The current standard of care for the treatment of mesothelioma is combination chemotherapy using pemetrexed (Alimta) and cisplatin. The US FDA first approved this therapy in 2004, soon after the results of a large-scale, Phase III clinical trial were published that showed statistically significant improvements in median survival and time-to-progression for patients with pleural mesothelioma. Subsequent trials confirmed the clinical benefits this study found and the intervening years have seen approvals of the therapy from every other major nation’s health care regulatory agency. However, this treatment is still not a curative solution for mesothelioma, so research into improving its efficacy, along with additional research into the combination of these agents with other modalities of treatment, continues on a number of other fronts.

An article describing the history of pemetrexed use, from its earliest Phase I studies to the 2004 Phase III study that led to its approval, has been published in the journal Therapeutics and Clinical Risk Management. The authors provide a full literature review of these various trials and they describe pemetrexed’s mechanism of action and the initial studies that investigated its use, as well as a detailed description of the study design and results of the Phase III study that led to pemetrexed’s approval.

The following is a partial summary of that article, “Review of Pemetrexed in Combination with Cisplatin for the Treatment of Malignant Pleural Mesothelioma.”

Cisplatin and Pemetrexed

Cisplatin is a chemotherapy drug in the class of drugs known as platinum agents. Cisplatin was first introduced in 1978 and its efficacy for the treatment of a number of cancers has been shown time and time again. Pemetrexed is an antimetabolite chemotherapy agent, whose efficacy arises from its ability to inhibit folate (folic acid) from being metabolized.

Phase I and Phase II Clinical Trials

A number of different chemotherapy agents have been used to treat mesothelioma, but the results have been disappointing. Preclinical studies of cisplatin and pemetrexed showed efficacy for the treatment of non-small cell lung cancer, so researchers considered it possibly beneficial for mesothelioma treatment. In a Phase I evaluation, a number of patients with various cancers, including pleural mesothelioma, were given pemetrexed in combination with cisplatin. This trial investigated dosage recommendations and their relationship with treatment toxicities. The study concluded with a recommendation of 600 mg/m² of pemetrexed and 75 mg/m² of cisplatin and a call for more research.

A Phase II study of the combination chemotherapy was not conducted with mesothelioma patients, but was conducted for untreated patients with Stage IIIB or IV non-small cell lung cancer. In this trial, pemetrexed levels were reduced to 500 mg/m² and cisplatin levels remained the same. Overall response was 45% and the treatment was well-tolerated, so a Phase III trial was planned for mesothelioma patients.

EMPHACIS III Clinical Trial and FDA Approval

The Evaluation of Mesothelioma in a Phase III Trial of Pemetrexed with Cisplatin (EMPHACIS) enrolled 448 chemonaive patients into a trial that randomized patients into one of two groups: a group that received pemetrexed + cisplatin and a group that received cisplatin alone. Administrations were given every 21 days. When B12 and folic acid deficiency were discovered as common side effects, vitamin supplementation administrations were added to the trial design. This was the largest study of mesothelioma patents ever attempted.

The initial study results showed a median survival time for the combination arm at 12.1 months, compared to 9.3 months for the cisplatin only group. Although not statistically significant, subgroup analysis of the patient cohort showed that patients who received both the combination therapy and vitamin supplements had a 13.3 month median survival vs. 10.0 months for the cisplatin + vitamin crowd. Final results of the study were released in 2005, with a 12.8 month median survival noted for the combination therapy patients vs. only 9 months for the cisplatin-alone patients. These results also demonstrated improvements in pulmonary function tests.

This study led to the FDA’s approval of pemetrexed and cisplatin in 2004. The FDA could not fully confirm all of the results of the EMPHACIS trial, but they could confirm that this treatment arm was more effective than previous trials had been. The FDA’s dose recommendation also incorporated the recommendation for vitamin supplements, as well as the use of dexamethasone to prevent pemetrexed-caused rashes.

International Approval and Quality of Life Issues

The FDA was the first major regulatory agency to approve pemetrexed + cisplatin for the treatment of pleural mesothelioma. Since that time, most other national healthcare agencies have also approved its use. As was alluded to in our description of the Phase III trial, pemetrexed’s efficacy is not simply based on increased survival time, but is also based on real improvements in patient quality of life. A number of studies have shown statistically significant improvements in disease-related dyspnea, pain and cough.

Other Studies and Combinations

Even as this combination has proven the most effective chemotherapy treatment in clinical trials, research into other pemetrexed-based combinations also continues. In place of cisplatin, carboplatin is sometimes used because it typically has a more favorable toxicity profile. Overall response rates and efficacy tend to be higher with cisplatin, but carboplatin has demonstrated easier tolerability for many patients. However, Phase III trials have not been conducted for this combination.

Labels: chemotherapy, mesothelioma, treatments