The evolving role of pemetrexed (Alimta) in lung cancer

The Evolving Role of Pemetrexed (Alimta) in Lung Cancer Mark A. Socinski, Thomas E. Stinchcombe, and D. Neil Hayes Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/ vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamindeficient (folate and vitamin B12) patients, and can be ameliorated by the co-administration of folate and vitamin B12. The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non–small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of singleagent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted. Semin Oncol 32(supp 2):S16-S22 © 2005 Elsevier Inc. All rights reserved.

L

ung cancer remains the leading cause of cancer-related mortality in the United States with approximately 170,000 new cases and 160,000 deaths annually.1 Non– small cell lung cancer (NSCLC) histologies comprise approximately 85% of all new cases, with the majority of patients

Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC. Dr Socinski has received research grant support from Bristol-Myers Squibb, Eli Lilly and Company, Pfizer Inc, Sanofi-Aventis, AstraZeneca, and Amgen. He has received honoraria from Bristol-Myers Squibb, Eli Lilly and Company, Pfizer Inc, Sanofi-Aventis, AstraZeneca, Amgen, and Genentech Inc. He is a member of the Speakers Bureaus of Bristol-Myers Squibb, Eli Lilly and Company, Pfizer Inc, Sanofi-Aventis, AstraZeneca, Amgen, and Genentech Inc. Address reprint requests to Mark A. Socinski, MD, Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599.

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0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.02.008

presenting with locally advanced (stage III) or metastatic (stage IV) disease.2 Although certain subsets of stage III disease are curable with combined-modality therapy, the goal of therapy in the more advanced patients is prolongation of survival and palliation of symptoms. The current American Society of Clinical Oncology guidelines for the treatment of patients who possess good performance status (PS) recommend platinum-based doublets in the first-line setting, although the use of certain nonplatinum-based doublets is deemed acceptable.3 No particular regimen is recommended, and current results from several phase III trials suggest there are several platinum-based doublets that may be “standardof-care” regimens. Likewise, in small cell lung cancer (SCLC), the majority of patients present with extensive-stage disease where the goal of therapy is similar to that in metastatic NSCLC. Again, platinum-based doublets have emerged as the standard of care.4 As survival outcomes in both advanced

Evolving role of pemetrexed in lung cancer

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Table 1 Single-Agent Pemetrexed in Advanced NSCLC

No. of patients Median age (range) Gender (% male) ECOG PS (%) 0 1 2 Histology (%) Adeno Squamous Other % Stage IV Dose (mg/m2) RR (%) Median TDP (mo) Survival Median (mo) 1-Year

Rusthoven et al10 1st-Line

Clarke et al11 1st-Line

Smit et al12 2nd-Line

33 63 (42–74) 79

59 59 (39–74) 66

79 61 (32–80) NS

20 48 32

25 75 0

55 27 18 76 600¡500 21.2 3.8

34 17 49 66 600 15.8 4.4

NS NS NS 81 500 5*/14† 2.3*/1.6†

9.2 25

7.2 32

6.4*/4.0† 25*/20†

39 58 3

Abbreviations: ECOG, Eastern Cooperative Oncology Group; NS, not stated; PS, performance status; RR, response rate; TDP, time to disease progression. *Platinum-pretreated group. †Non-platinum pretreated group.

metastatic NSCLC and SCLC have apparently plateaued, new therapeutic approaches that either improve outcomes or retain similar efficacy with less toxicity might be beneficial to this increasingly large group of patients. The previously mentioned American Society of Clinical Oncology guidelines recommend docetaxel in the secondline setting once patients progress following first-line therapy.3 In 2004, the US Food and Drug Administration approved the use of pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) in the second-line setting, when it was shown to possess similar efficacy outcomes but less toxicity in a large phase III trial of Hanna et al5 comparing it with docetaxel. Pemetrexed is a multitargeted antifolate that inhibits several folate-dependent enzymes involved in purine and pyrimidine synthesis including thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.6 Pemetrexed is a prodrug that enters the cell via the reduced folate carrier and once intracellular, is polyglutamated to the active pentaglutamide by folylpolyglutamate synthase,7 an intracellular process that traps pemetrexed. Pemetrexed appears to be one of the best substrates for folylpolyglutamate synthase when compared with other antifolates. Inhibition of the folate-dependent enzymes leads to cellular death, which is probably mediated primarily through TS inhibition because pemetrexed is a more potent inhibitor of this pathway than the other enzymes. However, not all the cytotoxicity is mediated by inhibition of TS; pemetrexed possesses activity against cell lines that possess resistance to the classic TS inhibitors (5-fluorouracil and raltitrexed) because of TS amplification. The principal toxicities observed during treatment with

pemetrexed are neutropenia, skin rash, diarrhea, mucositis, and nausea/vomiting.6 In the early clinical experience with pemetrexed, this toxicity was often severe and unpredictable. Because pemetrexed inhibits the folate-dependent enzymes, it was hypothesized that toxicity might be more severe in folate-deficient patients. A multivariate, stepwise regression analysis by Niyikiza et al8 of baseline demographic and physiologic variables suggested that severe toxicity correlated with elevated plasma homocysteine levels, a sensitive measure of folate deficiency. Vogelzang et al9 confirmed the validity of this putative mechanism in a prospective, phase III trial comparing cisplatin with cisplatin plus pemetrexed in malignant pleural mesothelioma. (Routine vitamin supplementation was not used when the trial was initiated.) After accrual of the initial 43 patients to the cisplatin/pemetrexed arm, the investigators observed that the rates of bone marrow and gastrointestinal toxicity were excessive on the cisplatin/ pemetrexed arm compared with that on cisplatin alone. In addition, treatment-related deaths occurred in 7.3% of patients in the combination arm. Given these findings, routine administration of folic acid (350 to 1,000 ␮g orally daily) and vitamin B12 (1,000 ␮g intramuscularly every 9 weeks) was instituted and resulted in a reduction in the rate of bone marrow and gastrointestinal toxicity associated with pemetrexed but without an apparent decrease in efficacy.9 Notably, many of the initial trials of pemetrexed in lung cancer were conducted without routine vitamin supplementation. It is also recommended that patients receiving pemetrexed receive rash prophylaxis with steroids (eg, dexamethasone 4 mg oral twice daily the day before, of, and after), as indirect and nonrandomized com-

S18 parisons suggest that steroid use decreases the rate of severe rash.

Single-Agent Pemetrexed in NSCLC Three trials have assessed the single-agent activity of pemetrexed in advanced NSCLC (Table 1). Two trials10,11 were completed in previously untreated patients and showed response rates of 15.8% to 21.2%, with median survival times and 1-year survival rates of 7.2 to 9.2 months and 25% to 32%, respectively. While the initial dose of pemetrexed was 600 mg/m2 every 21 days in both trials, it was subsequently decreased to 500 mg/m2 every 21 days because of toxicity in the trial of Rusthoven et al.10 Neither study initially implemented routine steroid prophylaxis or vitamin supplementation in the study design. Grade 3/4 neutropenia occurred in 39% to 42% of patients, but only 3% of patients had febrile neutropenic events; grade 4 thrombocytopenia occurred in 3% to 5%. Grade 3/4 cutaneous toxicity (skin rash) occurred in 31% to 39% of patients, but apparently decreased with prophylactic oral dexamethasone. Other grade 3/4 nonhematologic toxicities were fatigue (5% to 27%), diarrhea (3% to 9%), vomiting (8% to 9%), mucositis (5% to 6%), and elevations of liver enzymes (amino alanine transferase [ALT] and/or aspartate amino transferase [AST]; 6% to 20%). Grade 1 or 2 alopecia occurred in approximately 20% of patients. Smit et al12 conducted a second-line trial of pemetrexed (500 mg/m2 intravenous [IV] day 1 every 21 days without vitamin supplementation) in 79 previously treated patients. Of 79 patients accrued, 44 had previously received a platinum-based regimen, while 35 had received nonplatinumbased therapies. When data from these patient groups were compared, response rates, median survival times, and 1-year survival rates were 5% versus 14%, 6.4 months versus 4.0 months, and 25% versus 20% in the platinum-pretreated versus non-platinum-pretreated groups, respectively. The rates of hematologic and nonhematologic toxicities were similar to those reported in two first-line trials with the exception of skin rash. In this trial, routine steroid prophylaxis (dexamethasone 4 mg oral twice daily day before, of, and after pemetrexed administration) was used and the reported rate of grade 3/4 skin rash was 5% (all grade 3). The activity reported in the second-line trial12 led to the implementation of a large phase III comparison to docetaxel in this treatment setting by Hanna et al.5 (At the time of the study, docetaxel was the only approved cytotoxic agent in the second-line setting.) Five hundred seventy-one patients were randomized to either docetaxel (75 mg/m2 IV every 21 days [n ⫽ 288]) or pemetrexed (500 mg/m2 IV every 21 days [n ⫽ 283]). Patients were well balanced with regard to age, gender, PS, stage, time since last chemotherapy, prior response to first-line therapy, and prior platinum and taxane exposure. Routine steroid prophylaxis and folate/B12 supplementation were administered in patients receiving pemetrexed. All 571 randomized patients were assessable for survival, with 538 of 541

M.A. Socinski, T.E. Stinchcombe, and D.N. Hayes Table 2 Results of the Randomized Phase III Trial Comparing Docetaxel Versus Pemetrexed in the Second-Line Treatment of Advanced NSCLC5 Docetaxel (n ⴝ 288) RR (%) Rate of SD (%) Median PFS (mo) Survival Median (mo) 1-Year (%) Hematologic toxicity (Grade 3/4) Neutropenia (%) Febrile neutropenia (%)

Pemetrexed (n ⴝ 283)

8.8 46.4 2.9

9.1 45.8 2.9

7.9 29.7

8.3 29.7

40.2* 12.7*

5.3 1.9

Abbreviations: PFS, progression-free survival; RR, response rate; SD, stable disease. *P < .001.

patients (pemetrexed, n ⫽ 265; docetaxel, n ⫽ 276) who received therapy assessable for response. As shown in Table 2, the response rates and survival outcomes were identical between the two arms. Figure 1 shows the survival experience of the patients accrued on this trial. Notably, pemetrexed was significantly less myelosuppressive with fewer adverse and febrile neutropenic events occurring. There was also less alopecia, but more grade 3/4 elevations in liver enzymes associated with pemetrexed. This pivotal trial lead to the 2004 approval by the US Food and Drug Administration of pemetrexed for use in the second-line therapy of relapsed or progressive NSCLC.

Platinum-Based Doublets Including Pemetrexed Table 3 details the results from the four phase II trials that evaluated platinum/pemetrexed combinations. Two trials used the identical doses of cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 given on day 1 of a 21 day cycle.13,14 However, although neither trial used routine vitamin supplementation, both used prophylactic dexamethasone. A total of 67 patients were treated in the two trials, and the response rates were 39% to 45% with median survival times and 1-year survival rates of 8.9 to 10.9 months and 49% to 50%, respectively. The principal grade 3/4 toxicities included neutropenia (37% to 59%), thrombocytopenia (3% to 17%), diarrhea (6% to 10%), and nausea/vomiting (3% to 6%). Grade 3/4 biochemical abnormalities (mainly AST and ALT) were seen in less than 10% of patients. No grade 3/4 cutaneous reactions were reported in either trial however grade 1/2 skin rash was reported in 29% to 36% of patients. Koshy et al15 at The University of Texas M. D. Anderson Cancer Center (Houston, TX) recently reported results from a phase II trial of carboplatin (area under the curve [AUC] of 6 IV given on day 1 every 21 days) and pemetrexed (500 mg/m2 IV day 1 every 21 days). The investigators administered routine steroid prophylaxis and vitamin supplementa-

Evolving role of pemetrexed in lung cancer

S19

Figure 1 Median survival in the phase III trial comparing pemetrexed to docetaxel in refractory NSCLC. (Reprinted with permission.5)

consisting of neutropenia (7%), thrombocytopenia (2%), vomiting (7%), diarrhea (2%), and neuropathy (2%). The data presented in Table 3 suggest that platinum/pemetrexed combinations possess clinical activity similar to that of other platinum-based doublets that are routinely used in the treatment of advanced NSCLC. In Europe, a large randomized phase III trial (H3E-MC JMDB) is being conducted in which cisplatin/pemetrexed is compared with the standard regimen of cisplatin/gemcitabine (Fig 2). The primary endpoint of this trial is overall survival, and this trial will accrue approximately 1,700 patients. The resulting data should provide valuable information regarding the role of pemetrexedbased therapy in the first-line treatment setting. Although novel platinum-based doublets may not necessarily improve survival, they might provide similar efficacy outcomes with less toxicity. Although the clinical experience with pemetrexed/platinum combinations is somewhat limited, the toxicity profile seen in the phase II experience reported thus far is impressive, particularly in combination with carboplatin

tion. Fifty patients were entered, all with a PS of 0 –1. The overall response rate was 29%, with respective median survival time and 1-year survival rates of 13.5 months and 56%. Grade 3/4 toxicities included neutropenia (30%), thrombocytopenia (4%), nausea/vomiting (6%), and diarrhea (2%). Scagliotti et al16 reported a randomized phase II trial evaluating carboplatin (AUC 6 IV every 21 days) plus pemetrexed (500 mg/m2 IV every 21 days) as well as oxaliplatin (120 mg/m2 IV every 21 days) plus pemetrexed (500 mg/m2 IV every 21 days). They used routine steroid prophylaxis and vitamin supplementation on both study arms, and reported response rates of approximately 30% for both arms. Median survival time was 9.9 months for the carboplatin/pemetrexed arm versus 8.3 months for oxaliplatin/pemetrexed. Grade 3/4 toxicity on the carboplatin/pemetrexed arm consisted of neutropenia (26%), thrombocytopenia (18%), fatigue (8%), and mucositis (3%), while the oxaliplatin/pemetrexed arm had an extremely favorable toxicity profile with grade 3/4 toxicities

Table 3 Platinum-Pemetrexed Combinations in Advanced NSCLC Scagliotti et al16* No. of Patients Median age (range) % Male PS 0–1 (%) Stage IV (%) Dose Cisplatin (mg/m2) Carboplatin (AUC) Oxaliplatin (mg/m2) Pemetrexed (mg/m2) RR (%) Median TDP (mo) Survival Median (mo) 1-Year (%)

Manegold et al13

Shepherd et al14

36 58 (26–73) 81 97 50

31 60 35 84 84

75 – – 500 39 6.3

75 – – 500 45 NR

10.9 50

8.9 49

Arm 1 39 60 82 100 62

Arm 2 41 60 68 98 66

Koshy et al15 50 62 62 100 92

– 6 – 500 32 4.5

– – 120 500 27 4.5

– 6 – 500 29 4.8

9.9 NR

8.3 NR

13.5 56

Abbreviations: AUC, area under the concentration time curve; NR, not reported; PS, performance status; RR, response rate; TDP, time to disease progression. *Randomized phase II trial: Arm 1, carboplatin ⴙ pemetrexed; Arm 2, oxaliplatin ⴙ pemetrexed.

M.A. Socinski, T.E. Stinchcombe, and D.N. Hayes

S20

Figure 2 Design of randomized phase III trial comparing cisplatin/pemetrexed with cisplatin/gemcitabine.

and oxaliplatin. This observation makes these regimens attractive for evaluation in certain patient subsets (ie, elderly and/or poor PS) as well as certain clinical settings (ie, adjuvant and neoadjuvant in surgical patients and in combination with radiotherapy in stage III NSCLC).

Nonplatinum-Based Regimens With Pemetrexed Pemetrexed has been evaluated in combination with gemcitabine. There have been inconsistencies regarding the optimal sequencing and timing in combining these two agents when using preclinical studies with various cell lines as a means to guiding the design of clinical trials. Most reports suggest synergy between the two agents, but this may be clearly schedule- and cell-line dependent. Adjei et al17 first reported a phase I trial testing two different schedules of this combination. They recommended a phase II dose and schedule of gemcitabine 1,250 mg/m2 days 1 and 8 with pemetrexed 500 mg/m2 on day 8, 90 minutes after gemcitabine. Given the uncertainties of the optimal sequence and tim-

ing for gemcitabine/pemetrexed, Adjei et al18 conducted a subsequent randomized phase II trial in which both timing and schedule issues were explored. Patients in arm 1 of this trial received pemetrexed 500 mg/m2 on day 1 given 90 minutes before gemcitabine 1,250 mg/m2 on days 1 and 8, while those in arm 2 differed only in that pemetrexed was delivered 90 minutes after gemcitabine on day 1. Those in arm 3 received the same doses of both agents but pemetrexed was administered on day 8 and 90 minutes before the day-8 administration of gemcitabine. (Investigators administered routine vitamin supplementation and steroids.) As shown in Table 4, the response rate of arm 2 was only 8.7% compared with the 31% and 16.7% seen on arms 1 and 3, respectively. After this interim observation, arm 2 was suspended. It is interesting to note that despite the low response rate on this arm, the median survival time was 10.4 months, similar to that seen in the other two arms (approximately 11.5 months). Grade 3/4 neutropenia occurred in 66% to 70% of the patients on all arms; however, patients on arm 2 had a 20% rate of grade 3 febrile neutropenia versus 5% on the other two arms.

Table 4 Pemetrexed-Gemcitabine Combinations in Advanced NSCLC (Phase II) Adjei et al18 No. of patients Median age (yrs) % Male Stage IV (%) PS 0–1 (%) Dose/schedule Pemetrexed (mg/m2) Gemcitabine (mg/m2; d1,8) RR (%) Survival Median (mo) 1-Yr (%)

Arm 1

Arm 2

Arm 3

Ettinger et al19

Treat et al20

58 60 66 86 100

30 59 73 93 100

60 65 62 87 100

60 58 50 87 100

48 60 65 87 100

500 d1* 1,250 31

500 d1† 1,250 8.7

500 d8* 1,250 16.7

500 d8† 1,250 16.7

500d1‡ 1,250 32.1

11.4 NR

10.4 NR

11.6 NR

11.3 44

Abbreviation: NR, not reported; PS, performance status; RR, response rate. *90 Minutes before gemcitabine. †90 Minutes after gemcitabine. ‡Immediately after gemcitabine.

NR NR

Evolving role of pemetrexed in lung cancer Grade 3/4 thrombocytopenia occurred in 18% of patients on arm 3 versus 13% on arm 2 and 9% on arm 1. Grade 3/4 fatigue occurred in 26% of patients on arm 2 compared with 17% on arm 3 and 12% on arm 1. Grade 3 rash occurred in 12% of patients on arm 1 versus 5% to 6% on arms 2 and 3. The authors concluded that the regimen/ schedule administered in arm 1 (pemetrexed 500 mg/m2 on day 1 given 90 minutes before gemcitabine 1,250 mg/m2 on days 1 and 8) used the optimal approach, based on its activity and acceptable toxicity profile and should be the regimen tested in future trials. Ettinger et al19 reported a phase II trial using a similar dose and schedule of the pemetrexed/gemcitabine combination administered to arm 2 of the above trial by Adjei et al,18 but with pemetrexed administered 90 minutes after gemcitabine on day 8 (instead of day 1). Sixty patients were accrued, and the overall response rate was 16.7%. Despite the low objective response rate for doublet-based therapy, the median survival time and 1-year survival rate were 11.3 months and 44%, respectively. The primary hematologic toxicity was neutropenia (63%, grade 3/4) with 15% of patients experiencing grade 3/4 febrile neutropenia. Grade 3/4 nonhematologic toxicities consisted of fatigue (25%), diarrhea (5%), rash (3%), and elevations in AST and/or ALT (16% to 21%). Notably, routine vitamin supplementation was initiated after the first 10 patients were enrolled. Treat et al20 used a similar regimen, but these investigators administered pemetrexed 500 mg/m2 immediately on day 1 after gemcitabine 1,250 mg/m2 days 1 and 8. (Routine vitamin supplementation was used.) Forty-eight patients were entered on trial, and preliminary efficacy data on 28 patients showed a response rate of 32.1%. Again, neutropenia was the primary hematologic toxicity, but only 19.6% of patients experienced grade 3/4 neutropenia. Fatigue, dyspnea, and rash were the primary non-hematologic toxicities but grade 3/4 adverse events occurred in less than 5% of cycles. However, no survival data has yet been presented for the patients entered on this trial. Pemetrexed 500 mg/m2 on day 1 has also been combined with vinorelbine 30 mg/m2 days 1 and 8 in a phase II trial by the Australian investigators of Clarke et al.21 They reported an overall response rate of 37% in 35 evaluable patients with advanced NSCLC; no survival data are yet available. The primary grade 3/4 toxicities were neutropenia (43% grade 4), fatigue (20%), dyspnea (14%), and nausea (9%). Thus, the role of nonplatinum-based doublets in the treatment of advanced NSCLC remains controversial. The bulk of the evidence suggests that they are no more efficacious or less toxic than standard platinum-based regimens. Indeed, the pemetrexed/gemcitabine combination appears promising, but the optimal sequence/timing of administration of the two agents remains elusive. When evaluating the experience with this regimen summarized in Table 4, median survival times are generally similar across these phase II trials despite various objective response rates. Future clinical trials evaluating this doublet will hopefully clarify some of these issues.

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Pemetrexed With Radiation Therapy in Stage III NSCLC Pemetrexed appears to have a radio-enhancing effect in preclinical models evaluating this issue.22,23 This, in combination with its excellent toxicity profile and activity in NSCLC, makes permetrexed an excellent candidate to evaluate in the combined modality setting. Only one trial has so far has been reported using concurrent pemetrexed with thoracic radiation therapy (RT). Vokes et al24 at the University of Chicago reported phase I data in a mixed group of both NSCLC and esophageal cancer patients. Initially, pemetrexed was administered alone with RT starting at a dose of 200 mg/m2 IV every 3 weeks. In successive cohorts, the dose of pemetrexed was escalated by 100 mg/m2 to 600 mg/m2 IV every 3 weeks without dose-limiting toxicity. Subsequently, carboplatin was added at an initial dose of AUC 4 every 3 weeks. Although the trial is still accruing and the data preliminary, the investigators have escalated the dose of carboplatin to an AUC of 5 (and subsequently 6) without dose-limiting toxicity. These preliminary data suggest that full systemic doses of carboplatin/pemetrexed can be given concurrently with thoracic RT. A word of caution is in order because the RT delivered varied in the population evaluated. Certainly phase II data are needed in more uniform populations and RT prescriptions, and such efforts are under way in other institutions as well as the Cancer and Leukemia Group B.

Pemetrexed in SCLC A randomized phase II trial evaluating cisplatin (75 mg/m2 IV day 1 every 21 days) and pemetrexed (500 mg/m2 IV day 1 every 21 days), as well as carboplatin (AUC 5 IV day 1 every 21 days) and pemetrexed (500 mg/m2 IV day 1 every 21 days) in extensive stage SCLC has been completed by our investigative group.25 Eighty patients were randomized, and the details are provided elsewhere in this supplement.26 Briefly, clinical activity was seen based on objective responses with grade 3/4 hematologic and nonhematologic toxicities occurring in less than 10% of patients. The trial is not yet mature enough for analysis of the survival outcomes of these patients. Pemetrexed is also being evaluated in the second-line therapy of both sensitive and refractory-relapse SCLC patients. This trial is currently ongoing and actively accruing patients and will evaluate what role single-agent pemetrexed may have in the palliative treatment of relapsed or progressive SCLC.

Conclusion Pemetrexed possesses significant single-agent activity in NSCLC that is comparable to that of other third-generation agents (paclitaxel, docetaxel, vinorelbine, irinotecan, and gemcitabine). Its primary toxicities are bone marrow, skin, and gastrointestinal in nature. The frequency of these toxicities is decreased by the concomitant administration of folate,

S22 vitamin B12, and steroids. Pemetrexed can be safely administered with the platinums, a combination that leads to clinical activity similar to other platinum-based doublets; direct, comparative trials are either under way or planned. The excellent toxicity profile seen thus far in the phase II experience makes a pemetrexed-based therapy attractive for evaluation in the elderly, poor-PS population, and adjuvant and neoadjuvant settings with both surgery and thoracic RT. The role of pemetrexed in nonplatinum-based doublets is evolving. The majority of the current data are in combination with gemcitabine. Preliminary data suggest that pemetrexed can be combined with thoracic RT but substantially more information is needed before drawing any conclusions regarding its role in stage III NSCLC. Pemetrexed/platinum combinations also appear active in SCLC.25 Pemetrexed is an ideal candidate for combination with the new targeted agents (eg, epidermal growth factor receptordirected, anti-angiogenic). Trials are under way that examine the feasibility of these approaches and novel strategies that might improve the overall efficacy of pemetrexed-based therapy. Another strategy worth pursuing is targeting specific patients in whom the activity and clinical benefit derived from pemetrexed is enhanced (“targeted therapy in targeted patients”). There is some evidence by Leichman et al27 that intratumoral TS levels may predict response to TS-directed therapy. Perhaps with further elucidation of the complex relationship between the levels of all the folate-dependent enzymes, folate transport receptors, and the genetic variation seen in the population, identification of a population of patients that would receive greater benefit from pemetrexed therapy could be identified. This remains as a hypothesis but gives clinicians hope that we can move from the use of targeted agents, such as pemetrexed, in unselected populations to enriched populations where the agent’s clinical benefit is enhanced. Continued efforts in well-designed clinical trials are necessary to further elucidate these issues.

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