Martin Reck, MD, PhD, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany
Onkologie 19. Jänner 2016
PD-L1 expression is a nightmare in terms of complexity
Immunotherapies offer advantages in unselected patients. However, the implementation of biomarkers would be highly welcome. One of the reasons for this would be containment of the financial strain on health systems, as physicians could then exclude patients who are unlikely to benefit from treatment. Where are we today regarding biomarker development?
There are two issues that are tied to the topic of biomarkers in immunotherapies. First, all attempts to define biomarkers have focused primarily on response as a marker of efficacy. We have to be aware, however, that immunotherapies are not targeted therapies, and fast tumor shrinkage is not necessarily observed with this kind of treatment. The efficacy of an immunotherapy is defined by long-lasting tumor stabilization. We have to question whether response rates are the appropriate endpoint here.
The second issue is the necessity to define the purpose of biomarker development in immunotherapies. There are two options: Biomarkers can identify patients who derive benefit from a specific treatment, or they can exclude those patients who are unlikely to benefit. This is something that needs to be defined. Currently, both strategies are being explored.
What kind of evidence is available at present?
What do we know about tumors with low mutational burden; for example, those with activating EGFR mutations?
PD-L1 expression has been the main focus of biomarker research for quite some time. How would you rate the relevance of this marker?
PD-L1 is not an easy-to-handle marker. Actually, it is a nightmare in terms of complexity, with a number of issues regarding biology, assays, and logistics (Table). In practice, different assays are used for measurement, and with different definitions of PD-L1 positivity added in, the story of PD-L1 assessment becomes very complicated. At the moment, at least four different test methods are in use. This will not be practical if we are going to apply immunotherapy in the clinic.
Undoubtedly, further development and harmonisation of PD-L1 assessment is urgently needed. An ongoing global initiative, which was put together by drug manufacturers, companies that provide testing systems, scientific societies, and regulatory authorities, is aimed at providing practical guidance on the use of PD-L1 expression.
What about additional markers?
Apart from EGFR mutation, which molecular targets will gain importance in the future?
We are at a stage now where we can talk about the whole treatment. The patients will not be cured, but we can offer them a long period of disease-free survival or stable disease. The sequence of therapies will become very important, which also applies to the possibility of offering the patient another active compound after progression. This is already a reality in EGFR-mutated patients; after progression, treatment can be continued with a third-generation agent. In the future, fourth-generation or fifth-generation TKIs might become available.
What are the greatest challenges at present in the treatment of lung-cancer patients from a practical point of view?
1 Reckamp K et al., WCLC 2015, abstract 736
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