Δευτέρα, 22 Φεβρουαρίου 2016

NEW DRUGS FOR SARCOMAS

When eribulin mesylate (Halaven, Eisai Inc.) was approved for liposarcoma last month, it became the third new drug for the treatment of sarcomas after decades of no progress.
The other recent drug is trabectedin (Yondelis, PharmaMar), which was approved in October 2015 for use in both liposarcoma or leiomyosarcoma, and the third drug is pazopanib (Votrient, Novartis Pharmaceuticals Corporation), which was approved for use in soft tissue sarcomas.
"The last 3 years have given us pazopanib, trabectedin, and now eribulin," said George D. Demetri, MD, professor of medicine at Harvard Medical School and director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston. He was also one of the investigators on the pivotal eribulin study that led to the recent approval; results from that study were reported at the 2015 annual meeting American Society of Clinical Oncology (ASCO), as reported by Medscape Medical News, and were published online February 10 in the Lancet.
There's a lot of activity in this area and its moving quickly, Dr Demetri said in an interview. "One of the messages is that doctors do need to stay abreast of these developments, as they are important to the patients."
"But I think that doctors are a bit confused because they may see only one or two sarcoma patients a year," he said. "And these approvals can be confusing."
For example, Dr Demetri noted, pazopanib is approved for leiomyosarcomas but not for liposarcomas, and trabectedin is approved for both of the L-sarcomas. And now eribulin has entered the market and is approved for liposarcomas but not leiomyosarcomas.
"The message is that these are very different diseases, and the choice of treatment matters," he told Medscape Medical News. "And the sequencing of treatment matters, as far what's likely to help the most and what's likely to harm."
Pazopanib is a small-molecule tyrosine kinase inhibitor that specifically targets receptors associated with angiogenesis and tumor cell proliferation. It is the first new drug to be approved for soft tissue sarcomas in decades, but is not a new agent; it was already marketed for the treatment of advanced renal cell carcinoma.
The drug approved for sarcomas prior to that, doxorubicin (Adriamycin), was approved in the early 1970s.
Eribulin was also already marketed in the United States; it was approved in 2010 for the treatment of metastatic breast cancer.
Trabectedin, a marine alkaloid with a unique mechanism of action, is new to the American market, although it has been available in Europe for use in sarcoma for some years.
Details of Eribulin Study
The eribulin study involved 452 patients with intermediate- or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Of these patients, 228 were randomized to eribulin and 224 were randomized to dacarbazine, which is a standard chemotherapy for sarcoma.
Overall survival was significantly better with eribulin than with dacarbazine (13.5 vs 11.5 months; hazard ratio [HR], 0.768; P = .0169). However, there was no difference in progression-free survival between the two groups.
Median progression-free survival was the same in the eribulin and dacarbazine groups (2.6 vs 2.6 months; HR, 0.88; P = 0.23).
There were no complete responses. Rates were similar in the eribulin and dacarbazine groups for partial response (4% vs 5%) and for stable disease (52% vs 48%).
In addition, the rate of objective response was similar in the eribulin and dacarbazine groups (4% vs 5%; P = .62).
There was no significance difference between the eribulin and dacarbazine groups for disease control (56% vs 53; P = .438).
However, although both types of L-sarcomas were evaluated in the study, eribulin was approved only for liposarcomas. At the time of the approval, the manufacturer pointed out that a preplanned exploratory subgroup analysis showed that the treatment effects of eribulin were limited to patients with liposarcoma, and that there was no evidence of efficacy in patients with advanced or metastatic leiomyosarcoma.
Approval by the US Food and Drug Administration (FDA) was granted on the basis of results from the subgroup of 143 patients with liposarcoma. The FDA described the better survival with eribulin than with dacarbazine in this subgroup as "clinically meaningful" (15.6 vs 8.4 months). Median progression-free survival, a secondary end point, was also better with eribulin (2.9 vs 1.7 months).
This is not as unusual as it seems. "When we dove into the data, we saw that the survival benefit was in the group with liposarcomas, even though they were the smaller population," Dr Demetri told Medscape Medical News.
But that doesn't mean that eribulin is ineffective for leiomyosarcomas, he noted. "It was just that the control drug, the older therapy, was very effective in this disease, so we didn't see that much of a survival difference."
"And that isn't a bad thing," Dr Demetri continued. "We didn't want to displace the older drug, but just wanted to add a tool for treating the disease. But that's not how the FDA looked at it, which is why approval was only given for liposarcomas."
Further research may be required to find out why it didn't work as well in leiomyosarcomas. "This helps bring home our point to the oncology community that all sarcomas are not the same, and this really is the future of all cancer medicines as we are going to get very precise about which drugs we use," he added.
Just as there are hundreds of different types of cancer, there are many different types of sarcomas, he said. Sarcomas arise in mesenchymal cells, which are found in soft tissue, such as fat, muscle, nerves, blood vessels, and other connective tissue.
After gastrointestinal stromal tumors, the most common types of sarcoma are liposarcomas (arising in fat cells) and leiomyosarcomas (arising in muscle cells). "But the only thing they have in common is that they begin with the letter L," Dr Demetri explained.
"Biologically they are totally different diseases," he emphasized.
But if the two sarcomas are unrelated to one another, why were they paired together in this trial?
The eribulin study was modeled on a similar clinical trial that involved patients with both types of L-sarcomas and pitted trabectedin against dacarbazine, Dr Demetri explained.
"Basically, we took out the trabectedin and put in eribulin, and tested the same population of patients," he said. "So we had two large international phase 3 trials for a relatively rare disease."
But in contrast to the eribulin study, the group treated with trabectedin showed a significant improvement in progression-free survival but no significant difference in overall survival.
Meaningful Survival?
When both of theses studies were presented at the ASCO meeting last year, discussant Ian Robert Judson, MD, from the sarcoma unit at the Royal Marsden Cancer Hospital in London, United Kingdom, highlighted the difference seen in the results, and asked which is more clinically meaningful: an improvement in overall survival or an improvement in progression-free survival?
In particular, he questioned the clinical benefit of eribulin, pointing out that it was more toxic than the standard therapy of dacarbazine.
Treatment-emergent adverse events that were more frequent with eribulin than with dacarbazine included neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%), and alopecia (35% vs 3%). The rate of grade 3 toxicity was higher with eribulin than with dacarbazine (63% vs 53%), as were the rates of grade 4 toxicity (26% vs 20%) and fatal toxicity (4% vs 1%).
Dr Judson noted that eribulin was not more active than dacarbazine when conventional measures of efficacy were used, such as percentage of responses or stable disease, and that it has no apparent effect on disease control. Previous studies have shown that effective chemotherapy improves pain and sleeplessness, but there appeared to be no effect on symptoms with eribulin.
There is also a question of cost. Eribulin comes with a price tag of about $5511 per cycle of treatment, whereas generic dacarbazine costs $78 per cycle.
"Is it affordable for a 2-month increase in survival with no reduction in tumor burden, in spite of significant toxicity?" he asked. "Without tumor shrinkage or improved quality of life, is a small increase in survival meaningful?"
Next Steps
In a comment accompanying the eribulin study, Robin J. Young MBChB, PhD, and Penella Woll, BMedSci, MBBS, PhD, both from the academic unit of clinical oncology at Weston Park Hospital in Sheffield, United Kingdom, ponder the next step for the treatment of soft tissue sarcoma.
In both the eribulin and trabectedin studies, the rate of objective response was low (4.4% vs 8.9%), "so patients should be counseled that treatment is offered to control disease, rather than shrink tumors," they write.
The toxicity profiles of both agents are manageable, but many patients might prefer eribulin because of its survival benefit, they point out.
Eribulin was approved for patients with advanced disease who had already received at least two lines of chemotherapy. But given the low rate of objective response, Drs Young and Woll don't see it as being "attractive as a first-line option for advanced soft-tissue sarcoma."
But there are other options to be explored. "If eribulin enhances the response to subsequent chemotherapy, should eribulin be used in combination or sequenced with other systemic treatments, and with which other drugs?" they ask.
"Further study of the mode of action of eribulin and the identification of biomarkers to guide patient selection would help to place it in the algorithm of treatments for relapse," Drs Young and Woll explain.
Dr Demetri agrees. "The old adage is that drug development only really starts once a drug gets FDA approval," he said. "We know that it works in liposarcoma, so now we've got to work on improving that."
"Eribulin has a marginal impact on survival," he pointed out. "Even though it was significant, it's still only 2 months. And while that's good for patients, it's not what we want to see."
"I'm not being negative, but I want to put it in perspective," he added.
Tissue specimens were collected from patients, so the next step is to look for biomarkers. "We can see if there are any exceptional responders who get more benefit," Dr Demetri said. "That's what the next generation of drugs is aiming to do, and that's the goal of precision medicine.
The eribulin study was funded by the manufacturer, Eisai. Dr Demetri reports receiving grants from Eisai, Pfizer, Threshold Pharmaceuticals, Janssen Oncology, Bayer, Novartis, and GlaxoSmithKline; receiving personal fees from Pfizer, Lilly, EMD Serono, Threshold Pharmaceuticals, Sanofi Oncology, GlaxoSmithKline, Daiichi Sankyo, Ariad, AstraZeneca, Ziopharm, Polaris Pharmaceuticals, Kolltan Pharmaceuticals, Blueprint Medicines, Caris Life Sciences, Champions Oncology, and Bessor Pharmaceuticals; holding stocks and/or stock options in Kolltan Pharmaceuticals, Blueprint Medicines, Caris Life Sciences, Champions Oncology, and Bessor Pharmaceuticals; and serving on the board of directors for Blueprint Medicines. Several coauthors report relationships with industry, as noted in the publication. Dr Young and Dr Woll have disclosed no relevant financial relationships.
Lancet. Published online February 10, 2016. AbstractComment

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