Zosia Chustecka

June 11, 2015

CHICAGO — For the first time, a drug has been shown to improve survival in patients with liposarcoma (LPS) or leiomyosarcoma (LMS), collectively referred to as L-sarcomas.

The new result was achieved with eribulin (Halaven, Eisai Inc), which is currently approved for the treatment of advanced breast cancer. The new data are being submitted for approval of the L-sarcomas as another indication for the drug.

In a trial conducted in 452 patients, eribulin improved overall survival (OS) by 2 months compared with standard therapy, dacarbazine (DTIC-Dome, Bayer HealthCare Pharmaceuticals) (13.5 months with eribulin vs 11.5 months with dacarbazine; hazard ratio [HR], 0.768; P = .0169). However, there was no difference in progression-free survival (PFS) between the two groups.

The results were presented at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting at a session on soft-tissue sarcomas. At that session, another large phase 3 trial was presented showing that trabectedin (Yondelis, PharmaMar) improved PFS in patients with L-sarcomas, but not OS. These data on trabectedin are also to be filed for approval in the United States (the drug is currently approved for the treatment of sarcoma in Europe, Canada, and other countries).

Both trials were hailed as positive, and both will be used in approval submissions, and yet they have exactly opposite results ― eribulin improved OS but not PFS, whereas trabectedin improved PFS but not OS.

But which is clinically more meaningful? This remains an important question, said the discussant for the presentations, Ian Robert Judson, MD, from the sarcoma unit at the Royal Marsden Cancer Hospital, London, United Kingdom.

Eribulin Survival Benefit

The eribulin survival benefit was seen in patients who were on their third line of sarcoma therapy. "Patients whose disease progresses despite two or more lines of treatment have a very poor prognosis," commented lead author of the eribulin study, Patrick Schöffski, MD, MPH, head of the Department of General Medical Oncology, University Hospitals Leuven, in Belgium. "For a disease where such few treatment options exist, a 2-month improvement [as seen with eribulin] in survival is significant," he added.

However, "the survival gain seen with eribulin must be weighed against the burden of side effects patients experienced," commented Gary K. Schwartz, MD, chief of the Division of Hematology and Oncology at Columbia University Medical Center, in New York City, who is an ASCO spokesperson.

In his discussion of the paper, Dr Judson noted that the results with eribulin in sarcoma follow the same pattern that was seen with this drug in breast cancer (in the pivotal EMBRACE trial), which also showed an improvement in OS of around 2 months but also no improvement in PFS.

This contrasts with what is usually seen with drugs active against cancer, he commented ― usually they prolong PFS and are also shown to improve OS. This is the opposite, and "we don't know quite what is going on here," he said, adding that it might be due to a different mechanism of action. Eribulin acts as an inhibitor of microtubule dynamics, and it may be affecting the tumor microenvironment, he suggested. "It does look like a true biological effect," he added.

However, eribulin was more toxic than dacarbazine, Dr Judson noted. Treatment-emergent adverse events (TEAEs) were more frequent in patients treated with eribulin than in those treated with dacarbazine. TEAEs included neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%), and alopecia (35% vs 3%). Also more frequent were TEAEs of grade 3 (63% vs 53%) and grade 4 (26% vs 20%), as well as fatal TEAEs (4% vs 1%), the researchers noted.

Dr Judson commented that eribulin was not more active that dacarbazine on conventional measures of efficacy, 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.

In addition, it is very much more expensive. Eribulin costs $5511 per cycle of treatment, whereas the comparator and standard therapy, dacarbazine, costs $78 per cycle. So there is a question mark over its cost-effectiveness, he said.

"Is it affordable for a 2-month increase in survival with no reduction in tumor burden, in spite off significant toxicity?" he asked. "Without tumor shrinkage or improved quality of life, is a small increase in survival meaningful?"

Trabectedin Improvement in PFS

The trabectedin trial is the first phase 3 study of this drug in sarcoma, but the drug is already known to be active in sarcoma (it was approved in Europe in 2007 on the basis of a randomized phase 2 trial [J Clin Oncol. 2009;27:4188]).

The phase 3 study, presented by George D. Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute, in Boston, was conducted in 518 patients and showed that trabectedin had "improved efficacy" compared with dacarbazine.

There was a highly statistically significant difference in PFS (4.2 months with trabectedin vs 1.5 months with dacarbazine; HR = .55; P < .0001).

Also, the results for time to postprotocol therapy show a significant difference (6.9 months with trabectedin vs 3.7 months with dacarbazine; HR = 0.47; P < .0001).

"Trabectedin offers a meaningful treatment option for patients with advanced liposarcoma or leiomyosarcoma," the researchers concluded.

However, this trial found no improvement in OS (12.4 months with trabectedin vs 12.9 months with dacarbazine). In his discussion, Dr Judson noted that the median OS in the dacarbazine group exceeded by 3 months what had been expected, so the lack of a difference is "perhaps not so surprising." He also commented that posttrial chemotherapy was likely a confounder.

Dr Judson congratulated the researchers for conducting a phase 3 study with trabectedin, and he noted that this study shows the same benefit that has been seen in "every other trial with trabectedin": about 20% to 30% of patients show a prolonged clinical benefit.

Unfortunately, there is as yet no way of identifying which patients will have the prolonged benefit. "Further research is needed to find a biomarker that would identify these patients," he added.

Trabectedin was "somewhat more toxic" than dacarbazine, Dr Judson noted, with patients reporting more nausea, vomiting, fatigue, and diarrhea.

Because trabectedin is not available in the United States, there is no US price to consider. But Dr Judson noted that trabectedin is considered to be cost-effective in the United Kingdom; it was approved for reimbursement by the National Institute of Clinical Excellence in 2010.

Dr Judson also commented that an OS benefit is difficult to show from a clinical trial in sarcoma, because a number of drugs can be used post protocol that may affect survival in both arms of the study. But overall, the drugs are making a difference in survival, he said: for patients with metastatic sarcoma who receive no treatment, the median OS is around 12 months, whereas the median OS is now approximately 20 months for patients who have received various drug treatments.

In recent years, the targeted agent pazopanib (Votrient, Novartis Pharmaceuticals Corporation) was approved for use in sarcoma on the basis of a trial showing a PFS improvement (but no OS benefit) and is considered by experts to be of benefit in controlling the disease.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstracts LBA10502 (eribulin study) and 10503 (trabectedin study). Presented June 1, 2015.

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