Journal of the National Cancer Institute Advance Access originally published online on August 26, 2008
JNCI Journal of the National Cancer Institute 2008 100(17):1202-1203; doi:10.1093/jnci/djn316
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© Oxford University Press 2008.
NEWS |
Major Treatment Improvements Encourage Kidney Cancer Researchers To Seek Further Gains
Targeted therapies have improved clinical outcomes over the past several years for patients with advanced renal cell cancer. Data presented at this year's annual meeting of the American Society for Clinical Oncology (ASCO) showed that overall survival for previously untreated patients has increased from just over 1 year to more than 2, and patients who relapsed while being treated with antiangiogenesis therapies can benefit from treatment with a different targeted drug.
Researchers are cautiously optimistic that combinations of existing therapies will allow the trend to continue, though early trial data suggest that another substantial improvement will be hard to find with existing molecular targets and drugs. Some researchers, however, contend that extending median survival is no longer an adequate goal and that the field really should be pushing for curative therapy.
"This field had basically nothing—cytokines—for years and years, and with targeted therapy it has taken a quantum leap," said Brian Rini, M.D., a staff member in the department of solid tumor oncology at the Cleveland Clinic Taussig Cancer Center in Ohio. "Now I think we will move slowly from that new baseline. Is there another quantum leap down the road? Maybe. I don’t see it. I don’t think combination therapy is it, but you never know. If a new drug or a new mechanism comes along, that might do it."
First- and Second-line Therapies
For the past 2.5 years, oncologists have been using sorafenib or sunitinib, which are tyrosine kinase inhibitors of the vascular endothelial growth factor (VEGF) receptor, to treat patients with newly diagnosed advanced renal cell cancer, despite lacking overall survival data from phase III trials. That situation changed when researchers presented the final data from a 750-patient trial at the ASCO meeting in June.
Patients with previously untreated metastatic disease who received sunitinib had a median overall survival of 26.4 months compared with 21.8 months for patients who received interferon, a cytokine that was the previous standard of care, reported Robert Figlin, M.D., chair of the division of medical oncology and experimental therapeutics and associate director for clinical research at the City of Hope in Duarte, Calif. When the researchers included all the patients who had been enrolled in the trial in the analysis, the results were borderline statistically significant with a P value of 0.051. When the 25 patients who were initially treated with interferon but then received sunitinib after progression were excluded from the analysis, the median overall survival in the control arm dropped to 20 months and the difference reached statistical significance with a P value of 0.0362.
The new data did not change anyone's mind about sunitinib, Rini said. "For me, the data support what I already knew about the drug––it is making people live longer," he said. "These numbers are much higher than anything we have seen in kidney cancer before."
But there were data presented at the meeting that some experts thought were more important for clinical practice. Researchers found that patients whose disease progressed on sunitinib, sorafenib, or both could benefit from everolimus, a targeted agent that inhibits the mTOR protein. More than 400 patients were randomly assigned to receive either everolimus or placebo in a two-to-one fashion. At the first planned interim analysis, the data safety monitoring committee recommended closing the trial because the primary endpoint of improved progression-free survival had already been met. Specifically, patients treated with the active drug had a median progression-free survival of 4 months compared with 1.9 months for patients taking placebo, reported Robert Motzer, M.D., an attending physician at Memorial Sloan-Kettering Cancer Center in New York who led the trial.
"The targeted therapies clearly improve progression-free and overall survival, but nearly all patients develop resistance and progress at some point," Motzer said. "We don’t know why. But one of the attractive aspects of everolimus is that it has a different mechanism of action and seems to be particularly effective in tumors that are resistant to the other agents."
Researchers who were not involved in the trial agree that it is a major step forward. "It is an important trial; there is no doubt," said Keith Flaherty, M.D., assistant professor of medicine at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. A subset analysis showed that the hazard ratios for disease progression were nearly identical, ranging from 0.28 to 0.30, for patients treated with everolimus, regardless of whether they had previously relapsed on sunitinib, sorafenib, or both. That observation, although based on a subset analysis and therefore not conclusive, is heartening, Flaherty said. Many clinicians already use the two VEGF tyrosine kinase inhibitors in sequence, and the analysis suggests that they can reserve everolimus for third-line therapy.
Combining Agents
The next improvements in progression-free and overall survival for patients with advanced kidney cancer are likely to come, experts agree, from combinations of the existing targeted agents, including sunitinib, sorafenib, and everolimus. Investigators reported phase I and II data from several of the combination trials at the ASCO meeting. Everyone involved emphasized that this work is still preliminary, however, and not ready for clinical use.
Patients with metastatic kidney cancer can tolerate a combination of everolimus and bevacizumab, an antibody that targets VEGF, reported John Hainsworth, M.D., chief scientific officer at the Sarah Cannon Research Institute in Nashville. About 60 patients enrolled in the trial, half of whom had previously received either sorafenib or sunitinib and half who had received no prior therapy. Twenty percent of patients had an objective response to the combination based on RECIST criteria, and nearly all the patients (86%) had some evidence of tumor shrinkage. Hainsworth noted that there was no obvious difference in response between the previously treated and untreated patients, with median progression-free survivals of 11 months and 12 months, respectively.
Although bevacizumab and everolimus could be used together at their full standard doses, researchers have not found that to be the case with most of the combinations tried thus far, and sometimes the combinations are too toxic to be used at all. For example, Motzer presented data at the meeting from a phase I trial showing that patients treated with a combination of sunitinib and bevacizumab are at risk of developing life-threatening anemia.
Patients can tolerate a combination of bevacizumab and sorafenib when the drugs are each given at half the standard dose, according to final phase I data presented by Jeffrey Sosman, M.D., professor of medicine and medical oncologist at Vanderbilt–Ingram Cancer Center in Nashville. The combination, which is being further tested in an ongoing phase II trial by the Eastern Oncology Cooperative Group, showed activity in the early trial. Forty-one of the 48 patients who participated in the trial had some degree of tumor shrinkage, including 25 who had a partial response.
Flaherty, who was a coinvestigator on Sosman's trial, expects that these combinations are the most promising avenue available with current resources, but notes that the approach is limited by the drugs’ mechanism of action. "Even if we perfect antiangiogenic therapy, that is still unlikely to eradicate tumors," he said. Angiogenesis is thought to be necessary for tumor growth only when the tumor grows beyond the size that can be supported by diffusion from existing vasculature. "We are witnessing that. We see on scans that some patients have dramatic regression, but what survives is a thin rim of viable tumor tissue at the outer edge that does not need tumor vessels. That would imply a need to kill off that residual disease with a therapy that is able to directly trigger the tumor cells to die" to get a complete response.
Pushing for the Next Advance
With that concept in mind, some researchers think that new agents with new mechanisms of action are needed. Figlin, for example, thinks that combining the existing targeted agents with immunotherapy may be the way forward. To support that assertion, he pointed out that high-dose interleukin 2, an immunotherapy that is hard to administer and hard for patients to tolerate, does induce durable complete responses in some patients. "My own bias is that you build immune therapy on the back of targeted therapy," he said.
In fact, researchers have already found that the current targeted therapies, such as sunitinib, alter the type and number of T lymphocytes and dendritic cells. Figlin interprets these observations as evidence that the drugs may be indirectly relieving immune system suppression by lowering the burden of disease. If that's true, he contends, then following these agents with an antitumor vaccine or some other immunotherapy may be powerful.
Immunotherapy may have a place in the future, Flaherty said, but he does not see a drug or therapy that is currently poised to fill the gap. Several research groups have generated monoclonal antibodies that are relatively specific for renal cancer cells. One possibility would be to attach a toxin or radioactive isotope to one of these antibodies and use it to kill off the residual tumor after the bulk of a patient's tumor is killed off with antiangiogenic therapy. But these ideas are early, he emphasized.
Rini is more cautious when speculating about what is likely to generate that next big transition, but he agrees that the issue is paramount. "That is the question right now: How do we translate a group of very active drugs that have clearly shifted the survival curve into one that makes the tail of the curve much more significant? Is it combinations? Patient selection? I don’t know what it is," he said. "If I knew that I’d be accepting my Nobel prize in Stockholm."
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