Pharmaceutical companies are increasingly relying on biomarkers to deliver precision medicine in immuno-oncology. Biomarkers can accelerate drug development and reduce the overall cost; they also allow sponsors to identify failed treatments sooner so that resources are not wasted on expensive, late-stage trials with unsafe or inactive compounds. Finally, these tests lead to better outcomes for patients, which help companies make a stronger case for reimbursement.
然而，Biomarker发现需要大量的时间和资源。虽然开支可能会被提高的发展效率超过，但企业必须确保药物和诊断时间表密切对齐，以便治疗和测试可以同时发射。技术，工作流程和商业因素对成功使用免疫肿瘤生物标志物至关重要。
是什么成功的生物标志物？
生物标志物in drug development fall into five categories:
- Determine whether a drug hits its target and measure the impact on the pathway being modulated. These biomarkers help developers evaluate the treatment’s mechanism of action and define a biologically effective dose.
- 确定最有可能响应药物或最不可能遭受不利事件的患者。这些测试可以成为伴侣诊断，在治疗之前需要，或者互补诊断，这些诊断只能通知医生。
- Identify patients who could be resistant or become resistant to the drug. For example, mutation analyses can reveal whether a patient has a genetic abnormality linked with resistance.
- Predict the course of disease independent of a specific treatment. Tests such as CellSearch®和mammaprint.®陷入此类别。
- Approve registrational endpoints that can be evaluated with commercialized diagnostic tests, such as LDL or viral load.
从1998年到2016年，美国食品和药物管理局（FDA）批准了167种肿瘤药物。但只有大约10％的治疗方法伴随着伴侣诊断。例子包括腰巴盆®EGFR Mutation Test v2 for use with osimertinib, PD-L1 IHC 22C3 pharmDX with pembrolizumab and FoundationFocusTM值CDX.BRCA with rucaparib.
Successful tests show a large effect in clinical trials –that is, patients with the predictive biomarker respond much better to treatment than those without it. These diagnostics are present in early development, and they usually test a single analyte using established technology such as PCR or immunohistochemistry.
重点案例研究：YEvoy®and erdafitinib
One example of a drug that has benefited from pharmacodynamic biomarker studies is YERVOY®(ipilimumab). Approved by the FDA for metastatic melanoma in 2011, this treatment is an antibody that blocks human cytotoxic T-lymphocyte associated protein 4 (CTLA4).
To determine the mechanism of action, researchers studied biomarkers in the tissues of patients before and after YERVOY treatment. Staining the tumors with hematoxylin and eosin (H&E), showed that lymphocyte infiltration increased after the drug was administered. In patients who benefited from treatment, expression of the genes FoxP3 and IDO was higher at baseline than those that did not improve with treatment. The result with the H&E staining suggests that the drug draws more lymphocytes to the cancer; importantly, the research also demonstrated to the FDA that tumors treated with an immuno-oncology compound may grow before shrinking. The tests with IDO and FoxP3 indicated that the tumors that had previously been exposed to attack by the immune systems, were the ones deriving more benefit.
预测生物标志物很难找到，因为赞助商必须同时发生有效的药物并鉴定正确的生物标志物。如果开发人员不知道预测的生物标志物，则纳入这种测试可能为时已晚。
药物Erdafitinib是一个小分子FGFR抑制剂，是一个相关的示例。为了找到预测性生物标志物，处理约240例癌细胞系以确定哪些肿瘤对药物敏感或耐药。FGFR1，FGFR2和FGFR4的过表达与敏感性相关联，而RAS / RAF突变与抗性相关。这进一步验证了I阶段临床试验是患者对治疗非常好的患者是否具有导致FGFR途径过度表达的突变。
Aligning drug and diagnostic development
一个关键挑战正在协调药物和伴侣诊断的发展，以便它们可以同时释放。制药公司通常不仅依赖于诊断伙伴，而且依靠诊断伙伴，而是管理临床研究和检测发展的CRO。即使单独的FDA组处理其批准，也必须对齐两种产品的监管路径。最后，合作伙伴需要在每个开发阶段执行对测定的正确验证。
To define the right test, sponsors should consider three types of factors:
- 开发人员必须确定要评估的分析物，相关技术和测定的分析性质如特异性和敏感性。
- This process spans sample collection to delivery of results. Key considerations include sample requirements and pre-analytic, post-analytic and time in motion steps. Even the difference between a serum and plasma sample can be crucial, and processing can sometimes add hours to the overall turnaround time.
- 赞助商需要评估核心市场的技术，整体成本结构，设备采用和报销。例如，如果测试过于昂贵或需要一个笨重的机器，则不太可能成功。
Covance提供全面的生物标志物服务，从Biomarker发现到伴侣诊断的商业化。我们的专家可以执行超过550种测定，并提供对基因组检测，下一代测序，解剖病理学，免疫组化和流式细胞术等解决方案的访问。
