Heading towards Targeted Therapy 2.0 #Targets2013

Conferences are vehicles for transfer of knowledge and new ideas. For scientific conferences like the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting in Boston #Targets13 very specific information is communicated but what is perhaps more interesting is to try and spot emerging themes. One thing I’d say about this conference compared to last year and looking over the last few years of new drugs is that the era of targeted therapies is changing: let’s say we are moving from Targeted Therapy 1.0 to Targeted Therapy 2.0.

Over a decade ago I went to my first ASCO meeting and the excitement in the air was all about the new era of targeted therapy. Imatinib (Glivec) for CML and GIST was the poster child. Since that time there have been many new drugs that have come to market and now there is no common cancer and many less common cancers that have a therapy: tyrosine kinase modulation, angiogenesis inhibition and immunomodulation have all been validated.

Yet there is a big ”but” which is that the imatinib story is the exception rather than the rule. Imitanib targeted dominant driver molecular changes in the malignancies in which it was active. For most of the other targeted therapies the individual molecular targets were not dominant drivers. The consequence is that the majority of the targeted therapies since imatinib have generally translated into only modest improvements in clinical outcomes like PFS and OS and this is often the case even when the therapy can be guided by a companion diagnostic.

So getting beyond the hype of targeted therapies what have we learned (or perhaps re-discovered) now? Resistance to most targeted therapies emerges rapidly. Feedback loops and redundancy are ubiquitous. As a consequence blockade of a single molecular target is usually only partial. Primary tumours and their metastases exhibit much more molecular heterogeneity than previously acknowledged. The targeted agents themselves have led to the recognition that individual histological types of cancer are actually multiple different types of cancer when examined at the molecular level.

So what will Targeted Therapy 2.0 look like? Fundamentally the definition of the target is going to be redefined. The target will not not be just the molecule of interest – that will just be the starting point. The target will be the molecular pathway or the whole network of pathways that cluster around the molecule. Combinations of 2 or more 1st generation targeted therapies will be used to target a pathway at multiple points to overcome redundancy or 2 or more agents will be used across a network of pathways to exploit synthetic lethality. Multiple Hallmarks of Cancer will be targeted simultaneously. Combinations of targeted therapies have been tried before but I think this was largely because this is what oncologists have always done – combine drugs together to see what happens.

The second aspect of Target Therapy 2.0 that will become prevalent is the use of repeated molecular characterization of the cancer before and after exposure to therapeutic agents. This might be through repeated conventional biopsies or analysis of circulating tumour cells.

What are the barriers? The biggest challenge from a clinical perspective will be toxicity and tolerance of combining these agents. The secondary challenge will be the cost of therapy in clinical practice. Both of these barriers could drive greater interest in interventions of large magnitude of effect and perhaps with the expectation of significant short term toxicity (a bit like how we use chemotherapy).

The cost of these therapies might also lead to more creative thinking about the use of surgical therapy and adjuvant immunotherapy to minimise the need for non-immunological targeted therapies.

So it is now time for Targeted Therapy 2.0.

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