The Role of Pemetrexed in the Treatment of Gastrointestinal Malignancy

Comprehensive

Review

The Role of Pemetrexed in the Treatment of Gastrointestinal Malignancy Howard S. Hochster Abstract Although advanced colorectal cancer (CRC) is a leading cause of morbidity and mortality in the United States and Europe, chemotherapeutic options have only recently expanded with concomitant improvements in survival. Through the 1980s and early 1990s, research focused mainly on the major fluoropyrimidine 5-fluorouracil, a thymidylate synthase (TS) inhibitor, and methods to enhance its activity through scheduling changes or by biochemical modulation. Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to TS. This agent has theoretical and preclinical advantages over fluoropyrimidines and more specific antifolates. Phase II studies have shown a broad spectrum of activity in solid tumors, including CRC and pancreatic cancer. Combinations of pemetrexed with gemcitabine, irinotecan, and oxaliplatin have also proven feasible. Further studies of higher and biweekly doses with the use of vitamin supplementation are under way. In pancreatic cancer, the phase II studies of pemetrexed and gemcitabine were sufficiently promising to warrant a completed phase III comparison. Based on a recent abstract presentation, it appears that this combination did not improve survival compared with gemcitabine alone. Nonetheless, pemetrexed has important promise for new and improved regimens in the therapy of gastrointestinal cancer.

Clinical Colorectal Cancer, Vol. 4, No. 3, 190-195, 2004 Key words: Antifolate, Combination therapy, 5-FU, Gemcitabine, Methotrexate, Targeted therapy, Thymidylate synthase

Introduction Colorectal cancer accounts for > 150,000 new cases in the United States yearly with nearly 30% of these presenting with advanced disease. While combination chemotherapy has nearly doubled the expectation of survival for these patients with the use of new chemotherapy agents, few of these patients are actually cured of their disease. The treatment of pancreatic cancer presents even greater challenges. With nearly 30,000 newly diagnosed patients in the United States yearly, fewer than 20% of the earliest stage patients will be cured with surgery plus adjuvant chemotherapy or radiation therapy. Those with metastic disease have median survival in the range of 6-9 months. Therefore, newer agents must be developed to meet these challenges, including newer molecularbased treatments, but also newer cytotoxic agents for use in combination therapy programs. New York University School of Medicine, New York Submitted: Dec 3, 2003; Revised: Aug 17, 2004; Accepted: Aug 18, 2004 Address for correspondence: Howard S. Hochster, MD, New York University School of Medicine and the NYU Cancer Institute, 160 East 34th St, New York, NY 10016 Fax: 212-731-5502; e-mail: [email protected]

Chemotherapy for Colorectal Cancer 5-Fluorouracil Therapeutic options for colorectal cancer (CRC) have expanded greatly over the past several years. Through the decades of the 1980s and early 1990s, research mainly focused on the major fluoropyrimidine 5-fluorouracil (5-FU) and methods to enhance its activity through scheduling changes or by biochemical modulation. This has resulted in the routine use of leucovorin (LV) in conjunction with 5-FU for the treatment of CRC, which has consistently demonstrated a greater response rate but no improvement in survival.1 Randomized phase II and III studies have failed to demonstrate significant improvement in survival for any of these methods, although metaanalyses of randomized studies suggested that infusional 5-FU produces a superior therapeutic index and somewhat greater response rate.2 More recently, irinotecan, a topoisomerase I inhibitor, has been approved throughout the world and in the United States as second-line therapy for CRC,3 and in the year 2000, it was also approved in the United States as first-line therapy for CRC. Approval in the first-line setting was based on 2 large international multi-

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center randomized studies comparing bolus IFL (irinotecan/5-FU/ LV) to 5-FU/LV given according to the Mayo regimen and to irinotecan alone,4 as well as a European study comparing FOLFIRI (irinotecan plus infusional 5-FU) versus FULV2 (infusional 5-FU/LV).5 In both of these large randomized studies, the response rate was approximately doubled by the addition of irinotecan as first-line therapy for CRC, and median survival was improved at 15-16 months for the combination compared to 12-13 months for 5-FU plus LV.

Oxaliplatin Oxaliplatin is a novel platinum agent with a diaminocyclohexane side group conferring resistance to excision of DNAplatinum adducts by mismatch repair enzymes. This compound has unique preclinical activity in CRC cell lines. The drug has shown excellent clinical activity in the treatment of CRC and was approved for the treatment of CRC in the United States in late 2002. The randomized study by de Gramont et al of oxaliplatin with 5-FU/LV as a 48-hour infusion (FOLFOX4) versus FULV2 showed a similar doubling in response rate and increase in median survival but did not show a survival advantage that was statistically significant.6 Since this study was underpowered (and was never designed to show a survival advantage) oxaliplatin did not meet US Food and Drug Administration criteria for first-line approval in the year 2000. Oxaliplatin was later approved for second-line therapy based on the study of FOLFOX4 versus FULV2 versus oxaliplatin following IFL first-line therapy. In this setting, FOLFOX showed a 10% response rate whereas the other arms had < 1%7 response rate; superior clinical benefit was seen with FOLFOX than that of the single-agent arms. In addition, the US Intergroup study N9741, a randomized first-line study of 795 patients, showed that FOLFOX caused superior survival in the control arm of IFL (19.5 vs. 15.6 months) and a higher response rate.8 The GERCOR collaborative group compared the sequence of FOLFIRI followed by FOLFOX versus FOLFOX followed by FOLFIRI. Survival was equal in both arms of the study without effect of treatment sequence (whether the irinotecan or oxaliplatin regimen was given as first- or second-line).9 Of particular note is that median survival for both arms of the study was > 21 months, which may be compared with 16 months for first-line regimens with either oxaliplatin or irinotecan with 5-FU/LV and to 12-13 months for 5FU/LV regimens by any schedule or modulation. It is within this context that we must consider the role of pemetrexed and how it may be developed for the treatment CRC.

Pemetrexed Pemetrexed, a methotrexate analogue chemically modified to a 5-member ring, is a folate antimetabolite that can inhibit multiple folate-dependent enzymatic pathways essential for cell replication. Inhibition of the enzyme thymidylate synthase (TS) is the primary mechanism of action of pemetrexed. Thymidylate synthase, a folate-dependent enzyme, catalyzes the transformation of deoxyuridine monophosphate to deoxythymidine monophosphate. Inhibition of TS results in a

decrease in thymidine, a pyrimidine necessary for DNA synthesis. Pemetrexed also inhibits dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT), a folate-dependent enzyme that is involved in purine synthesis. These targets are related to the cytotoxicity of pemetrexed, since both thymidine and hypoxanthine are required to circumvent cellular death caused by this agent. Pemetrexed gains entry to the cell via the reduced folate carrier and, once localized, is an excellent substrate for folylpolyglutamate synthetase. The pentaglutamate form of pemetrexed is the predominant intracellular form and is > 60-fold more potent in its inhibition of TS than the monoglutamate. Initial studies with pemetrexed showed myelosuppression, diarrhea, and rash to be dose-limiting toxicities. In the early studies, patients with high homocysteine levels, showing relative folate deficiency, were those most likely to have severe neutropenia, infection, and diarrhea, as well as toxic death. All patients were then supplemented with 1000 μg of vitamin B12 administered intramuscularly (IM) on a monthly basis and folic acid 350-1000 μg orally daily with a substantial decrease in toxicity and the ability to receive escalated doses, in some cases beyond the 500-600 mg/m2 intravenously every-3-week dose. Phase II Trials of Pemetrexed as a Single Agent. Two studies of pemetrexed in previously untreated patients with advanced or metastatic CRC have been reported and were conducted without the benefit of vitamin supplementation. In a study conducted by the National Cancer Institute of Canada,10 pemetrexed was given at a dose of 600 mg/m2, day 1 repeated every 21 days, but this dose was too toxic in the first 9 patients treated, with 3 of 9 patients developing grade 4 neutropenia and 2 of 9 patients developing grade 4 thrombocytopenia. Therefore, the starting dose was decreased to 500 mg/m2 with more acceptable toxicity. Thirty-two eligible patients were entered into the study and 29 were evaluable for response. Of 29 evaluable patients, there was 1 complete response (CR) and 4 partial responses (PRs) for an overall response rate (ORR) of 17%. Fourteen patients were reported to have stable disease (SD). Seven of 23 patients treated at the 500-mg/m2 dose level developed grade 3 neutropenia and 4 of 23 grade 4 neutropenia. Thirteen patients developed grade 3 rash, which was alleviated by the use of dexamethasone. In a multicenter study conducted in the United States, pemetrexed was given at a dose of 600 mg/m2 every 3 weeks to 46 patients; 35 with colon cancer and 11 with rectal cancer.11 Adjuvant therapy was allowed if completed 1 year before study entry. Responses among 39 patients evaluable for efficacy included 1 CR and 5 PRs, for an ORR of 15.4%. Fourteen patients had SD. The authors also reported that 18% of patients had grade 3/4 thrombocytopenia, 56% had grade 3/4 neutropenia, and 53% had grade 2/3 rash ameliorated by dexamethasone. Median survival was prolonged at 16.2 months, which is in the same range as the reported survival with combination therapy in the phase III studies cited above. These 2 studies demonstrate that pemetrexed has consistent single-agent activity in the same range reported for other sin-

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Pemetrexed for Gastrointestinal Cancer gle agents when used for the treatment of CRC, and is certainly comparable to modulated 5-FU in the first-line setting. Paulson et al reported a phase II trial of pemetrexed 500 mg/m2 in 31 patients who had previously progressed on both 5-FU and irinotecan.12 Half of the patients had received 2 prior regimens and half had received ≥ 3 prior regimens. In this study, there were no observable responses; however, 40% (12 patients) had SD with a median time to progression of 5.4 months. In this study, median overall survival was 8.8 months with 10.2 months observed for patients with SD. Combination of Pemetrexed and Oxaliplatin. Currently, a phase II study is being undertaken in the United States and Europe combining pemetrexed 300 mg/m2 with irinotecan 175 mg/m2 every 3 weeks for patients who have progressed on 5FU– based first-line therapy. In this second-line trial most of the patients were treated with vitamin B12 (1000 μg every month) and folate supplementation (300-600 μg/day). There was no significant toxicity in the initial 20-plus patients treated on this trial, and the trial has been recently amended to escalate the pemetrexed dose to achieve dose-limiting toxicity. A phase I study has been reported by Misset et al giving pemetrexed and oxaliplatin every 21 days.13 In this phase I study, doses of both drugs were escalated from pemetrexed 300 mg/m2 plus oxaliplatin 85 mg/m2 to pemetrexed 500 mg/m2 plus oxaliplatin 130 mg/m2. No vitamin supplementation was given. At the sixth dose level, among 16 patients, there were 5 dose-limiting toxicities: febrile neutropenia (n = 2), diarrhea (n = 2), paresthesia (n = 10), and toxic death after cycle 2 (n = 1). This study served as a basis for a phase II National Surgical Adjuvant Breast and Bowel Project study for firstline therapy of CRC.14 In this study, 54 chemotherapy-naive patients were treated with oxaliplatin 120 mg/m2 and pemetrexed 500 mg/m2 (with vitamin supplementation) every 3 weeks. In this study, the objective response rate was only 28% (1 CR, 14 PRs) though the toxicity rates were quite low. While this response rate was suboptimal, it appears that vitamin supplementation may allow escalation of pemtrexed doses to a more active level. To that aim, new phase I studies at Vanderbilt University and the North Central Cancer Treatment Group will investigate biweekly administration of pemetrexed with oxaliplatin, allowing a simplified and hopefully more active regimen.

Chemotherapy for Pancreatic Cancer Gemcitabine Advanced pancreatic cancer (locally unresectable or metastatic) is generally treated with chemotherapy. The current standard of care includes single-agent gemcitabine based on the phase III study showing improved survival and clinical benefit response (CBR) compared with 5-FU.15 One hundred twenty six patients randomized to gemcitabine 1000 mg/m2 over 30 minutes weekly for 7 days and then weekly for 3 days every 8 weeks, gave a 5% response rate, 24% CBR, and median survival of 5.7 months compared with < 1% RR, 18%

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CBR, and median survival of 4.4 months for 5-FU. Gemcitabine is an antimetabolite cytosine nucleoside analogue which requires metabolic conversion to its active triphosphate form (dFdCTP). This false base competes with dCTP for incorporation into DNA causing chain termination. It also potentiates its own activity by the inhibition of dCTP formation through inhibition of ribonucleotide reductase. The conversion of dFdC to dFdCDP and dFdCTP is accomplished by the ratelimiting enzyme deoxycytidine kinase. Investigation by Gandhi et al showed that the enzyme can be easily overwhelmed by elevated concentrations of gemcitabine and slower infusions at approximately 10 mg/m2 per minute tends to optimize dFdCTP formation in leukemic and mononuclear cells.16 A recently published randomized phase II study of gemcitabine 2200 mg/m2 over 30 minutes versus 1500 mg/m2 over 150 minutes (fixed dose rate of 10 mg/m2 per minute) showed that the fixed-dose rate arm produced a higher response rate, greater triphosphate metabolites of gemcitabine (dFdCTP), and improved survival compared with a 30-minute infusion of even double the conventional gemcitabine dose.17 This observation is now being further studied in an Eastern Cooperative Oncology Group (ECOG) phase III trial (E6201).

Pemtrexed Pemetrexed as a Single Agent. In this setting, pemetrexed has shown substantial promise for the treatment of patients with pancreatic cancer. In the initial phase I studies of pemetrexed, responses were noted in 2 patients with pancreatic cancer of the 4 responses seen (in 37 entered).18 Based on this clinical observation, a phase II study of 42 patients treated with pemetrexed 600 mg/m2 every 21 days was conducted.19 In this study, 79% of those treated had metastatic disease, and 87% were ECOG performance status 0/1. Thirty-five patients received ≥ 2 cycles of treatment and were evaluable for response, with 1 CR and 1 PR reported plus 40% with SD. Median survival was 6.5 months with 28% 1-year survival. Toxicity was relatively mild with only 41% grade 3/4 neutropenia but no infections > grade 1. Combination of Pemetrexed and Gemcitabine. Following this study, phase I combinations of pemetrexed (day 1 or 8) plus gemcitabine (days 1 and 8 every 21 days), demonstrated the feasibility of this combination.20 The day 8 pemetrexed schedule was preferred because of less hematologic toxicity requiring dose modification on day 8. A multicenter phase II study of the combination including gemcitabine 1250 mg/m2 days 1 and 8 plus pemetrexed 500 mg/m2 day 8 (with vitamin supplementation) was performed and reported. Forty-two patients were enrolled in this study including 95% with stage IV disease and 5% with locally advanced disease. Among 40 patients evaluable for response, there were 6 PRs. Of 33 eligible patients, 15% had a clinical benefit response. Median survival was 6.5 months with a 1-year survival rate of 29%.21 This result was sufficiently promising that a phase III study was completed, involving 565 patients of which 90% had metastatic disease. Patients

Howard S. Hochster Table 1

Randomized Trials of Gemcitabine Versus Combinations in Advanced Pancreatic Adenocarcinoma Total Patients

Phase III Agents Studied

Median Survival

1-Year Survival

Progression-Free Survival

Burris et al15 1997

126

Gemcitabine vs. 5-FU

5.7 Months* 4.2 Months

18% 2%

2.3 Months* 0.9 Months

Van Cutsem et al23 2002

688

Gemcitabine + placebo vs. Gemcitabine + Tipifarnib

6.1 Months 6.4 Months

24% 27%

3.6 Months 3.7 Months

Berlin et al24 2002

327

Gemcitabine vs. Gemcitabine + bolus 5-FU

5.4 Months 6.7 Months

< 20% Both arms

2.2 Months 3.4 Months

Moore et al25 2003

277

Gemcitabine vs. BAY12-9566

6.6 Months* 3.7 Months

25% 10%

3.5 Months* 1.7 Months

Bramhall et al26 2001

414

Gemcitabine vs. Marimastat 25 mg

5.6 Months 4.2 Months

19% 20%

3.8 Months 1.9 Months

Bramhall et al27 2002

239

Gemcitabine + placebo vs. Gemcitabine + Marimastat

5.5 Months 5.5 Months

17% 18%

2.1 Months (TTF) 3.6 Months

Colucci et al28 2002

107

Gemcitabine vs. Gemcitabine + Cisplatin

5.0 Months 7.5 Months

11% 11%

2.0 Months (TTP) 5.0 Months*

Tempero et al17 2003

92

Gemcitabine vs. fixed dose rate Gemcitabine

5.0 Months 8.0 Months

7% 24%

5.0 Months 8.0 Months

Heinemann et al29 2003

192

Gemcitabine vs. Gemcitabine + Cisplatin

6.0 Months 7.6 Months

Not reported

2.5 Months (TTP) 4.6 Months*

Rocha Lima et al30 2003

342

Gemcitabine vs. Gemcitabine + Irinotecan

6.6 Months 6.3 Months

22% 21%

3.0 Months (TTP) 3.5 Months

Louvet et al31 2003

313

Gemcitabine vs. Gemcitabine + Oxaliplatin

7.1 Months 9.0 Months

27% 35%*

3.7 Months (PFS) 5.8 Months*

Cheverton et al32 2004

339

Gemcitabine vs. Exatecan (DX-8951f)

6.7 Months 5.0 Months

23% 18%

4.5 Months (TTP) 2.9 Months

Richards et al22 2004

565

Gemcitabine vs. Gemcitabine + Pemetrexed

6.3 Months 6.2 Months

20% 21%

3.3 Months (PFS) 3.9 Months

Study

*Statistically

significant difference.

were equally randomized to the combination of pemetrexed plus gemcitabine regimen previously discussed versus single-agent gemcitabine. This study was reported at the 40th Annual Meeting of the American Society of Clinical Oncology in 2004.22 The addition of pemetrexed improved the ORR from 7% for single-agent gemcitabine to 15% for the combination, but unfortunately had no effect on time to progression or overall survival (Table 1).15,17,22-32 Additionally, as expected, the combination regimen resulted in increased grade 3/4 neutropenia, anemia, and thrombocytopenia. This combination in this schedule cannot be recommended for first-line therapy of pancreatic cancer today. Numerous other 2-drug combinations of chemotherapeutic or novel targeting agents (including 5-FU, cisplatin, irinotecan, matrix metalloproteinases inhibitors, and farnesyl transferase inhibitors) have failed to show a benefit in survival compared with gemcitabine monotherapy (Table 1).

Discussion Pemetrexed is a novel antimetabolite with inhibition of multiple metabolic pathways, including inhibition of DHFR and GARFT, beyond the inhibition of the primary target enzyme, TS. Because of these advantages, pemetrexed may

have increased activity in gastrointestinal cancers compared with other TS inhibitors such as 5-FU and raltitrexed. Phase II studies to date were performed without vitamin B12 and folic acid supplementation, as is now required in all studies (vitamin B12 1000 μg IM every month and folate 300-600 mg/day), and therefore had moderate toxicity with activity similar to that reported for conventional fluoropyrimidines. While this level of activity suggests that the drug should be developed in CRC, practical considerations are important in development of new agents in CRC today. The advent of the additional first-line chemotherapy drugs (irinotecan and oxaliplatin) has improved first-line therapy, and sequential second-line therapy, for this disease. At the same time, it has filled the first- and second-line therapy slots. Therefore, single-agent trials in refractory patients must examine a patient population already extensively pretreated with fluoropyrimidines plus newer agents. An alternative approach would be substitution of pemetrexed in first-line combination therapy comparing such a regimen to 5-FU combinations, potentially demonstrating that the pemetrexed combination would be more convenient (since given as a 10-minute infusion every 2-3 weeks rather than a prolonged infusion) and either more effective or less toxic. Phase I trials of biweekly combinations

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Pemetrexed for Gastrointestinal Cancer with irinotecan and oxaliplatin plus randomized phase II studies utilizing this approach are currently beginning. In the area of pancreatic cancer, pemetrexed has already made substantial inroads when used in combination with gemcitabine. A multicenter phase II study of the combination has shown greater promise than many other doublets tested to date. However, a large randomized phase III trial of this regimen compared with gemcitabine alone failed to demonstrate an improvement in outcome for metastatic pancreatic cancer. Phase I/II studies of pemetrexed plus fixed-dose rate gemcitabine are also under investigation using a biweekly schedule. Other tumors of the biliary tract (cholangiocarcinoma and related bile-duct tumors) may be also a primary target for therapy with pemetrexed based on moderate activity of both 5-FU and gemcitabine; a phase I/II study is currently under way in biliary tumors with biweekly fixed-dose rate of gemcitabine and pemetrexed. Additionally, we must consider the ongoing development of more novel agents in the treatment of gastrointestinal cancer including drugs directed against the epidermal growth factor receptor (cetuximab, gefitinib, and erlotinib) and antiangiogenic drugs such as bevacizumab (anti-vascular endothelial cell growth factor monoclonal antibody) plus a host of other agents in earlier development. Innovative studies with pemetrexed will certainly utilize these targeted agents as well as traditional cytotoxic combinations.

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22:251 (Abstract #1005). 31. Louvet C, Labianca R, Hammel P, et al. GemOx (gemcitabine + oxaliplatin) versus Gem (gemcitabine) in non-resectable pancreatic adenocarcinoma: final results of the GERCOR/GISCAD Intergroup Phase III. Proc Am Soc Clin Oncol (post-meeting edition) 2004; 22 (Abstract #4008). 32. Cheverton P, Friess H, Andras C, et al. Phase III results of exactecan (DX-8951f) versus gemcitabine (Gem) in chemotherapynaive patients with advanced pancreatic cancer (APC). Proc Am Soc Clin Oncol (post-meeting edition) 2004; 22 (Abstract #4005).

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