Three drugs, which use different mechanisms to target cancer, highlighted at annual oncology meeting.
For three tough cancers, new drugs are bringing some extra muscle.
One’s goal is to hijack the immune system. Another’s focus is to stop cancer cell division dead in its tracks, and the third drug attempts to snuff out the signal that tells the disease to grow.
Researchers are using this trio of up-and-coming drugs to treat metastatic melanoma, metastatic breast cancer, and drug-resistant medulloblastoma—all long known as three hard-to-beat cancers. Scientists highlighted their findings in early June at the annual meeting of the American Society of Clinical Oncology in Chicago.
We’ve never had a drug show survival benefit in metastatic melanoma,” said lead researcher Steven O’Day, MD, of The Angeles Clinic and Research Institute in California.
O’Day was talking about ipilimumab, an immune system-targeted drug that helped patients with metastatic melanoma live almost four months longer than those in the control group. The drug works by releasing a brake on the immune system, which activates T cells—the soldiers of the immune system—to go out and kill cancer cells.
The phase 3 study included 676 patients with metastatic melanoma whose disease had progressed during prior therapy. The participants were randomly assigned to receive one of three treatment options: ipilimumab, an investigational vaccine called gp100, or ipilimumab plus gp100.
For the group who received only ipilimumab, O’Day called the findings “historic.” Median overall survival for those patients reached 10.1 months, compared with 6.4 months for those receiving gp100 alone. Interestingly, combining the agents didn’t improve survival any better than ipilimumab alone: survival for patients who got both was still around 10 months. The median survival time for patients with metastatic melanoma is 6.2 months, according to a recent analysis of more than 40 clinical trials.
Ipilimumab also showed long-term promise, as 24 percent of patients continued to benefit from the drug for at least two years, compared with 14 percent for gp100.
We have patients on this trial out as far as four and a half years still alive,” O’Day told at the meeting. “And with our previous studies, we now have some of the earliest patients who went on this drug now seven and a half to eight years out. So it does look like some of those patients may—I don’t like to use the word ‘cure’—but [have]long-term survival, and that’s very exciting.”
Common side effects of ipilimumab, an intravenous drug, included diarrhea and fatigue. Up to 15 percent of patients experienced severe immune side effects, such as rash and inflammation of the colon, which required treatment with steroids—this is probably due to autoimmune effects on normal cells once the immune system is hyperactivated. Seven deaths were associated with these immune-related side effects.
The maker of ipilimumab, Bristol-Myers Squibb, plans to file the drug for approval in previously treated metastatic melanoma before the end of this year, spokeswoman Tracy Furey said. The drug is currently being made available to patients through a compassionate use trial. (For more information, visit www.clinicaltrials.gov.)
Following the success with ipilimumab as a single agent, O’Day said researchers will start to look at the agent in combination with other drugs. One possible avenue is chemotherapy drugs, or agents that target a gene called BRAF, which is mutated in more than half of patients with melanoma.
Ipilimumab also looks promising in lung and prostate cancers, O’Day said.
Eribulin is another new drug—and although it uses a more traditional approach for killing cancer cells, researchers said the results were just as significant.
A chemotherapy drug, eribulin extended survival by two and a half months in women with locally recurrent or metastatic breast cancer that had progressed on as many as five previous chemotherapy regimens.
What we’ve never seen before is a drug that can prolong survival in women who have received so many previous lines of chemotherapy,” lead researcher Christopher Twelves, MD, of the University of Leeds and St. James’s Institute of Oncology in the United Kingdom, told .
Eribulin is an intravenous drug derived from a sea sponge that attacks the scaffolding within a cell that allows it to divide. Unable to divide, the cancer cell ultimately dies.
Two-thirds of 762 patients in the phase 3 study received eribulin. The remaining third were prescribed by their physician another round of single-agent treatment—either another chemotherapy, a hormonal therapy, biological drug, or supportive care. Because no standard treatment exists for women with such heavily pretreated advanced breast cancer, researchers wanted the control arm to reflect real-life choices.
Patients on eribulin lived a median of just over 13 months compared with 10.7 months for women in the “treatment of physician’s choice” arm. Side effects of eribulin included fatigue, low white blood cell count, and peripheral neuropathy.
Twelves said although chemotherapy is sometimes thought of as a “blunt instrument,” the eribulin research shows that chemotherapy drugs can be targeted.
What we want and what our patients want are drugs that work. I don’t think that oncologists or patients with cancer are too concerned with what it says on the label provided the drug works,” he said.
Eisai, the maker of eribulin, filed the drug for approval in March for locally advanced or metastatic breast cancer that has been previously treated with at least two chemotherapy regimens. The Food and Drug Administration recently granted priority review for the application, which means the agency will decide whether to approve the drug by September.
Twelves said his institution is currently conducting a study comparing eribulin with Xeloda (capecitabine) as second-line breast cancer therapy. Eribulin is also in clinical testing for advanced non-small cell lung cancer and advanced soft-tissue sarcoma.
Taking a direct shot at the most common type of brain tumor in children is GDC-0449, an oral agent that shuts down the sonic hedgehog pathway. Typically turned off in normal cells, the hedgehog pathway is abnormally activated in about 20 percent of medulloblastomas, plus other cancers. Researchers believe this pathway may play a key role in the growth and survival of cancer cells.
Among 13 children with recurrent or drug-resistant medulloblastoma, 12 tolerated the drug well, with side effects including fatigue and muscle cramps.
The primary objectives of the phase 1 study were to confirm safety and find the right dose. But researchers also stumbled upon some apparent success: one patient remained on the drug for close to six months before the disease progressed, and another patient is still on treatment more than a year later, said Amar Gajjar, MD, of St. Jude Children’s Research Hospital in Memphis. Both patients were found to have an activated sonic hedgehog pathway in their tumors, he said. Currently, less than five percent of children with recurrent medulloblastoma survive.
Gajjar said a phase 2 study with GDC-0449 will begin enrolling children with relapsed medulloblastoma by early January, and a phase 2 study in young adults with recurrent medulloblastoma is currently under way.
Previous early-phase studies suggest the sonic hedgehog pathway inhibitor may also be effective in adults with advanced basal cell carcinoma, a common type of skin cancer. The agent is also being tested in advanced ovarian cancer.
New technology and a better understanding of what drives cancer has allowed doctors and researchers to stop grouping tumors into one big category, Gajjar told .
“We just lumped them all and hit them with the same hammer,” he said. “We’re just learning that actually these are different diseases that are becoming cancer by different pathways, so [we’re] trying to direct the treatment based on what is actually going wrong with the cell. And that’s going to take a lot more time and effort.”