Science Editor

From old stalwarts like Gleevec (imatinib, Novartis AG) to new stars like vemurafenib (PLX4032/RG7204, Plexxikon Inc./Roche AG), targeted therapies work well until they don't. Sooner or later, resistance – in the form of secondary mutations – rears its ugly head.

But an ounce of prevention may do a lot of good in delaying the appearance of such mutations. And surprisingly, even after mutations have emerged, such drugs continue to be useful in delaying tumor progression.

Those are the conclusions of a recent study, published in the July 6, 2011, issue of Science Translational Medicine.

In their work, the authors looked at EGFR-mutated lung tumors, which are the targets of Iressa (gefitinib, AstraZeneca plc) and Tarceva (erlotinib, Astellas Pharma Inc. and Roche AG).

The majority of EGFR-mutated tumors at first respond well to EGFR inhibitors. But sooner or later mutations develop. About half of the time, those mutations are at one specific site and lead to the replacement of a threonine with a methionine at position 790 of the EGF receptor – the T790M mutation.

It is the drug itself that puts selective pressure on the tumor, favoring escape mutations. But such selective pressure can be minimized through alternative dosing strategies. Indeed, while the drugs themselves are rationally designed, "you can come up with much more rational treatment strategies," co-author Vincent Miller, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, told BioWorld Insight.

In their paper, the authors treated cell lines that were genetically identical except for the presence or absence of the T790M mutation, and used them to test different dosing strategies that might prevent the emergence of resistance. The most promising such strategy appears to be combining low daily doses of erlotinib with intermittent higher-dose pulses.

Surprisingly, their results also suggested that continuing treatment with erlotinib after resistance has developed could be indicated clinically.

The reason is that a tumor that contains cells with the T790M mutation does not contain only cells with the T790M mutation: "One of the key pieces is that the tumor is a mixture of cells that have just the original mutation, and those that have the second mutation, the T790M site, as well," Miller said.

And if erlotinib treatment is stopped for such a tumor, the cells with just the original EGFR mutation will undergo a growth spurt of sorts. Such cells already divide more often than those with the T790M mutation, which makes cells resistant to EGFR inhibitors at the price of slowing their growth.

Given the oft-bemoaned costs of targeted therapies, the idea of continuing to give a patient a drug to which resistance has developed might seem like it will crash and burn for economic reasons no matter what its scientific merits.

But both Miller and Bruce Johnson, head of the thoracic oncology program at Dana Farber Cancer Institute, said that the costs of erlotinib could actually turn out to be less than those of alternative treatments.

At about $3,000 per month, erlotinib is expensive, but not in the same stratospheric region as some monoclonal antibodies. "Standard chemo," Johnson told BioWorld Insight, "costs a lot more than that."

Partly because it is an intravenous drug as opposed to a pill, Alimta (pemetrexed, Eli Lilly and Co.), the primary chemotherapy drug for lung cancer, is itself no bargain-basement drug: It costs about $5,000 per dose, and is given every three weeks.

Add to that the fact that severe toxicities are, Johnson said, "a third less frequent" with erlotinib than with chemotherapy, and the comparison looks better still.

Testing the paper's suggestions clinically will take at least two years. But Miller agreed that whatever the hurdles to its practical use are, the cost of treatment is not likely to be its death knell. Continuing targeted treatment, he agreed with Johnson, "might be more effective from a financial standpoint."