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© Oxford University Press 2006.
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Two Targets, One Drug for New EGFR Inhibitors
The new drug that garnered the most media attention at this year's American Society of Clinical Oncology meeting was lapatinib (Tykerb), a targeted agent that showed a tumor response in metastatic breast cancer resistant to trastuzumab (Herceptin). In an international phase III trial, lapatinib with capecitabine significantly improved the time to progression compared with capecitabine alone. The findings prompted early closing of the trial and put lapatinib on track for regulatory review later this year.
But lapatinib drew attention for another reason as well: It was designed to hit two receptors at once—the epidermal growth factor receptor (EGFR) and HER2. Both receptors are important targets of already-approved drugs: Trastuzumab targets HER2, and cetuximab, gefitinib, and erlotinib aim at EGFR. But as the first successful agent designed to hit both receptors, lapatinib marks the coming of age of a new generation.
"We're moving now from the era of single-targeted agents to agents that are multitargeted," said Ronald Natale, M.D., director of the national lung cancer research program at Cedars-Sinai Medical Center in Los Angeles. Natale presented positive findings for another new drug that aims at two targets: ZD6474 (Zactima).
Lapatinib and ZD6474 have many younger cousins in this second generation of dual-targeted drugs. At least eight agents that aim at EGFR and one or more other targets are in clinical trials (see box), and many others are in preclinical pipelines.
As this new wave of multitargeted drugs moves into and through clinical trials, investigators are working through several key questions: Is hitting two targets better than one? If so, is one molecule with two targets superior to a combination of two separate drugs? And are there meaningful differences between drugs that have the same two or three targets?
Two Targets Versus One
There are a few good reasons to think that it's better to hit two targets, whether using a dual-target drugs or two single-target drugs, said Jose Baselga, M.D., chairman of the Medical Oncology Service at Vall D'Hebron University Hospital in Barcelona and a leading researcher on combined, targeted therapies. Tumors can develop resistance to single-target drugs, so hitting a second target may overcome or circumvent that resistance. Lapatinib's success in trastuzumab-resistant breast cancer seems to confirm this scenario.
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Also, blocking two critical targets could be valuable in cancers that may involve alterations in more than one growth pathway. The relatively modest results obtained so far with gefitinib and erlotinib, for instance, may be greatly improved when more pathways are blocked, said Baselga.
"It's just a miracle that by blocking one pathway you can see response rates," he said. "So if we're smart enough and we're hitting two critical pathways ... I think we could basically have results that are as dramatic or even better than with chemotherapy."
Early trials of combined, single-target therapies show some evidence of an enhanced effect. The EGFR inhibitor erlotinib combined with bevacizumab, which targets the vascular endothelial growth factor receptor (VEGFR), has produced a response rate of 22% in 40 patients with advanced non–small-cell lung cancer (NSCLC), said Roy Herbst, M.D., Ph.D., a leading lung cancer researcher at University of Texas M. D. Anderson Comprehensive Cancer Center in Houston. It's a result that "appears to be superior to what one would expect with the EGFR agent alone," he said. The combination is now being tested in two phase III trials.
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More evidence in favor of hitting multiple targets comes from trials of ZD6474, which takes triple aim at EGFR, HER2, and VEGFR. At ASCO, Natale reported on a randomized phase II trial in 168 patients with advanced NSCLC that used ZD6474 in one arm of the study and gefitinib in the other. Those taking ZD6474 had a median progression-free survival time of 11 weeks, whereas the gefitinib patients survival was 8.1 weeks. The objective response was 8% versus 1%, respectively
ZD6474 will now be compared to erlotinib in a randomized, phase III trial in NSCLC. That trial is already enrolling patients.
Multitargeted Agent Versus Combined Therapy
Hitting two or mare targets may prove more effective than hitting one, but would it be better to attack with one combined drug or two separate compounds?
The advantages to multitargeted agents are partly logistical. It's simply "more convenient to have everything in the same molecule, in one pill," Herbst said. The cost is also potentially lower, he noted.
On the other hand, there are some unanswered questions about the usefulness of all-in-one agents versus combined therapies.
"Do the activities exist at the level you want for any given patient?" Herbst asked. "Might it not be easier to have the combined drugs ... then dial up the activities we want in a more personalized way?"
Another potential downside is the result of side effects. Hitting one target might cause side effects that would force doctors to cut back on the drug, so the second target might not receive a knockout blow. "We may reach the dose that has side effects and when we get there, maybe we have not fully cashed in on all the beneficial effects [of a multitargeted agent] on different molecules," said Baselga.
For instance, lapatinib investigators cannot be sure that, at the maximum tolerated dosage, it is having an optimal effect on both EGFR and HER2. Ezra Cohen, M.D., from the University of Chicago, who discussed the results at ASCO for several EGFR-targeted candidates, noted that lapatinib results are all in breast cancer. It has not demonstrated activity in EGFR-dominated malignancies, such as NSCLC, head and neck cancer, or colorectal cancer. Also, the rash typical with other anti-EGFR agents is not seen with lapatinib, raising doubts about its effect on that receptor.
Sorting out these questions will take time and, perhaps most important, improvements in technology. "Our technology and reagents are not as advanced as our drugs," said David Agus, M.D., research director of Cedar-Sinai's Louis Warschaw Prostate Cancer Center in Los Angeles, which is conducting trials with BIBW-2992. He noted that researchers don't yet have the biomarkers they need to determine whether an agent is hitting an intended target and having an effect on it. And they don't know what other receptors it may be hitting.
"We may be hitting some targets we don't even know exist," he said. "As technology improves, we will find out."
Small Differences
Although questions about multitargeted agents remain, they are being developed at a rapid pace, many with identical targets. Lapatinib, HKI-272, BIBW-2992, and BMS-599626, for instance, all aim at EGFR and HER2. One question that will become more pressing as these drugs move forward is how they compare to one another.
| Dual-Target EGFR Drugs in the Pipeline EGFR, also known as HER1, belongs to the same erbB family of receptors that includes HER2, HER3, and HER4. The family is important in several major cancers, transmitting growth signals that can be ratcheted up to cancer-causing levels when the receptors are overexpressed or mutated, or when other mechanisms (that are not yet completely understood) go awry.
Blocking the receptors stops the growth signals that fuel the tumor, which stops the cancerous cells from growing. Trastuzumab and cetuximab are monoclonal antibodies that block HER2 and EGFR, respectively, by binding to the part of the receptor that extends outside the cell. Lapatinib, like gefitinib and erlotinib, is a small molecule that can be taken orally and obstructs growth signals by binding to the receptors' tyrosine kinase domains inside the cell. Here are drugs currently in testing:
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HKI-272 has shown promise in a phase I study, reported at ASCO by Kwok K. Wong, M.D., from the Dana-Farber Cancer Institute in Boston. Seven patients with advanced breast cancer showed a partial response, and five patients with advanced NSCLC showed stable disease of more than 24 weeks. Phase II studies are now under way in those two diseases.
The data are "clearly very early but very promising," said Baselga, who discussed this paper at ASCO. But he added, "My questions would be: Is it similar to lapatinib, and if so, how much better?"
BIBW-2992 also shows promise, according to phase I results presented in four different poster sessions at ASCO. The drug was well tolerated, and stable disease was shown in some patients with advanced solid tumors. Some instances of tumor shrinkage, including a few objective responses, were also seen.
But the question remains, "Do we need more EGFR inhibitors?" said the University of Chicago's Cohen. He and others agree that the answer is yes because of potential differences among the agents.
For example, one difference among tyrosine kinase inhibitors is that some, like lapatinib, are reversible, whereas others, like HKI-272 and BIBW-2992, are irreversible—once the receptor is blocked it remains that way. This fact could make a difference in the drug's effectiveness, and Cohen noted that in preclinical studies, "irreversibility has improved efficacy in specific molecular subsets, such as the EGFR vIII mutation, which is prominent in certain epithelial cancers."
Another factor that could make a difference in the drug's activity is the inhibition constant—a gauge of how tightly the agent binds to the receptor. Other factors, Agus noted, are dose, schedule, bioabsorption, and the chemistry of each agent, "slight nuances" that we may not yet be aware of.
"Little differences could be determinant," Baselga said. "Very small differences can make a difference in the end."
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