Pemetrexed in Advanced Colorectal Cancer

Pemetrexed (Alimta) is a multitargeted antifolate agent that inhibits several enzymes in pyrimidine and purine biosynthesis pathways, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GRFT).[1,2] Pemetrexed(Drug information on pemetrexed) exhibits single-agent activity against a number of solid tumors, including non-small-cell lung cancer, mesothelioma, and pancreas, colorectal, gastric, bladder, breast, and head and neck cancers.[2] The characteristic toxicities of antifolate agents are well recognized, with the primary toxicity being myelosuppression. In early studies of pemetrexed performed without folic acid(Drug information on folic acid)/ vitamin B₁₂ supplementation, the primary toxicities of pemetrexed were myelosuppression, skin rash, and mucositis, with neutropenia being the primary dose-limiting toxicity. Analysis of data from patients in pemetrexed phase II studies performed without vitamin supplementation showed a highly significant association of myelosuppression with elevated plasma levels of homocysteine (> 12 mM)-a sensitive marker for reduced functional availability of folate or vitamin B₁₂.[3] Supplementation with folic acid and vitamin B₁₂ is now routinely included in pemetrexed treatment in clinical trials. As shown in Table 1, routine supplementation markedly reduces rates of severe hematologic and nonhematologic toxicities.[4] Pemetrexed exhibits good single-agent activity in metastatic colorectal cancer and is being evaluated in combination with oxaliplatin(Drug information on oxaliplatin) (Eloxatin) and irinotecan(Drug information on irinotecan) (Camptosar) in this setting. The improved toxicity and tolerability of pemetrexed with vitamin supplementation raises the possibility of delivering higher doses than those suggested by phase I studies performed without supplementation. Single-Agent Pemetrexed in Metastatic Colorectal Cancer Pemetrexed has been evaluated in two phase II studies in patients with advanced colorectal cancer.[5,6] In both studies, no prior chemotherapy for metastatic disease was permitted, and adjuvant therapy had to have been completed more than 12 months prior to study entry. No vitamin supplementation was used in either trial. John et al reported data from a US multicenter trial in which 46 patients (27 male) with a median age of 59 years (range: 33 to 86 years) received pemetrexed at 600 mg/m² via 10-minute intravenous (IV) infusion every 3 weeks.[5] Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 in 28 patients, 1 in 11, and 2 in 1, with status unknown in 6. Fifteen patients had received prior adjuvant chemotherapy and eight had received prior radiation therapy. Among 39 patients evaluable for response, complete response was observed in one patient and partial response was observed in five, yielding a response rate of 15.4%. Median survival was 16.2 months, and median time to disease progression was 4.4 months. Among 41 patients evaluable for toxicity, hematologic toxicity was the most common toxicity, with grade 3/4 neutropenia occurring in 56% of patients (Table 2). In a Canadian multicenter trial of Cripps et al, 33 patients (17 female) with a median age of 68 years (range: 45 to 77 years) received pemetrexed at 600 mg/m² via 10-minute infusion every 3 weeks, or at 500 mg/m² following a decision to reduce the study dose.[6] ECOG performance status was 0 in 13 patients, 1 in 18, and 2 in 2. Nine patients had received prior adjuvant therapy and 3 had received prior radiation therapy. Among 29 patients evaluable for response, complete response occurred in 1 patient and partial response occurred in 4, yielding a response rate of 17.2%. Median survival was 15.1 months, and median time to disease progression was 3.3 months. Among the 33 patients evaluable for toxicity, hematologic toxicity was the most common toxicity (Table 2). Grade 3/4 neutropenia occurred in 56% of patients at the 600-mg/m² dose and in 48% at the 500-mg/m² dose. Dosing at 500 mg/m² was associated with marked reductions in rates of grade 3/4 thrombocytopenia (4% vs 33%) and anemia (9% vs 22%). Figure 1(A) shows a comparison of response rates with pemetrexed in these phase II studies with response rates observed in relevant phase II and/or phase III studies with other single-agent regimens with activity in metastatic colorectal cancer (presented as a cumulative total for comparison). The comparative data suggest that responses with pemetrexed are similar to those with other bolus TS inhibitors. Figure 1(B) compares selected grade 3/4 toxicity rates in phase II studies of pemetrexed in various settings that have included routine vitamin supplementation with toxicity rates reported for the other regimens in phase II and III studies in metastatic colorectal cancer. Pemetrexed treatment with routine vitamin supplementation is associated with an approximately 10% rate of grade 3/4 neutropenia, and rates of mucositis, diarrhea, and hand-foot syndrome are lower than or similar to rates observed with the other regimens. Pemetrexed Plus Oxaliplatin Both pemetrexed and oxaliplatin have shown clinical activity as single agents in colorectal cancer. The finding of synergistic antitumor effects with the combination in preclinical models, and the different mechanisms of action and toxicity patterns of the two agents make pemetrexed/oxaliplatin an attractive combination regimen. Raymond et al evaluated the antiproliferative potential of pemetrexed combined with drugs with known therapeutic activity against colorectal cancer (ie, fluorouracil(Drug information on fluorouracil) [5-FU], oxaliplatin, and the active metabolite of irinotecan SN38).[7] The activity of single-agent pemetrexed or combinations with one the three agents was assessed in parental human HT29 colorectal cancer lines and in 5-FU-resistant HT29-5FU cells, with either simultaneous or sequential administration. (Median-effect plot analysis expressed the possible functional interaction between the agents.) Figure 2 shows results of simultaneous or sequential exposure of human HT29 and 5-FU-resistant HT29 colorectal cancer tumor cells to pemetrexed and oxaliplatin. Results show clear synergy, indicated by a combination index < 1, when the drugs are administered together. The drug combinations and sequence with optimal effects were also evaluated in athymic mice bearing human HT29 tumor cell xenografts. Figure 3 illustrates results using the agents alone or in combination compared with controls in human HT29 xenografts, indicating a superior effect in delaying tumor growth with the combination. Misset et al conducted a phase I study (without vitamin supplementation) in 36 patients with metastatic solid tumors who received pemetrexed at an initial dose of 300 mg/m² by 10-minute infusion followed by oxaliplatin at an initial dose of 85 mg/m² via 2-hour infusion on day 1 every 21 days.[8] The combination was given at six dose levels up to pemetrexed at 500 mg/m² and oxaliplatin at 130 mg/m². Of 45 patients enrolled, 36 were evaluable for toxicity and response. Dose-limiting toxicities occurred in 5 patients out of 16 at the pemetrexed at 500 mg/m² plus oxaliplatin at 130 mg/m² dose level, with the dose-limiting toxicities consisting of grade 3/4 diarrhea in two patients, grade 3/4 febrile neutropenia in two, grade 3 paresthesias in one; there was one toxic death. The maximum tolerated dose was thought to be pemetrexed at 500 mg/m² and oxaliplatin at 130 mg/m². Five responses (all partial) were reported over a broad range of solid tumors. The recommended regimen without vitamins for phase II studies was pemetrexed at 500 mg/m² plus oxaliplatin at 120 mg/m². In a phase II trial performed by Atkins et al and the National Surgical Adjuvant Breast and Bowel Project (NSABP) foundation research program, 54 patients with previously untreated stage IV colorectal cancer were treated with pemetrexed at 500 mg/m² plus oxaliplatin at 120 mg/m² every 21 days with folic acid/vitamin B₁₂ supplementation throughout the course of study treatment.[9] In the absence of progressive disease, treatment was to continue for at least six cycles, and could be continued at the discretion of the investigator until disease progression or unacceptable toxicity occurred. Patients had a median age of 60 years (range: 33 to 80 years), 30 (55.6%) were male, and 45 (83.3%) had colon cancer and 9 (16.7%) had rectal cancer. ECOG PS was 0 in 30 patients (55.6%) and 1 or 2 in 24 (44.4%). Two patients (3.7%) had received prior radiation therapy and 16 (29.6%) had received prior chemotherapy. (However, no prior chemotherapy for advanced disease and no adjuvant chemotherapy within 6 months were allowed.) Tumor sites consisted of the liver alone in 22 patients (40.7%), the liver and an additional site in 22 (40.7%), and other sites in 10 (18.5%). Patients received a median of six treatment cycles (mean: 6.35 cycles). A total of 54 patients were evaluable for toxicity and 47 for response. The confirmed objective response rate was 23% (Table 3). Three additional patients (5.6%) had unconfirmed partial response (partial response at one visit); 27 patients (50%) had stable disease. Early death occurred in one patient, who died unexpectedly at home after the first treatment cycle. Median progression-free survival was 5.3 months and median duration of response was 5.7 months. Overall survival was approximately 11.05 months. Table 4 shows rates of grade 1/2 and grade 3/4 diarrhea, neutropenia, neutropenic complications, cutaneous toxicity, mucositis, neurologic toxicity, and pharyngeal/laryngeal dyses- thesias in this trial and reported rates of these toxicities from phase III trials of the IFL (irinotecan plus 5-FU/leucovorin) regimen [10] and the FOLFOX4 (oxaliplatin plus 5-FU/ leucovorin) regimen reported by de Gramont and colleagues[11] in advanced colorectal cancer. Also included in Table 4 for comparison are grade 3/4 toxicities rates from the NSABP N9741 phase III trial of Goldberg et al, who compared IFL, FOLFOX4, and irinotecan/oxaliplatin (IROX) as first-line treatment in patients with advanced disease.[12] As can be seen, the pemetrexed/oxaliplatin combination with vitamin supplementation resulted in no grade 3/4 diarrhea and a notably low rate of grade 3/4 neutropenia. Other grade 3/ 4 toxicities consisted of fatigue (13.0%), thrombocytopenia (11.1%), hyperglycemia (11.1%), nausea (9.3%), anemia (7.5%), thrombosis/ embolism (5.6%), vomiting (3.7%), and allergic reactions (1.9%). These findings suggest the potential for using higher doses of pemetrexed in combination with oxaliplatin when routine vitamin supplementation is provided, with the possibility of optimizing therapeutic response. Pemetrexed Plus Irinotecan In a phase I trial of the combination of pemetrexed and irinotecan performed without vitamin supplementation, pemetrexed was given via 10-minute infusion at an initial dose of 300 mg/m² on day 1 and irinotecan was given via 90-minute infusion at an initial dose of 175 mg/m² on day 1 every 21 days. The dose suggested for phase II study in patients with advanced or metastatic colorectal cancer was pemetrexed at 400 mg/m² and irinotecan at 250 mg/m².[13,14] Kroening et al further conducted a phase I dose-escalation trial (of the phase II amendment) in 12 patients in the second-line setting (with vitamin supplementation). The authors reported that the combination of pemetrexed at 500 mg/m² plus irinotecan at 300 mg/m² was well tolerated and selected for a phase II trial in second-line colorectal cancer in patients with locally advanced or metastatic disease.[14] However, given the findings on improved toxicity with vitamin supplementation, a new phase I/II study has been undertaken. This US and European multicenter trial is enrolling patients who have had one prior course of chemotherapy for metastatic colorectal cancer but no prior exposure to irinotecan. All patients are to receive folic acid and vitamin B₁₂ supplementation. The initial dose in the phase I portion of the study is pemetrexed at 300 mg/m² plus irinotecan at 175 mg/m² on day 1 every 3 weeks. Thus far, minimal toxicity has been observed in the first 20 patients enrolled. Conclusion Pemetrexed is active as a single agent in first-line treatment of advanced colorectal cancer. Administration of folic acid and vitamin B₁₂ with pemetrexed markedly reduces hematologic and other toxicities; all trials of pemetrexed now include routine vitamin supplementation. Pemetrexed has a convenient administration schedule and can be safely administered in combination with a full single- agent dose of oxaliplatin. The pemetrexed/oxaliplatin combination is active and well tolerated in patients with metastatic colorectal cancer. Ongoing and planned studies will help determine optimal schedules for pemetrexed in combination with oxaliplatin and irinotecan. In addition to the ongoing phase I/ II study of pemetrexed/irinotecan in second-line treatment, a phase I study is planned to examine the combination of pemetrexed and oxaliplatin given every 2 weeks as first-line treatment, and a phase I/II trial is planned to identify the optimal pemetrexed/ oxaliplatin dose in a 21-day schedule with vitamin supplementation and to compare pemetrexed/oxaliplatin with FOLFOX4 in randomized fashion in first-line treatment of metastatic disease. Pending the outcome of the randomized phase II portion of the latter trial is the initiation of a planned phase III trial comparing the 3-week pemetrexed/ oxaliplatin regimen with FOLFOX4 as first-line treatment.