Phase II Studies of Pemetrexed in Metastatic Breast and Gynecologic Cancers

Pemetrexed (Alimta) is an antifolate agent that possesses antitumor activity in a variety of solid tumors, including mesothelioma and non-small-cell lung, gastrointestinal, head and neck, breast, and gynecologic cancers.[1] Earlyphase studies showed that neutropenia, a common antimetabolite toxicity, was the primary dose-limiting toxicity of pemetrexed(Drug information on pemetrexed) treatment. Elevated homocysteine levels, a marker for reduced functional availability of folate and vitamin B₁₂, were shown to be associated with increased risk of myelosuppression with pemetrexed treatment in an analysis of phase II trial data from patients with a variety of solid tumors.[2] This finding resulted in adoption of folic acid(Drug information on folic acid) and vitamin B₁₂ supplementation in clinical trials of pemetrexed, and a subsequent analysis of toxicities among patients with a variety of solid tumor types that indicated substantial reductions in rates of grade 4 hematologic toxicity and neutropenia with routine folic acid and B₁₂ supplementation.[ 3] Pemetrexed has been evaluated in patients with metastatic breast cancer and gynecologic cancer with or without vitamin supplementation. Metastatic Breast Cancer Phase I studies of pemetrexed, performed without folic acid and vitamin B₁₂ supplementation, indicated an optimal regimen of 600 mg/m² given every 3 weeks. Four phase II trials of pemetrexed in largely pretreated patients with metastatic breast cancer have been reported: two using the 600- mg/m² dose[4,5] and two with a 500- mg/m² dose[6,7]. The latter two trials included vitamin supplementation in a proportion of patients. In a study from Great Britain reported by Miles and colleagues,[4] 38 patients received pemetrexed at 600 mg/m² without vitamin supplementation or steroid pretreatment for skin rash. A total of 33 patients had re-ceived prior chemotherapy consisting of adjuvant treatment in 16, treatment for metastatic disease in 12, and both in 5. The objective response rate among 36 evaluable patients was 28%, and median time to disease progression was 5.0 months. Treatment was generally well tolerated. Toxicities included grade 3/4 neutropenia in 53% of patients, neutropenic fever in 13%, and elevated liver transaminases in 18%. In the European study of Martin and colleagues,[5] 72 patients with prior anthracycline treatment received pemetrexed at 600 mg/m² every 3 weeks without vitamin supplementation or steroid prophylaxis; 43% of patients had received anthracycline and taxane treatment in the locally advanced or metastatic setting. Results were very similar to those of Miles et al[4]: the response rate among 72 evaluable patients was 21%, and the median time to disease progression was 5.1 months. Analysis by prior treatment characteristics indicated response rates of 17% in patients with anthracyclinerefractory disease that progressed within 30 days of treatment, 24% in those with anthracycline-refractory disease that progressed after 30 days, and 26% in those who had received prior taxane treatment. Toxicities included grade 3/4 neutropenia in 56% of patients, neutropenic fever in 12%, and elevated transaminases in 11%. As in the Miles et al study,[4] the neutropenia was generally manageable and not a major clinical problem in most cases.[5] In a study conducted by Llombart- Cussac et al in the United States, Italy, and Spain, 78 patients with prior anthracycline and taxane treatment received pemetrexed at 500 mg/m² every 3 weeks, with vitamin supplementation being instituted in the trial after enrollment of approximately 45% of the study population.[6] Patients had to have had no more than three prior courses of chemotherapy and at least one course in the metastatic disease setting. The overall response rate was 9%, lower than response rates observed in the trials using the 600-mg/m² dose. Treatment was generally well tolerated, irrespective of vitamin supplementation, and unlike reports dealing with the use of vitamin supplementation in patients with other types of solid tumors, use of supplementation did not appear to have a pronounced effect on occurrences of toxicity. In a United States study of Mennel et al, 58 patients with prior anthracycline, taxane, and capecitabine(Drug information on capecitabine) (Xeloda) treatment received pemetrexed at 500 mg/m² every 3 weeks, with vitamin supplementation being instituted after approximately 25% of patients had been enrolled; patients had to have had no more than five prior chemotherapy courses and no more than two prior antifolate treatment schedules.[7] Overall treatment outcome and toxicities according to vitamin supplementation status are listed in Table 1. The overall objective response rate was 9.5%-lower than that observed in the studies using the higher pemetrexed dose, although this was a more heavily pretreated patient population as all patients received prior anthracyclines, taxanes, and cape-citabine. These results were consistent with the results in the study of Llombart-Cussac et al using 500 mg/m² in anthracycline- and taxane-pretreated patients.[6] Also consistent with the findings of Llombart- Cussac et al, the use of vitamin B₁₂ supplementation did not appear to affect frequency of toxicities. Pemetrexed treatment was generally well tolerated, irrespective of whether vitamin supplementation was used. Concerns over the possibility that vitamin supplementation was associated with poorer treatment responses prompted an analysis of outcomes according to vitamin supplementation status among patients in the two trials using the 500-mg/m² pemetrexed dose. No difference in median time to disease progression was found between patients receiving vitamin supplementation and nonsupplemented patients (unpublished data, Eli Lilly and Company, data on file). It is, however, hypothesized by some that the 500-mg/m² dose is insufficient in metastatic breast cancer. Thus, an international phase II trial has been initiated in which treatmentnaive patients with advanced breast cancer are to be randomized in a double-blind manner to receive treatment with pemetrexed at 600 or 900 mg/m², with all patients receiving folic acid and vitamin B₁₂ supplementation. The objectives of the study include exploration of molecular markers of pemetrexed activity and toxicity. Depending on initial findings, the study may be expanded to a phase III trial. Gynecologic Cancers In a phase II trial reported by Goedhals et al,[8] 24 patients with locally advanced or metastatic cervical cancer who had received no prior chemotherapy received pemetrexed at 600 mg/m² every 3 weeks, with the dose reduced to 500 mg/m² in 18 subsequently enrolled patients; patients treated with 500 mg/m² received folic acid and vitamin supplementation, and all patients received dexamethasone(Drug information on dexamethasone) pretreatment. Among the 34 evaluable patients, the objective response rate was 18%; the median duration of response was 4 months, and the median duration of survival was 15 months. There was no difference observed in responses rates between patients receiving the lower pemetrexed dose and those receiving the higher dose. The frequency of grade 4 neutropenia among patients receiving 500 mg/m² with folic acid supplementation was 27%, which was somewhat lower than the 41% frequency in the patients receiving 600 mg/m². The observation of responses in patients with ovarian cancer in phase I studies of the combination of pemetrexed and gemcitabine(Drug information on gemcitabine) prompted the development of a phase II trial of the combination as secondline chemotherapy in patients with recurrent platinum-sensitive or -resistant ovarian primary cancers. The study regimen consists of gemcitabine at 1,000 mg/m² on days 1 and 8 in combination with pemetrexed at 500 mg/m² on day 8 every 21 days, with pemetrexed being given before gemcitabine on day 8. All patients are receiving folic acid and B₁₂ supplementation and dexamethasone pretreatment. Among the first five evaluable patients accrued (four with platinum-sensitive disease), measurable disease response and decreased cancer antigen- 125 levels have been observed in four. Four of these patients are off study- three due to toxicity and one due to progressive disease; one patient has received at least four cycles of study treatment. To date, six patients are enrolled (five with platinum-sensitive disease, one platinum-resistant); no formal efficacy analysis has been conducted. There may be a particularly strong rationale for use of pemetrexed in the setting of ovarian cancer. Folate receptor- alpha is a marker for ovarian cancer found in approximately 70% of ovarian tumors,[9] and expression of the receptor is associated with poorer survival[10]; the targeting of these receptors by folate enables ¹¹¹INDTPA folate to be used to image ovarian tumors.[11] There is evidence that pemetrexed targets these receptors, suggesting the potential for preferential activity of the drug in ovarian tumor cells. Conclusion Pemetrexed given at a dose of 600 mg/m² without folic acid and vitamin B₁₂ supplementation shows good activity in patients with pretreated metastatic breast cancer, with treatment being generally well tolerated. Responses in pretreated patients receiving 500 mg/m² appears to be suboptimal, with treatment being generally well tolerated irrespective of whether vitamin supplementation is provided. An ongoing randomized phase II trial should help to determine the optimal dose of pemetrexed in this setting and provide information on whether folic acid and B₁₂ supplementation reduces toxicity at higher pemetrexed doses. Pemetrexed also possesses activity in pretreated patients with cervical cancer, with some indication of reduced toxicity with vitamin B₁₂ supplementation at a dose of 500 mg/m₂ compared with the 600-mg/m² dose without supplementation. Preliminary findings in ovarian cancer also indicate activity of pemetrexed in this setting. Ongoing and planned studies will help to establish the optimal uses and role of pemetrexed in gynecologic cancers.