，使用了 261 种药物。144 项（31%）试验使用了单药治疗，321 项（69%）试验使用了联合治疗。所有研究期间的治疗相关死亡率为 0.7%（95%CI，0.5-0.8）。治疗相关死亡风险随时间没有变化（p=0.52）。研究期间所有治疗相关的死亡风险为 8.0%（95%CI，7.6-8.5）。最常见的 3-4 级不良事件为血液学事件；中性粒细胞减少症在 13847 名患者中占 16.9%（2336 例），淋巴细胞减少症占 8.9%（1230 例），贫血占 6.5%（894 例），血小板减少症占 7.1%（979 例）。整个研究期间，所有试验的总反应率为 12.2%（95%CI，11.5-12.8；1133 例/9325 例），完全缓解率为 2.7%（95%CI，2.4-3.0；249 例/9325 例）。总反应率从 2000-05 年的 9.6%（95%CI，8.7-10.6）增加到 2013-19 年的 18.0%（15.7-20.5），完全缓解率从 2.5%（2.0-3.0）增加到 4.3%（3.2-5.7）。联合治疗的总反应率明显高于单药治疗（15.8%[15.0-16.8] vs 3.5%[2.8-4.2]）。不同疾病的药物类别之间的总反应率不同。抗血管生成药物与膀胱癌、结肠癌、肾癌和卵巢癌的总反应率较高有关。DNA 修复抑制剂与卵巢癌和胰腺癌的总反应率较高有关。不同疾病的总反应率随时间显著不同；膀胱癌、乳腺癌和肾癌以及黑色素瘤的反应率显著提高，但胰腺癌和结肠癌的反应率没有变化。
在过去的 20 年中，1 期临床试验的反应率几乎翻了一番，而治疗相关死亡率没有增加。然而，不同因素（如癌症类型、研究药物和试验设计）对总反应率的影响存在显著的异质性。因此，在参与 1 期临床试验之前，患者需要做出明智的决定。本研究提供了更新的、令人鼓舞的实体肿瘤 1 期临床试验结果。
美国国立癌症研究所。
