Abstract

BACKGROUND AND OBJECTIVES: Pemetrexed is a multitargeted folate pathway inhibitor with documented activity in non-small cell lung cancer (NSCLC). The presumed maximum tolerated dose is 500 mg/m2 every 3 weeks, but pemetrexed-related toxicity is ameliorated when folate and B12 supplementation is provided and therefore a higher dose intensity may be tolerated. The current exploratory study assessed the feasibility of administration of pemetrexed at a fixed dose of 1000 mg every 2 weeks in patients with relapsed or refractory NSCLC.

PATIENTS AND METHODS: The first cohort of 12 patients received pemetrexed monotherapy. No dose-limiting grade 4 toxicity was noted after 4 cycles, so the subsequent cohort of 14 patients received additional anticancer agents (bevacizumab, erlotinib, carboplatin, docetaxel, vinorelbine) given along with dose-dense pemetrexed.

RESULTS: Toxicity overall was reversible and manageable. Among 19 patients who received pemetrexed either alone or with non-myelosuppressive targeted agents, there were only 2 instances of grade 4 neutropenia after prolonged treatment. Grade 3-4 hematologic toxicity was eventually noted in 11 of the 26 patients (42%; 95% confidence interval, 23% to 61%) after a median of 4 cycles (range, 2-14 cycles). There was no significant additional toxicity nor any treatment-related deaths.

CONCLUSION: Our preliminary observations indicate that dose-dense pemetrexed every 2 weeks is feasible and this regimen can be used as monotherapy. These data may serve as a scaffold for combination studies.

Pemetrexed is a novel, multitargeted antifolate chemotherapeutic drug initially approved for the treatment of mesothelioma, but with well-documented activity in the treatment of non-small cell lung cancer (NSCLC) and other malignancies.^1,2 Although its main mechanism of action is to inhibit thimidylate synthetase and thus interferes with pyrimidine synthesis, it also inhibits dihydrofolate reductase and glycanamide ribonucleotide formyl transferase, enzymes required for purine synthesis. Its therapeutic efficacy in NSCLC has been documented in large randomized studies where it has been proven equivalent to docetaxel as a second-line agent³ and at least equivalent to gemcitabine, and likely better for adenocarcinoma, when combined with platinum as first-line treatment.⁴ In the former study, the safety profile was better in pemetrexed-treated patients. Specifically, pemetrexed at 500 mg/m² every 3 weeks produced only a 5.3% rate of grade 3 and 4 neutropenia. This favorable profile results from vitamin B12 and folate supplementation, which is currently routinely coadministered. In fact, the mesothelioma phase 3 study had to be amended to mandate vitamin supplementation.⁵

 Because of reduced hematologic toxicity, pemetrexed should be safe to use in combination with other drugs, and combinations have been explored or are under investigation.⁶ A dose-intensified schedule of higher dose of pemetrexed given every 3 weeks has been shown to be well tolerated, albeit without obvious clinical benefit.⁷ Dose intensification by increasing administration frequency (dose-dense administration) is an effective approach in the treatment of lymphoma and breast cancer.⁸ The currently approved dosage of pemetrexed at 500 mg/m² every 3 weeks was established as the maximum tolerated dose prior to the awareness of the alleviation of the hematologic toxicity conferred by vitamin supplementation.⁹ In the current study we present the feasibity of a dose-dense, every-2-week administration of pemetrexed in patients with relapsed and refractory NSCLC, as monotherapy. The data from this study should serve as a potentially useful base for combination studies.

Patients and Methods

Patients with a histologic or cytologic diagnosis of NSCLC with relapsed or refractory disease were considered for enrollment in the study. Eligible patients met the following criteria: at least one prior chemotherapy regimen for advanced disease, no prior pemetrexed exposure, Eastern Cooperative Oncology Group performance status of 0-3, granulocyte count >2500/mm³, platelet count >150000/mm³, serum creatinine level of <1.5 mg/dL, normal levels of transaminases and bilirubin, life expectancy >3 months and at least a 3-week washout period from preceding chemotherapy. All patients signed an Institutional Review Board-approved consent form and were treated at Interbalkan Medical Center in Thessaloniki, province of Macedonia, Greece.

All patients underwent routine clinical and laboratory investigation at baseline, including disease assessment by CT scans. Patients received a fixed pemetrexed dose of 1000 mg as a 15-minute intravenous infusion. The administration was repeated every 2 weeks, until disease progression or intolerance. Patients received vitamin supplementation with 1 mg of B12 every 8 weeks given intravenously and folic acid 700-1250 mcg, both beginning on day 1, prior to the administration of pemetrexed. A dose of 8 mg of dexamethasone was given as premedication along with antiemetics. Granulocyte-stimulating growth factors were allowed for secondary prophylaxis for grade 4 neutropenia, and following treatment delay, for neutropenia. Erythropoetin was administered for a hemoglobin level below 10 g/dL. Tumor measurements were performed after the 4th cycle (8th week of treatment) and every 4 cycles thereafter or upon evidence of progression. RECIST (Response Evaluation Criteria In Solid Tumors) criteria and National Cancer Institute Common Toxicity Criteria version 3.0 were used for response and toxicity assessment. Chemotherapy administration was allowed if the absolute neutrophil count was >1500/mm3, platelets >100_000/mm³ and all other toxicity had returned to grade 1 or less, except for anemia, or else treatment was postponed by a maximum of 1 week. If a delay was again required at subsequent cycles, a 25% dose reduction of pemetrexed (750 mg) was allowed once. No further dose attenuation or delay >week was  permitted.

The first cohort of 12 patients received pemetrexed monotherapy and were assessed for toxicity after all had completed 4 cycles (stage 1). If the safety criteria described below were met, subsequent patients were allowed to receive combinations with other agents, based on the pemetrexed 1000 mg every 2 weeks schedule (stage 2); the choice of the accompanying drugs was left to the judgement of the treating physician and was not controlled by the study design. The experimental part of the study remained the biweekly administration of pemetrexed.

This was a preliminary study of a new treatment schedule for an established drug. At the first stage, 12 patients were enrolled and analyzed for safety. If no toxicity or at maximum only one grade 4 toxicity was noted after all 12 patients completed 4 cycles, the study was expanded to include additional patients who received the same dose of pemetrexed every 2 weeks in combination with other agents. If more than one incident of grade 4 toxicity occurred, the study would have been terminated. The premise of this design is that if none of the 12 patients experienced grade 4 toxicity during the observation period of 4 cycles, then the true incidence of grade 4 toxicity is below 25% (a<0.05) and for 1 occurrence <35% (a<0.05), respectively.

Results

Between April 2006 and October 2008, 26 patients enrolled with a median age of 67 years (Table 1). The majority of patients had adenocarcinoma, although in the beginning of the study patients with squamous cell histology were included, as the impact of histology on outcome was not known at that time. Median body surface (BS) was 1.86 m2 (range, 1.7-2.03 m²). Pemetrexed was a second-line regimen for the majority of patients. Patients received a median of 4 cycles (range 1-14 cycles).

Pemetrexed monotherapy (Stage 1)

The first cohort of 12 patients (group A) that received pemetrexed monotherapy had the following characteristics: male 10, female 2; performance status 0 in 2 patients, performance status 1 in 3 patients, performance status 2 in 5 patients and performance status 3 in 2 patients. The patients had received a median of 1 prior chemotherapy courses (range, 1-4 courses). The patients received a median of 4 pemetrexed cycles every 2 weeks (range of 2-12 cycles). Disease progression was the reason for treatment discontinuation for all patients. No grade 4 toxicity was observed in any of the patients while on pemetrexed treatment for the first 4 cycles, so that the premise of the study was fulfilled, thus establishing safety of this approach (Table 2). A treatment delay of 1 week was only required in the two instances of grade 3 neutropenia. Toxicity encountered after the 4th cycle is discussed below.

Combinations with other agents (Stage 2)

Subsequently enrolled patients (n=14) received pemetrexed-based combinations (group B). Pemetrexed was combined with presumably non-myelotoxic, targeted agents in 7 patients (bevacizumab 10 mg/kg every 2 weeks in 5 patients, erlotinib 150 mg daily in one patient, and both in 1 patient). In 7 patients, pemetrexed was coadministered with cytotoxic chemotherapy also given every 2 weeks (docetaxel 50 mg/m² in 1 patient, carboplatin AUC 4 mg/hoursxmin (area under the concentration versus time curve in mg/mLxmin) in 4 patients, vinorelbine 25 mg/m² in 1 patient, cisplatin 50 mg/m², 1 patient). The most common toxicity encountered was hematologic, which was easily managed and reversible. As expected, hematologic toxicity was more common in patients who received concurrent chemotherapy. Overall, grade 3 or 4 hematologic toxicity of one or more lineages was observed in 11 of the 26 patients (42%; 95% confidence interval, 23% to 61%); grade 3-4 neutropenia was observed in 7, grade 3 anemia in 7 and thrombocytopenia grade 3 in 3 patients. Hematopoetic growth factor was at some point administered in 13 patients (including patients with grade 2 neutropenia). Dose reduction of pemetrexed was required in 2 patients after the 6th and 9th cycle. There was no apparent association of toxicity with BSA.

Biweekly pemetrexed with or without targeted agents

Among patients who did not receive concurrent myelotoxic chemotherapy, i.e. monotherapy or combination with either bevacizumab or erlotinib, hematologic toxicity grade 3 or 4 was observed at any time in 7 of the 19 patients (37%; 95% confidence interval, 18% to 56%), after a median of 7 cycles. In particular, grade 3 anemia, grade 3-4 neutropenia or grade 3 thrombocytopenia was observed in 3 (16%), 3 (16%) and 1 (5%) patient. Of interest, grade 4 neutropenia was only observed in long-term treated patients: one patient receiving pemetrexed monotherapy and one in combination with erlotinib, developed grade 4 neutropenia after the 9th and 8th cycle, respectively.

Non-hematologic toxicity

Non hematologic toxicity was trivial and included a patient with grade 3 fatigue, a patient with superficial vein thrombosis of the arm and a patient who developed symptomatic eruption of both metatarsal areas (grade 2) prompting reverting to every 3 weeks pemetrexed after the 8th cycle. Brief febrile neutropenia occurred in one patient with PS 3.

Tolerance of long-term pemetrexed

Thirteen patients overall continued pemetrexed for over 4 cycles. A trend for increased occurrence of neutropenia or fatigue was observed after prolonged administration. One patient a receiving combination with bevacizumab and one with erlotinib discontinued treatment after the 11th and 10th cycle because of fatigue grade 2 persisting for over 3 weeks. Granulocyte colony stimulating factor (GCSF) support was required for 5 of 7 patients receiving dose-dense pemetrexed for over 8 cycles, although these patients were not receiving a second myelotoxic chemotherapy agent.

Disease assessment

Although assessment of the efficacy of the regimen was not within the scope of this study, we observed the following outcomes: overall 4 patients achieved a partial response (PR), 9 patients had stable disease (SD) and 13 patients had progressive disease (PD). The outcomes for the group of pemetrexed monotherapy were as follows: 1 PR (8%), 4 SD (33.3%) and 7 PD (58%). The median time to progression (TTP) for the whole group was 8 weeks (range, 2-24 weeks). Six of the 7 patients with squamous cell histology manifested progressive disease by the 4th cycle. The median TTP for patients with non-squamous histology was 14 weeks. After a median follow-up of 23 months, 4 patients remained alive 9-12 months after initiation of pemetrexed treatment.

Discussion

Administration of second-line chemotherapy for NSCLC has been asscociated with a small survival benefit.^10-13 When selecting treatment for such patients, it is very important to provide palliation with minimal toxicity, and in that regard pemetrexed is a clinically useful choice. Our exploratory study was based on the fact that pemetrexed, when given with vitamin supplementation, is particularly safe with favorable toxicity profile compared to other chemotherapeutic agents. The currently established dose approved by the regulatory authorities of 500 mg/m² every 3 weeks was based on early phase 1/2 studies where higher dosages caused deaths due to neutropenia, mucositis or other toxicity, and before the favorable impact of vitamin supplementation was fully understood.¹⁴ This became particularly apparent in the phase 3 study involving patients with mesothelioma which was amended in order to be safely concluded.¹⁵

As the currently established standard pemetrexed administration resulted from dose-limiting toxicities observed in early studies without vitamin supplementation, it is expected that further dose escalation is possible, since vitamin B12 and folate are routinely administered in clinical practice. In fact, a regimen employing dose escalation to 1000 mg/m² given every three weeks has been tested and has been compared to standard pemetrexed.¹⁶ Dose escalation was indeed feasible, with only slight exacerbation of toxicity. Unfortunately, no dose response correlation could be shown. Another trial employing intensified pemetrexed dosage tested the combination of gemcitabine with standard-dose pemetrexed given every 2 weeks in previously untreated patients;¹⁷ a response of 20.8% with clinical benefit in two-thirds of the patients was noted. Toxicity was manageable in this group of chemotherapy-naïve patients.

Our study addresses the question of feasibility of increasing dose intensity by increasing the dose density of pemetrexed in relapsed NSCLC patients, including those with relatively reduced performance status. Dose dense administration of chemotherapy offers theoretical advantages arising from the Gompertzian or sigmoidal kinetics of tumor growth, which is inversely proportional to total tumor mass, thus enabling in theory a more steep overall tumor reduction.¹⁸ This approach has resulted in the increased efficacy of standard-dose chemotherapy in aggressive lymphoma and there is also evidence of an advantage in breast cancer and perhaps other tumor types.^19,20 Our study documented the feasibility of administering pemetrexed at a fixed dose of 1000 mg every 2 weeks in relapsed or refractory patients, with vitamin supplementation. The observed toxicity was within an acceptable range and not dissimilar from what is expected in such a cohort. Furthermore, after having shown the safety of dose-dense pemetrexed, our limited study provides some evidence that combinations, especially with targeted non-myelosuppressive agents or with classical chemotherapy, may be possible in patients with relapsed NSCLC. The clinical benefit of such combinations is implied by early preclinical and clinical studies.^21,22 In addition, on the assumption that the maximum tolerated dose of pemetrexed is not the one approved by the regulatory agencies and because even higher doses of 600 mg/m² every 3 weeks were sufficiently tolerable in early phase 2 studies, our patients received a fixed dose of 1000 mg.²³ A typical patient, assuming a 1.8 m² body surface, receives 900 mg, whereas our smaller patient received the equivalent of 588 mg/m² deemed to be safe. Thus the variability of the actual dosage per m² delivered to our patients, combined with the feasibility of essentially doubling each dose as mentioned above, renders the design of our study reasonably safe. The potential merit of our findings should perhaps be tested in larger studies and weighed against the use of growth factors often required after prolonged administration.

In conclusion, our study indicates that pemetrexed can safely be given at the fixed dose of 1000 mg every two weeks in patients with relapsed non small cell lung cancer, when folate and vitamin B12 is provided. This dose-dense regimen may be a useful scaffold for developing combination regimens of potential usefulness in the treatment of patients with lung cancer. Clearly, larger studies are required to assess the potential benefit of such an approach.

References

1. Hanauske AR, Chen V, Paoletti P, Niyikiza C. Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. Oncologist. 2001;6(4):363-373.

2. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-2644.

3. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589-1597.

4. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551.

5. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-2644.

6. Ma CX, Nair S, Thomas S, Mandrekar SJ, Nikcevich DA, Rowland KM, et al. Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer. J Clin Oncol. 2005;23(25):5929-5937.

7. Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, et al. Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res. 2008;14(13):4206-4212.

8. Hudis CA, Schmitz N. Dose-dense chemotherapy in breast cancer and lymphoma. Semin Oncol. 2004;31(3 Suppl 8):19-26.

9. Rusthoven JJ, Eisenhauer E, Butts C, Gregg R, Dancey J, Fisher B, et al. Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1999;17(4):1194.

10. Marino P, Pampallona S, Preatoni A, Cantoni A, Invernizzi F. Chemotherapy vs supportive care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature. Chest. 1994;106(3):861-865.

11. Georgoulias VA. Second-line chemotherapy in relapsing or refractory patients with non-small cell lung cancer. Lung Cancer. 2002;38 Suppl 3:S61-S66.

12. Crino L, Foglietta J, Hamzaj A. Lung cancer. J Thorac Oncol. 2007;2(5 Suppl):S24-S26.

13. Hanna N. Advances in the treatment of second-line non-small-cell lung cancer. Lung Cancer. 2005;50 Suppl 1:S15-S17.

14. Clarke SJ, Abratt R, Goedhals L, Boyer MJ, Millward MJ, Ackland SP. Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naive patients with advanced non-small-cell lung cancer. Ann Oncol. 2002;13(5):737-741.

15. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-2644.

16. Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, et al. Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res. 2008;14(13):4206-4212.

17. Dudek AZ, Larson T, McCleod MJ, Schneider DJ, Dowell JE, Banerjee TK, et al. Phase 1/2 dose escalating study of twice-monthly pemetrexed and gemcitabine in patients with advanced cancer and non-small cell lung cancer. J Thorac Oncol. 2008;3(4):394-399.

18. Norton L. Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol. 1997;24(4 Suppl 10):S10.

19. Held G, Schubert J, Reiser M, Pfreundschuh M. Dose-intensified treatment of advanced-stage diffuse large B-cell lymphomas. Semin Hematol. 2006;43(4):221-229.

20. Hudis CA, Schmitz N. Dose-dense chemotherapy in breast cancer and lymphoma. Semin Oncol. 2004;31(3 Suppl 8):19-26.

21. Herbst RS, O'Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol. 2007;25(30):4743-4750.

22. Li T, Ling YH, Goldman ID, Perez-Soler R. Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res. 2007;13(11):3413-3422.

23. Spielmann M, Martin M, Namer M, duBois A, Unger C, Dodwell DJ. Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis. Clin Breast Cancer. 2001;2(1):47-51.