From nature biotechnologyvolume 28 number 8 AuGuST 2010 765 Merck’s ridaforolimus-dalotuzumab program, which is due to enter phase 2 trials later this year, is a key initiative and is being closely scrutinized. It exemplifies a science-based
approach to combining investigational drugs that may offer limited potential as single agents, but which may offer syner- gistic effects when admin- istered together, as well as reducing the risk of drug resistance. Trials of sev- eral other combinations of new types of agents are also underway (Table 1).
Although combination therapy in cancer—and other indications—is not a new theme, it has devel- oped historically through trial and error. “Our knowl- edge of biological pathways and networks is so superfi- cial it really is hard to come up with a strong rationale,” says Alan Ashworth, pro-
fessor of molecular biology at the Institute of Cancer Research in London. The ridaforolimus-dalotuzumab combination emerged from an unbiased screen of a colon cancer cell line in which individual genes were systematically switched off using short hair- pin RNAs, whereas each of the two drugs was tested in turn in a cell proliferation assay. This kind of synthetically lethal screen can unveil dependencies between related pathways and overcome compensatory mechanisms that cancer cells switch to when only one target is hit. “Those types of approaches couldn’t be done before,” says Eric Rubin, vice president of clinical oncology at Merck. The upcoming phase 2 trial will recruit around 200 breast cancer patients, who will be assigned to one of four treatment arms, comprising either ridaforolimus as monotherapy, dalotuzumab as monotherapy, the two drugs in combina- tion or exemestane, the active comparator.
The key question is whether that kind of design would need to be replicated in a large-scale reg- istration trial of a new combination comprising two investigational compounds. “What we have proposed—and others have as well—is to do this in a more limited setting,” Rubin says. Balancing regulators’ requirements for statistical power with patients’ needs for effective therapy is not a straightforward task, particularly if some trial participants are to receive single agents that are
The next generation of cancer treatments could be approved in pairs, at least judging by a growing trend among drug makers to combine drugs early in development and the US Food and Drug Administration’s (FDA)
willingness to regulate them. On 2 June, the FDA opened its public consultation into the formulation of guid- ance for combinations of investigational therapies. In the same week, Merck, of Whitehouse Station, New Jersey, reported at the annual American Society of Clinical Oncology meeting in Chicago that a combina- tion of ridaforolimus, an oral inhibitor of mam- malian target of rapamy- cin (mTOR) developed with Ariad of Cambridge, Massachusetts, and dalo- tuzumab, an antibody targeting the insulin-
like growth factor 1 receptor (IGFR1), led to responses in a cluster of patients with highly proliferative, estrogen-receptor- positive breast cancers in a phase 1b trial. Collaborations between different sponsors to combine drugs very early in development are unusual and pose new issues for regulators compared with oversight of combinations of agents already on the market.
The FDA initiative is not limited to can- cer—it also covers infection, seizure disor- ders and cardiovascular disease. But cancer drug makers, in particular, are grappling with some thorny questions as they attempt to translate their rapidly expanding knowledge of tumor biology into therapies that offer sig- nificant improvements on what is now avail- able. Foremost among their concerns is how to accelerate clinical development to deliver solid efficacy data without compromising patient safety. “We’ve talked to the FDA about specific combinations and have received guid- ance on an ad hoc basis,” says Pearl Huang, vice president and oncology franchise integrator at Merck. “For us, the burning issue is if we dem- onstrate great activity for the combination, are we obligated to demonstrate lack of activity for the single agent alone?”
Some claim combinations of investigational drugs could accelerate clinical development.
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