Pemetrexed disodium

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Alimta (Eli Lilly)
vials containing 500 mg powder for reconstitution
Approved indications: lung cancer, mesothelioma
Australian Medicines Handbook section 14.3

Pemetrexed disodium is an antifolate anticancer drug. It inhibits folate-dependent enzymes and inside cells it is converted to a metabolite which is a more potent inhibitor. Inhibiting the enzymes decreases the synthesis of nucleic acids and therefore reduces cell replication.

Although the use of chemotherapy for non-small cell lung cancer is increasing.¹ the prognosis remains grim. Pemetrexed has therefore been studied in patients with metastatic or locally advanced disease which has progressed despite previous chemotherapy. In a phase II study 79 patients were given an infusion of pemetrexed every 21 days. One patient had a complete response and six had partial responses. Although most of the responses occurred in patients who had not been previously treated with platinum-based chemotherapy, they did not live longer. Their median survival was four months, while patients who had already been treated with platinum-based chemotherapy had a median survival of 6.4 months.² The Australian approval of pemetrexed is limited to patients who have previously received platinum-based chemotherapy.

A phase III study randomised 283 patients with advanced non-small cell lung cancer to receive pemetrexed and 288 to receive docetaxel. The overall response rate was about 9% for both drugs, but pemetrexed appeared to be less toxic. The median survival time for each treatment group was approximately eight months.³

Pemetrexed has also been studied in patients with malignant pleural mesothelioma. As only a minority of patients can be treated with surgical resection, there is interest in assessing if chemotherapy has any benefits. In a trial involving 448 patients, pemetrexed and cisplatin were compared with cisplatin alone. As judged by computed tomography, there was a response to treatment in 16.7% of the patients given cisplatin and 41.3% of those given cisplatin and pemetrexed. The median survival with the combination was 12.1 months compared with 9.3 months for cisplatin alone.⁴

Like many anticancer drugs pemetrexed can cause serious adverse reactions, particularly myelosuppression. During the mesothelioma study there were several deaths at the start of the trial. Thereafter, all the patients enrolling in the study were given supplements of folic acid and vitamin B12 to try and reduce the toxicity of pemetrexed. Despite supplements, the combination of cisplatin and pemetrexed will cause neutropenia and leucopenia in 55-60% of patients, so there is a risk of infections and febrile neutropenia. Anaemia and thrombocytopenia are also common, so regular blood tests are needed to check if the patients are still fit for treatment. Although adverse reactions are less frequent when pemetrexed is used alone, supplements are still required. As skin rashes are very common, patients also require premedication with dexamethasone. Non-steroidal anti-inflammatory drugs should not be used with pemetrexed, particularly if renal function is impaired.

While pemetrexed has comparable efficacy to other drugs, such as docetaxel, its benefit to the patient dying of non-small cell lung cancer is less clear. Its effect on quality of life in the phase II study is difficult to interpret, partly because the median number of treatment cycles was only two.² There was no significant difference between pemetrexed and docetaxel in the quality of life analysis of the phase III study.³

Although pemetrexed and cisplatin had an overall advantage in mesothelioma, the choice of cisplatin for the single blind comparative study can be questioned: cisplatin may be an ineffective comparator. In addition, the survival advantage of combination treatment was only of borderline statistical significance (p = 0.051) in patients who followed the recommended regimen of cisplatin and pemetrexed with supplements of vitamin B12 and folic acid.⁴