The true face of the revolution in oncology drug development: a personal reflection
Michael Burgess1, Dinesh P de Alwis
1Roche Products ltd., 6 Falcon Way, Welwyn Garden City, Hertfordshire AL1 7TW, UK.
Abstract:
The majority of drugs approved for the treatment of malignant disease are traditional cytotoxic agents that, in many cases, have been in use for decades. In the recent past, we have seen the approval of the so-called targeted agents and with this have emerge concepts such as biomarker and optimal biological dose, but which came first and what is actually behind the paradigm shift that is all too evident in modern oncology drug development? Following critical examination of the issue, it can be argued that many, if not all, cytotoxic chemotherapies are targeted, for example, methotrexate, the folate pathway and the use of neutropenia as a biomarker although not titled as such, in the development of these agents. The most obvious change is the toxicity profile of the new molecular entities and, therefore, the recognition that driving a dose towards a maximally tolerated dose for use in later phase development is inappropriate. Again, it can be argued that this should never have been appropriate, however, the tools necessary to determine the underlying pharmacokinetic/pharmacodynamic (PK/PD) relationships were lacking. We believe this has brought about the most dramatic change in how oncology drugs are developed, rather than the classification as cytotoxic or targeted. We will argue that it is not practicable to develop a targeted agent using the traditional paradigm, but equally, the same would now be true for cytotoxics.
Insights
The development of cancer drugs has shifted focus from cytotoxic agents to targeted therapies. This change is driven by understanding pharmacokinetic/pharmacodynamic relationships, not just drug classification.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Most cancer drugs are traditional cytotoxic agents, some used for decades.
- Recent approvals include targeted agents, introducing concepts like biomarkers and optimal biological dose.
- The paradigm shift in oncology drug development warrants critical examination.
Purpose of the Study:
- To critically examine the paradigm shift in oncology drug development.
- To investigate the driving forces behind the evolution from cytotoxic to targeted cancer therapies.
- To re-evaluate the traditional drug development paradigm in light of modern oncology.
Main Methods:
- Critical analysis of historical and modern oncology drug development practices.
- Examination of the role of biomarkers and toxicity profiles in drug development.
- Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) relationships.
Main Results:
- Many traditional cytotoxic chemotherapies can be considered targeted (e.g., methotrexate targeting the folate pathway).
- The primary shift in oncology drug development is the recognition of appropriate toxicity profiles and PK/PD relationships, not merely the classification of drugs.
- Maximally tolerated dose (MTD) is an inappropriate endpoint for later-phase development, especially for newer agents.
Conclusions:
- The evolution of oncology drug development is fundamentally linked to understanding PK/PD relationships and appropriate dosing strategies.
- The traditional drug development paradigm is insufficient for both targeted agents and modern cytotoxic drugs.
- A revised development approach is necessary to effectively advance oncology therapeutics.
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