Unphased by MTTs

With the advent of molecularly targeted therapies (MTTs), the face of oncology clinical trial design is rapidly changing from the traditional approach seen for cytotoxic chemotherapeutics. This change is recognised throughout the industry, as evidenced by the plethora of meetings to discuss trial design and endpoints, position papers released by FDA (1), and the very recent press release, ‘New Federal Health Initiative to Improve Cancer Therapy’, from FDA, NCI and CMS announcing the Oncology Biomarker Qualification Initiative (OBQI). As a result, creative and adaptive trial designs are becoming ‘the new norm’ to accommodate novel endpoint collections, adaptive go/no-go decisions on flexible schedules and MTT’s mechanism of action.

Many of these MTT trials are being conducted by small to midsized pharma and biotech companies, often backed by venture capitalist (VC) funding. These companies outsource almost all clinical trial work to CROs, and need to tightly manage outsourcing and development funds. They place their financial ‘bets’ on only the most promising drug candidates, and must arrive at go/no-go, or proof-of-principle as soon as possible. All of the above requires that companies be agile with decision-making and the finances to support those decisions, often rapidly reallocating spend where it is best needed. However, it is not clear whether standard outsourcing, contracting, risk management and project planning activities within these companies, or the CROs that serve them, have kept pace with these changes and the need for more flexibility/adaptability.

In the oncology therapeutic arena, diseases have been categorised historically by organ pathology, even though the resultant disease categories are often heterogeneous. Today we are moving towards a genetic or metabolic pathway-based taxonomy of disease (2). It is becoming more common to see agents that are MTTs, that is, they are directed against specific cellular mechanisms (for example angiogenesis, signalling pathways) supporting tumour cells, and have little impact on healthy cells. MTTs are therefore theoretically more precise therapeutics than cytotoxic agents that generally target any rapidly dividing cell.

MTTs – CHALLENGES OF MODERN DRUG DEVELOPMENT

Phase II testing, the primary indicator of antitumour efficacy, is arguably the biggest challenge in modern oncology drug development (3). Historically, agents were prioritised for Phase III trials based upon their ability to induce objective tumour regression. This paradigm may not be appropriate for MTTs, which are often cytostatic rather than cytotoxic, and so may not induce significant tumour regression on a traditional response timescale. Recent examples include Avastin® (bevacizumab) and Erbitux® (cetuximab). Both had limited single agent activity when measured by traditional response evaluation criteria in solid tumours (RECIST) criteria. A lower level of response may be considered acceptable for agents with a mild toxicity profile and administration over a prolonged period of time. For MTTs, modest but durable tumour regression (or prolonged disease stability) are more appropriate measurements of success.