Full Title: Phase III Trial Of Pemetrexed Plus Best Supportive Care Compared With Best Supportive Care In Previously Treated Patients With Advanced Malignant Pleural Mesothelioma

A number of chemotherapy regimens have been deployed in the treatment of mesothelioma, although none of them have yet to demonstrate the efficacy seen in other forms of cancer. From the earliest studies on single-agent treatments utilizing drugs such as doxorubicin and ifosfamide to the recent multi-agent combination therapies using pemetrexed (Alimta®) along with platinum agents such as cisplatin or carboplatin, the use of chemotherapy in the treatment of pleural mesothelioma has often focused only on first-line use for chemo-naive patients. There has not been much study on the efficacy of second-line chemotherapy for patients with a favorable, but still incomplete, response to first-line therapy. To address this issue, an international team of researchers conducted a multicenter, Phase III study which compared the effectiveness of pemetrexed with best supportive care in patients with advanced malignant mesothelioma to a similar cohort of patients with advanced disease who only received best supportive care. The results from this study have recently been released and what follows here is a summary of their findings.

Overview of the Study

The researchers initially entered 252 patients from 45 international institutions into this study. All of the patients had histologically-confirmed mesothelioma, with advanced progression, and had previously undergone first-line chemotherapy. At the time the study began, pemetrexed had yet to be approved, so no one received this drug during his or her initial chemo treatment. Patients also had to meet a number of other important health criteria to stay enrolled, some of which included good performance status, measurable disease and a life expectancy greater than two months. Of the 252 patients initially enrolled, 9 were subsequently excluded, so the final sample size was 243. The patients were then randomly assigned to either the pemetrexed with best supportive care (P+BSC) group or to the group only receiving best supportive care (BSC). The P+BSC group had 123 patients and the BSC group was assigned 120.

The BSC group received the best palliative care the centers could provide. The goal was to maximize quality of life, but to not treat the underlying cancer at all. Along with receiving the same in supportive treatment, patients in the P+BSC group received a pemetrexed dose of 500mg/m² on the first day of a three week period and were scheduled for a period of eight cycles. They also received supplements of folic acid and vitamin b₁₂, which are standard for pemetrexed therapy. Doses and delivery were adjusted in response to specific patient reactions.

The primary endpoint of the study was overall survival, which the authors defined as the period from group assignment to death. They also setup a number of secondary endpoints as well, some of which included time to progression (TTP), progression-free survival (PFS), time to treatment failure (TTF), interval from group assignment to first signs of progressive disease, and interval from progressive disease to death.

Results

In terms of overall survival, the results did not show a statistically significant difference between the two groups, with the P+BSC group demonstrating a median survival time of 8.4 months and the BSC group demonstrating a figure of 9.7 months. The authors specifically note that their use of the statistical method used to compute these averages could possibly be thrown off by specific aspects of the study—aspects that may have obscured the overall survival numbers.

Unlike the overall survival numbers, all of the secondary endpoints showed a clear benefit to the P+BSC group. Progression-free survival, time to progression and time to treatment failure for this group all demonstrated median values of 3.6 or 3.7 months compared to 1.5 months for the BSC group. Response rate also significantly favored the P+BSC group, with 18.7% of the patients (23 out of 123) showing some partial treatment response while only 1.7% (2 of 120) of the other cohort showing partial response. The duration of response for the pemetrexed group demonstrated a figure of 3.5 months, and, when one looks at the overall survival figures in those patients who did show a response to treatment, median survival jumps from 8.4 months to 20.5 months.

Conclusion

The results as presented by the study clearly demonstrate the benefits of second-line therapy for at least some patients. Toxicity for this second-line administration was generally well-controlled and the P+BSC group showed significantly greater antitumor activity than did the BSC group. Further research is, of course, necessary to confirm the study’s positive finding, as well as to investigate why the overall survival figures were actually lower for the chemotherapy group than for the supportive care group, but these initial results are quite promising for future chemotherapy treatment for persons with mesothelioma.

Labels: mesothelioma