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  • Home > Blog > Chemotherapy > Chemotherapy for Mesothelioma Treatment: Tolerability of Pemetrexed at Higher Doses
Posted on Thursday, Jan 8, 2009

Chemotherapy for Mesothelioma Treatment: Tolerability of Pemetrexed at Higher Doses

Combination therapy with pemetrexed and cisplatin has been the standard of care for the treatment of mesothelioma since its approval in 2004 by the US FDA. The treatment’s approval was driven by the results of a large Phase III study that demonstrated greater treatment efficacy for patients with malignant mesothelioma than any other chemotherapy treatment had previously demonstrated. The currently approved treatment regimen involves 500 mg/m2 of pemetrexed and 75 mg/m2 of cisplatin in 21-day cycles, along with folic acid and vitamin B12 supplementation to reduce the potentially toxic side effects of the main agents. The latter supplements were added to this regimen after pemetrexed and cisplatin dosing levels were finalized and because they’ve been successful in reducing side effects, a number of physicians have wondered if an increase in pemetrexed levels would still be tolerable, as well as more effective, for individual patients. Some studies have looked at higher doses of single agent pemetrexed treatment, but few have looked at increasing pemetrexed levels when still used in combination with cisplatin and vitamin supplements.

To learn more about the tolerability of increased pemetrexed levels in this context, Eli Lilly—makers of Alimta, pemetrexed’s trade name—worked with a group of researchers to discover the maximum tolerated dose (MTD) of pemetrexed, as well as the highest recommended dose of the drug. The paper describing the results of this research, “Phase I and Pharmacokinetic Study of Pemetrexed plus Cisplatin in Chemonaive Patients with Locally Advanced or Metastatic Malignant Pleural Mesothelioma or Non-Small Cell Lung Cancer,” was recently published in the journal Clinical Cancer Research.

Introduction to the Study

To discover the maximum tolerated dose and highest recommended dose of pemetrexed in combination with cisplatin and vitamin supplementation, the researchers enrolled 21 chemonaive patients with locally-advanced or metastatic cases of pleural mesothelioma or non-small cell lung cancer. 12 of these patients had non-small cell lung cancer and 9 were diagnosed with pleural mesothelioma. These 21 patients were then split into 5 different pemetrexed dosing groups: 3 patients received a dose of 500 mg/m2, 3 received 600 mg/m2 and 3 more received 700 mg/m2 doses, while 6 patients received 800 mg/m2 and the final 6 received 900 mg/m2 doses. All patients received the standard cisplatin level of 75 mg/m2.

The patients were primarily evaluated on tolerability, but part of the study also included a pharmacokinetic (PK) analysis of the body’s reaction to the drug agent. PK analysis evaluates the manner in which the drug combination is broken down by the body and then absorbed, distributed and excreted from it. Results from this type of analysis can be useful in predicting the possible effects of dose escalation on treatment efficacy.

Results & Conclusion

The study found that 900 mg/m2 was the maximum tolerated dose, but was associated with a number of grade 3 toxicities and one patient experienced a grade 4 neutropenia and later died from sepsis (this is considered a Grade 5 toxicity). None of the patients who received the 800 mg/m2 dose administration experienced any dose limiting toxicities, so the researchers concluded that—in terms of tolerability—800 mg/m2 was the highest recommended dose.

However, the authors also note that the results of their own PK analysis, as well as the results of previous PK analyses and of studies that evaluated higher doses of pemetrexed in single-agent therapy, have not shown a likelihood of increased therapeutic efficacy from a larger dosing regimen. These studies have shown that the manner in which pemetrexed is metabolized by the body shows a very similar response curve over a wide range of dosing levels, so an increase from 500 mg/m2 to 800 mg/m2 would be unlikely to be show clinical benefit to the patient. Because of these findings, the authors recommend keeping the standard dosing level of pemetrexed at 500 mg/m2 for patients with pleural mesothelioma or non-small cell lung cancer.