What is the recipe for success in clinical studies that pair up new and investigational drugs?
“History teaches us that for most cancers, a single agent is not the most effective strategy,” says Scot Ebbinghaus, MD, medical director of oncology clinical research at Merck Research Laboratories in North Wales, PA. “In this era of molecularly targeted therapies, we need to come up with elegant ways to have more effective treatments by designing rational combinations.”
Carefully putting together targeted therapies to hit different molecular pathways, or different nodes in one pathway, may elicit more profound responses in cancer patients and help to prevent drug resistance. But that approach dramatically complicates difficult challenges in clinical research.
The growing trend of combining 2 novel drugs in a clinical trial pushes the envelope further past the traditional model of adding a single investigational drug to an approved therapy.
“Our goal is to combine new drugs much earlier in the development process,” declares Stuart Lutzker, MD, PhD, vice president of oncology exploratory clinical development at Genentech in South San Francisco, CA. His firm, for instance, is running novel clinical studies combining the phosphoinositide 3-kinase (PI3K) inhibitor GDC-0941 with the MAP/ERK kinase (MEK) inhibitor GDC-0973.
Ebbinghaus is overseeing a clinical trial combining 2 of Merck's investigational drugs. Ridaforolimus inhibits the mTOR pathway, a key suspect in cancer growth, but activates an oncoprotein called AKT that could encourage resistance. The other agent, the monoclonal antibody dalotuzumab, inhibits the insulin-like growth factor receptor (IGF-IR), which may counter AKT to prevent resistance.
Following Draft Guidelines
In 2010 the U.S. Food and Drug Administration (FDA) issued draft guidelines on how to proceed, and they are flexible regarding whether companies need to conduct formal preclinical toxicology studies for their drug combinations.
That was also an important consideration for Merck for the phase I study of the ridaforolimus/dalotuzumab combination, which began prior to the issuance of the draft guidelines, Ebbinghaus says. Merck decided not to do such toxicology studies because the drugs belong to different classes (small-molecule and antibody) that are thought to be unlikely to interact, and each agent also had undergone small clinical trials alone. So Merck started the combination testing with doses expected to be effective.
“If you have established activity with one drug, it becomes dramatically easier,” says David Solit, MD, a researcher at Memorial Sloan-Kettering Cancer Center in New York. “We know we have a good inhibitor of BRAF [vemurafenib; Genentech] because many patients respond to the drug alone. We're not sure we have an effective PI3K inhibitor.”
However, many curative cocktails may need to combine a drug that will never work by itself, points out Keith Flaherty, MD, director of developmental therapeutics at Massachusetts General Hospital's Cancer Center in Boston, MA. This may be likely in the case of certain PI3K and AKT inhibitors, he adds.
The FDA draft guidelines suggest the possibility of approving drugs that only work in combination. But must companies clinically show a single agent doesn't work as well as the combination?
Ebbinghaus says this difficult question requires a lot of discussion and must be evaluated on a case-by-case basis. “It's generally a low-value proposition for patients to take a single agent just to prove that it doesn't work, especially if there's a strong rationale that the combination works better, but in some cases, it may be necessary.”
Stepping Up the Pace
Among other federal initiatives, the National Cancer Institute's (NCI) National Center for Advancing Translational Sciences offers a lab-based screening process that “collides” drug molecules toward the goal of discovering promising combinations. NCI's Cancer Therapy Evaluation Program (CTEP) studies drugs from different companies and can run combination trials. “It's brilliant,” says Flaherty, who recruits drugs for CTEP. “It creates a safe harbor. But not many companies are donating their drugs.”
However, scientists say that the main holdups for combination trials are not corporate barriers but familiar obstacles in today's cancer research.
“We haven't presented companies with the patients to do these studies efficiently,” concludes Solit. “The challenge is how do we find the right patients with the right combination of mutations to put them on the right combination therapy?”
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