Phase II Studies of Pemetrexed in Metastatic Breast and Gynecologic Cancers
Pemetrexed (Alimta) is active in a variety of solid tumors, includingbreast and gynecologic cancers. Phase II trials of pemetrexed at a doseof 600 mg/m2 without vitamin B12 and folic acid supplementation inlargely pretreated metastatic breast cancer patients demonstrated objectiveresponse rates of 21% and 28%, with generally manageableneutropenia constituting the primary toxicity. In phase II trials using500 mg/m2 with or without vitamin supplementation in anthracyclineandtaxane-pretreated patients, response rates were lower (approximately9%) and treatment was generally well tolerated irrespective ofvitamin supplementation status. A phase II trial is currently comparingpemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementationin patients with previously untreated advanced breast cancer. In aphase II trial in patients with advanced cervical cancer, pemetrexed at600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementationproduced similar response rates, with the frequency of neutropeniabeing somewhat lower among patients receiving the lower doseand vitamin supplementation. Preliminary results in an ongoing phaseII trial indicate activity of the regimen of gemcitabine (Gemzar) at1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementationin patients with ovarian cancer. Ongoing and future studies willestablish optimal dosing regimens of pemetrexed and potential benefitsof vitamin supplementation in the settings of metastatic breastcancer and gynecologic malignancies.
ABSTRACT: Pemetrexed (Alimta) is active in a variety of solid tumors, includingbreast and gynecologic cancers. Phase II trials of pemetrexed at a doseof 600 mg/m2 without vitamin B12 and folic acid supplementation inlargely pretreated metastatic breast cancer patients demonstrated objectiveresponse rates of 21% and 28%, with generally manageableneutropenia constituting the primary toxicity. In phase II trials using500 mg/m2 with or without vitamin supplementation in anthracyclineandtaxane-pretreated patients, response rates were lower (approximately9%) and treatment was generally well tolerated irrespective ofvitamin supplementation status. A phase II trial is currently comparingpemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementationin patients with previously untreated advanced breast cancer. In aphase II trial in patients with advanced cervical cancer, pemetrexed at600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementationproduced similar response rates, with the frequency of neutropeniabeing somewhat lower among patients receiving the lower doseand vitamin supplementation. Preliminary results in an ongoing phaseII trial indicate activity of the regimen of gemcitabine (Gemzar) at1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementationin patients with ovarian cancer. Ongoing and future studies willestablish optimal dosing regimens of pemetrexed and potential benefitsof vitamin supplementation in the settings of metastatic breastcancer and gynecologic malignancies.
Pemetrexed (Alimta) is anantifolate agent that possessesantitumor activity in a varietyof solid tumors, including mesotheliomaand non-small-cell lung, gastrointestinal,head and neck, breast,and gynecologic cancers.[1] Earlyphasestudies showed that neutropenia,a common antimetabolite toxicity,was the primary dose-limiting toxicityof pemetrexed treatment. Elevatedhomocysteine levels, a markerfor reduced functional availability offolate and vitamin B12, were shown tobe associated with increased risk ofmyelosuppression with pemetrexedtreatment in an analysis of phase II trialdata from patients with a variety ofsolid tumors.[2]This finding resulted in adoption offolic acid and vitamin B12 supplementationin clinical trials of pemetrexed,and a subsequent analysis of toxicitiesamong patients with a variety of solidtumor types that indicated substantialreductions in rates of grade 4 hematologictoxicity and neutropenia with routinefolic acid and B12 supplementation.[3] Pemetrexed has been evaluatedin patients with metastatic breast cancerand gynecologic cancer with orwithout vitamin supplementation.Metastatic Breast CancerPhase I studies of pemetrexed, performedwithout folic acid and vitaminB12 supplementation, indicated an optimalregimen of 600 mg/m2 givenevery 3 weeks. Four phase II trials ofpemetrexed in largely pretreated patientswith metastatic breast cancerhave been reported: two using the 600-mg/m2 dose[4,5] and two with a 500-mg/m2 dose[6,7]. The latter two trialsincluded vitamin supplementation in a proportion of patients.In a study from Great Britain reportedby Miles and colleagues,[4] 38patients received pemetrexed at 600mg/m2 without vitamin supplementationor steroid pretreatment for skinrash. A total of 33 patients had re-ceived prior chemotherapy consistingof adjuvant treatment in 16, treatmentfor metastatic disease in 12, and bothin 5. The objective response rateamong 36 evaluable patients was 28%,and median time to disease progressionwas 5.0 months. Treatment wasgenerally well tolerated. Toxicities includedgrade 3/4 neutropenia in 53%of patients, neutropenic fever in 13%,and elevated liver transaminases in18%.In the European study of Martinand colleagues,[5] 72 patients withprior anthracycline treatment receivedpemetrexed at 600 mg/m2 every 3weeks without vitamin supplementationor steroid prophylaxis; 43% of patientshad received anthracycline andtaxane treatment in the locally advancedor metastatic setting.Results were very similar to those ofMiles et al[4]: the response rate among72 evaluable patients was 21%, and themedian time to disease progression was5.1 months. Analysis by prior treatmentcharacteristics indicated response ratesof 17% in patients with anthracyclinerefractorydisease that progressed within30 days of treatment, 24% in those withanthracycline-refractory disease thatprogressed after 30 days, and 26% inthose who had received prior taxanetreatment.Toxicities included grade 3/4 neutropeniain 56% of patients, neutropenicfever in 12%, and elevated transaminasesin 11%. As in the Miles etal study,[4] the neutropenia was generallymanageable and not a majorclinical problem in most cases.[5]In a study conducted by Llombart-Cussac et al in the United States, Italy,and Spain, 78 patients with prioranthracycline and taxane treatmentreceived pemetrexed at 500 mg/m2every 3 weeks, with vitamin supplementationbeing instituted in the trialafter enrollment of approximately45% of the study population.[6] Patientshad to have had no more thanthree prior courses of chemotherapyand at least one course in the metastaticdisease setting.The overall response rate was 9%,lower than response rates observed inthe trials using the 600-mg/m2 dose.Treatment was generally well tolerated,irrespective of vitamin supplementation,and unlike reports dealingwith the use of vitamin supplementationin patients with other types ofsolid tumors, use of supplementationdid not appear to have a pronouncedeffect on occurrences of toxicity.In a United States study of Mennelet al, 58 patients with prioranthracycline, taxane, and capecitabine(Xeloda) treatment received pemetrexedat 500 mg/m2 every 3 weeks, with vitaminsupplementation being institutedafter approximately 25% of patients hadbeen enrolled; patients had to have hadno more than five prior chemotherapycourses and no more than two priorantifolate treatment schedules.[7]Overall treatment outcome and toxicitiesaccording to vitamin supplementationstatus are listed in Table 1. Theoverall objective response rate was9.5%-lower than that observed in thestudies using the higher pemetrexeddose, although this was a more heavilypretreated patient population as all patientsreceived prior anthracyclines,taxanes, and cape-citabine. These resultswere consistent with the results inthe study of Llombart-Cussac et al using500 mg/m2 in anthracycline- andtaxane-pretreated patients.[6] Also consistentwith the findings of Llombart-Cussac et al, the use of vitamin B12supplementation did not appear to affectfrequency of toxicities. Pemetrexedtreatment was generally well tolerated,irrespective of whether vitamin supplementationwas used.Concerns over the possibility thatvitamin supplementation was associatedwith poorer treatment responsesprompted an analysis of outcomes accordingto vitamin supplementation statusamong patients in the two trials usingthe 500-mg/m2 pemetrexed dose. Nodifference in median time to diseaseprogression was found between patientsreceiving vitamin supplementation andnonsupplemented patients (unpublisheddata, Eli Lilly and Company, data onfile). It is, however, hypothesized bysome that the 500-mg/m2 dose is insufficientin metastatic breast cancer.Thus, an international phase II trialhas been initiated in which treatmentnaivepatients with advanced breastcancer are to be randomized in adouble-blind manner to receive treatmentwith pemetrexed at 600 or 900mg/m2, with all patients receivingfolic acid and vitamin B12 supplementation.The objectives of the study includeexploration of molecular markersof pemetrexed activity and toxicity.Depending on initial findings, thestudy may be expanded to a phase IIItrial.Gynecologic CancersIn a phase II trial reported byGoedhals et al,[8] 24 patients with locallyadvanced or metastatic cervicalcancer who had received no prior chemotherapyreceived pemetrexed at 600mg/m2 every 3 weeks, with the dosereduced to 500 mg/m2 in 18 subsequentlyenrolled patients; patientstreated with 500 mg/m2 received folicacid and vitamin supplementation, andall patients received dexamethasonepretreatment.Among the 34 evaluable patients,the objective response rate was 18%;the median duration of response was4 months, and the median duration ofsurvival was 15 months. There was nodifference observed in responses ratesbetween patients receiving the lowerpemetrexed dose and those receivingthe higher dose. The frequency ofgrade 4 neutropenia among patientsreceiving 500 mg/m2 with folic acidsupplementation was 27%, which wassomewhat lower than the 41% frequencyin the patients receiving600 mg/m2.The observation of responses inpatients with ovarian cancer in phaseI studies of the combination ofpemetrexed and gemcitabineprompted the development of a phaseII trial of the combination as secondlinechemotherapy in patients with recurrentplatinum-sensitive or -resistantovarian primary cancers. Thestudy regimen consists of gemcitabineat 1,000 mg/m2 on days 1 and 8 incombination with pemetrexed at 500mg/m2 on day 8 every 21 days, withpemetrexed being given beforegemcitabine on day 8. All patients arereceiving folic acid and B12 supplementationand dexamethasone pretreatment.Among the first five evaluable patientsaccrued (four with platinum-sensitivedisease), measurable disease responseand decreased cancer antigen-125 levels have been observed in four.Four of these patients are off study-three due to toxicity and one due toprogressive disease; one patient hasreceived at least four cycles of studytreatment. To date, six patients areenrolled (five with platinum-sensitivedisease, one platinum-resistant); noformal efficacy analysis has been conducted.There may be a particularly strongrationale for use of pemetrexed in thesetting of ovarian cancer. Folate receptor-alpha is a marker for ovariancancer found in approximately 70%of ovarian tumors,[9] and expressionof the receptor is associated withpoorer survival[10]; the targeting ofthese receptors by folate enables 111INDTPAfolate to be used to image ovariantumors.[11] There is evidencethat pemetrexed targets these receptors,suggesting the potential for preferentialactivity of the drug in ovariantumor cells.ConclusionPemetrexed given at a dose of 600mg/m2 without folic acid and vitaminB12 supplementation shows good activityin patients with pretreated metastaticbreast cancer, with treatmentbeing generally well tolerated. Responsesin pretreated patients receiving500 mg/m2 appears to be suboptimal,with treatment being generallywell tolerated irrespective of whethervitamin supplementation is provided.An ongoing randomized phase II trialshould help to determine the optimaldose of pemetrexed in this setting andprovide information on whether folicacid and B12 supplementation reducestoxicity at higher pemetrexed doses.Pemetrexed also possesses activityin pretreated patients with cervical cancer,with some indication of reducedtoxicity with vitamin B12 supplementationat a dose of 500 mg/m2 comparedwith the 600-mg/m2 dose withoutsupplementation. Preliminary findingsin ovarian cancer also indicate activityof pemetrexed in this setting. Ongoingand planned studies will help to establishthe optimal uses and role ofpemetrexed in gynecologic cancers.
Disclosures:
Dr. Smith has receivedhonoraria from Lilly for lecturing andchairing symposia.
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