ALIMTA® (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study

E. F. Smit1, K. Mattson2, J. von Pawel3, C. Manegold4, S. Clarke5 and P. E. Postmus1,+

1 Department of Pulmonary Diseases, Vrije Universiteit Medical Center Amsterdam, The Netherlands; 2 Division of Pulmonary Medicine, Helsinki University Central Hospital, Finland; 3 Zentralkrankenhaus Gauting, Gauting; 4 Thorax Hospital, Heidelberg, Germany; 5 Sydney Cancer Center, Sydney, Australia

Received 11 June 2002; revised 7 August 2002; accepted 10 September 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The purpose of this study was to evaluate ALIMTA® (pemetrexed disodium, LY231514), a multi-targeted antifolate with first-line activity against non-small-cell lung cancer (NSCLC), in a second-line setting.

Patients and methods:

Patients with NSCLC were eligible for this phase II study if they had progressive disease within 3 months after first-line chemotherapy or progression while being treated with first-line chemotherapy. In 81 patients studied, two cohorts of patients were assigned based on whether the first-line therapy had included a platinum regimen. ALIMTA was administered at 500 mg/m2 by 10-min intravenous infusion once every 21 days.

Results:

The response rate in the 79 evaluable patients with poor prognostic features was 8.9% [95% confidence interval (CI) 2.6% to 15.1%]. The response rate in the platinum-pretreated group was 4.5% and 14.1% in the non-platinum-pretreated group. The median duration of response was 6.8 months (95% CI 3.4–7.8 months, 0% censoring). The median survival time was 5.7 months (95% CI 4.0–8.3 months, 7.6% censoring). The probability of survival for at least 6 months was estimated to be 48%. The median time to disease progression was 2 months (95% CI 1.4–2.8 months, 0% censoring). The principal toxicity was myelosuppression, which was reversible.

Conclusions:

ALIMTA is active in a second-line setting in non-platinum-pretreated NSCLC patients progressing within 3 months of first-line chemotherapy. This study demonstrates that it is possible to evaluate new drugs against NSCLC in a second-line setting.

Key words: non-small-cell lung cancer, pemetrexed, second-line chemotherapy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The incorporation of chemotherapy into the treatment of advanced non-small-cell lung cancer (NSCLC) has become more frequent during the last decade. The primary reason for this has been the demonstration of efficacy of chemotherapeutics in prolonging survival [1] and improvement in the quality of life (QoL) of patients treated with chemotherapy versus the best supportive care [2]. Additionally, a number of new and active agents have been introduced during the last 5 years [3]. The inclusion of these newer agents into combination regimens has resulted in higher response rates, extended progression-free survival and improved QoL [46].

Despite these advances, therapeutic results are still far from optimal, and additional new therapies are needed, particularly drugs with a mechanism of action distinct from those currently in use. The emerging practice of using taxanes in the first-line treatment of NSCLC [7] also argues for the development of non-taxanes for use in second-line, although docetaxel may have some activity in this setting [8].

Many antifolates have been evaluated in the treatment of NSCLC, but have not yet gained a role in standard clinical practice [912]. Because ALIMTA® (pemetrexed disodium, LY231514; Eli Lilly & Company, Indianapolis, IN, USA), a novel multi-targeted antifolate, has multiple intracellular targets, it may have an advantage over older antifolates and may be more promising in this disease. In initial phase II studies testing the antitumor activity of ALIMTA in previously untreated patients with NSCLC, response rates of 17% and 23% were observed [13, 14]. The inclusion of new drugs into the currently available chemical weaponry against advanced NSCLC will probably depend on more than their activity in previously untreated patients. However, because many NSCLC patients now receive second-line treatment following failure of a front-line regimen, new drugs with greater efficacy in previously treated patients are needed.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Patients with performance status 0–1 (WHO) and age >=18 years, with histological or cytological proof of metastatic or locally advanced NSCLC were eligible if they had progressive disease while on first-line chemotherapy, or within 3 months after the last administration. Documentation of disease progression by computed tomography scan or chest X-ray was required. Other requirements for eligibility included bi-dimensionally measurable disease, estimated life expectancy >=8 weeks, adequate organ function including absolute granulocyte count >=1.5 x 109/l, platelets >=100 x 109/l, hemoglobin >=9 g/dl, bilirubin <1.5 x upper limit of normal, alanine aminotransferase and aspartate aminotransferase <3 x upper limit of normal, and calculated creatinine clearance >=45 ml/min. Patients were excluded for the following reasons: brain metastasis, active infection, pregnancy, breast-feeding, serious systemic disorders or clinically detectable effusions. All patients signed informed consents according to local ethical medical committee regulations.

Treatment
ALIMTA was supplied as a lyophilized powder in 100 and 500 mg vials. By adding normal saline, a solution was prepared and drug was administered as a 10-min intravenous infusion at a dose of 500 mg/m2 every 21 days. Dexamethasone 4 mg (or equivalent) was taken twice per day orally on the day before, the day of, and the day after each dose of ALIMTA. Dose adjustments were based on nadir blood counts or the occurrence of grade 3/4 non-hematological toxicities (National Cancer Institute common toxicity criteria) during the preceding cycle. Treatment was delayed for a maximum of 2 weeks to allow granulocytes to recover to >=1.5 x 109/l and to allow platelets to recover to >=100 x 109/l. No concomitant chemotherapy, immunotherapy, hormonal therapy or the routine use of hematopoietic growth factors was allowed. The administration of non-steroidal anti-inflammatory drugs was not permitted beginning 2 days before study and not until 2 days after each infusion. Radiotherapy was allowed only for the treatment of painful lesions. Leucovorin administration was recommended for any patient who experienced grade 4 neutropenia (lasting 5 days or more), grade 4 thrombocytopenia, or grade 3/4 mucositis.

Measurement of study end points
The primary objective of this study was to determine tumor response rate to ALIMTA therapy in patients with advanced NSCLC, who had received prior treatment for metastatic cancer. Standard South Western Oncology Group response criteria were used to define antitumor effects, and assessments occurred in alternate therapy cycles using a consistent method appropriate for the defined target lesion.

Secondary objectives included the measurement of the following time- to-event variables: duration of response for responding patients, time to progression, time to treatment failure, and survival time. Duration of response was measured from the first assessment of complete or partial response until progression or death. Time to treatment failure, time to progression, and survival times were measured beginning with the first dose of study drug. An additional secondary objective was to assess any changes in QoL scored with the European Organization for Research and Treatment of Cancer QLQ-C30 and LC 12 forms before each cycle of therapy. A final QoL score was obtained before each patient’s formal discontinuation from the study.

Statistics
Group A in this study included patients who had disease progression or recurrence following treatment with a platinum-containing regimen. Group B included patients who had disease progression or recurrence following treatment with a non-platinum-containing regimen. For each group, up to a total of 35 qualified patients were to be enrolled in a two-stage design [15]. Twenty patients were enrolled in the first stage in each group. If no responses within a group were observed, the accrual to this group would be stopped. If at least one patient responded to ALIMTA, another 15 patients were to be enrolled to this group into the second stage of the study for a total of 35 patients. If fewer than five patients exhibited a response to ALIMTA by the end of the second stage the conclusion could be drawn that the regimen was not worthy of further study in patients with this condition. This design tests the null hypothesis that the true response rate is 5% versus the alternative hypothesis that the true response rate is at least 20% at a significance level of 0.03 with a power of 86%.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Between November 1997 and April 1999, 82 patients previously treated for NSCLC signed informed consent documents to enter the study. One of these did not receive treatment due to a personal decision. Two patients were treated but were considered unevaluable for efficacy analysis. One patient did not have a bi-dimensionally measurable lesion and one had primary pancreatic cancer with lung metastases. Efficacy analysis and potential factors influencing efficacy were studied from the 79 patients considered evaluable; 44 had progressive disease during or shortly after platinum-containing therapy (group A), and 35 had progressive disease during or shortly after a non-platinum-containing regimen (group B). Safety analysis was assessed on 81 patients who received treatment. Patient characteristics are described in Table 1. Treatment was given on an outpatient basis. The total number of cycles given was 249; the median number of cycles was two (range one to eight cycles).


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Table 1. Patient characteristics
 
Toxicity
Three patients required dose reductions in a total of four cycles. One patient experienced thrombocytopenia that required an initial 50% dose reduction and a further 50% dose reduction in the following cycle. One patient experienced a rash. One patient experienced mucositis and an abnormal laboratory test, which led to a dose reduction. There were 16 cycle delays (6%) for toxicity. Anemia, thrombocytopenia and rash each led to the delay of two cycles. In addition, the following resulted in a single cycle delay: flu syndrome, abnormal liver function tests, asthenia, dyspnea, conjunctivitis, cholecystitis, pneumonia, rhinitis, infection and mucositis. Overall, toxicity was mild with grade 4 granulocytopenia seen in 15 patients (19%), and grade 4 thrombocytopenia in four patients (5%). Clinical toxicity occurred infrequently with grade 3 rash, infection, nausea, vomiting, fatigue and pulmonary toxicity in four (1.6%), one (0.4%), one (0.4%), two (0.8%), four (1.6%) and one (0.4%) cycles, respectively. Three patients died of septic complications while experiencing grade 4 neutropenia. One patient died of pneumonia, which was not felt to be drug-related. More detailed information is given in Tables 2 and 3. In seven patients, drug toxicity was the possible reason for discontinuation of treatment (four deaths, three adverse events).


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Table 2. Hematological and laboratory toxicity maximum grade per patient (n = 81)
 

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Table 3. Non-hematological toxicity maximum grade per patient (n = 81)
 
Response and survival
An independent, central review of response data indicated that there were six partial responses and one complete response. Thus, the overall response rate was 8.9% [95% confidence interval (CI) 2.6% to 15.1%] in the 79 evaluable patients. Two additional unconfirmed partial responses were reported by the treating physicians. Of the remaining patients, 25 (31.6%) achieved stable disease, 30 (38.0%) had progressive disease and 17 (21.5%) had no response assessment. Five of the responding patients in this study had not previously received treatment with platinum, compared with two responders in the platinum-pretreated group. All but one patient responding to second-line ALIMTA had an objective tumor response to first-line treatment. Response by patient group is described in detail in Table 4. Treatment was continued to a maximum of eight cycles. At the time of discontinuation, 47 patients had experienced progressive disease. Time off first-line treatment and type of chemotherapy used in the first-line did not have a discernable influence on the probability of response.


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Table 4. Response
 
The median duration of response was 6.8 months (95% CI 3.4–7.8 months, 0% censoring). The probability of a tumor response lasting 6 months or longer was estimated to be 57% for responding patients. The median survival time was 5.7 months (95% CI 4.0–8.3 months, 7.6% censoring). The probability of a patient surviving at least 6 months was estimated to be 48%. The median time to progression was 2 months (95% CI 1.4–2.8 months, 0% censoring). The median time to treatment failure was 1.6 months (95% CI 1.4–2.5 months, 0% censoring). Time to event evaluation by patient group is described in detail in Table 5.


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Table 5. Survival
 
In two patients, ALIMTA was restarted on a compassionate-need basis. One patient experienced a further response to treatment. The other patient experienced severe skin toxicity during the second cycle of retreatment. The third cycle of treatment was therefore given after administration of type H1 and H2 histamine receptor blockers, as well as dexamethasone. Using this protective approach, no further skin toxicity was seen in this patient.

Quality of life
A total of 76 qualified patients completed at least one QoL questionnaire. The median number of questionnaires completed by the 76 patients was three (range one to seven), which coincides with the median of two cycles of therapy. On-study compliance was 74.1% for eight cycles of therapy. At the end of cycle 5, only 11 patients completed questionnaires. Any results at this point or beyond were highly influenced by individual patient response. Therefore, only results from the first four cycles of therapy, when at least 30% of patients had completed questionnaires, were considered more representative of the larger population.

For the first four cycles of therapy, the changes in median score from baseline were 0 in all scales/items, except for a small improvement (i.e. 4.2 points) in emotional functioning and an improvement (i.e. 33.3 points) in hair loss after cycle 3. Owing to the decreasing number of observations over time and the lack of a control, interpretation of the QoL results was limited. Observations at later cycles may represent a selection bias of those patients with stable disease or with tumor responses. However, based on the available data, it appears that QoL of patients during their time on study was unchanged.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
It is unclear what the threshold of activity of a new drug in second-line treatment of NSCLC should be in order to consider the drug promising. Based on the predefined statistical analysis it may be concluded that ALIMTA is not worthy of further evaluation in platinum-pretreated patients. However, this study was designed before the landmark studies of docetaxel in second-line treatment of NSCLC were published. In these studies [8, 16] incorporating a less well-defined group of patients, the overall response rate was 7%. Moreover, even this low response rate was associated with improvement of QoL over best supportive care alone [16]. In the study reported here, the overall response rate was 8.9%. Further, the 1-year overall survival of 23% in patients treated with ALIMTA is comparable to that achieved with second-line docetaxel. Therefore, we feel the results from this study indicate that ALIMTA has activity as a single agent in the treatment of NSCLC confirming reports from phase II trials in previously untreated patients [13, 14].

Both hematological and non-hematological toxicities were moderate. As expected, myelotoxicity was the most significant adverse event. It is important to note that the addition of vitamin B12 and folic acid in ongoing trials has significantly reduced the myelotoxicity of ALIMTA and has allowed patients to receive more cycles of therapy [17]. It is reasonable to expect this intervention to have a similar impact in second-line NSCLC patients receiving ALIMTA.

Combination chemotherapies involving platinum-containing agents have resulted in improved survival in the front-line treatment of metastatic NSCLC [1]. Several new agents (taxanes, gemcitabine, vinorelbine, irinotecan) introduced in the last 5 years have led to further improvement. First-line chemotherapy commonly fails due to acquired chemoresistance, but ALIMTA may carry an advantage through its mechanism of action. ALIMTA potently inhibits thymidylate synthase, a highly expressed drug resistance-related enzyme, as well as a number of secondary enzyme targets [18]. This mechanism of action may explain why ALIMTA has activity in tumors refractory to standard regimens.

Unfortunately there is a high rate of failure of first-line therapies and effective salvage regimens are in demand. With the relative success and reported milder toxicity of new agents, the use of second-line chemotherapy has become an accepted reality. Guidelines to apply this in daily practice are not available. Because first-line regimens are increasingly active, the bar for testing new drugs in previously untreated patients has been raised accordingly. New standards for evaluating novel NSCLC agents are therefore needed. A recent review of second-line treatment in NSCLC [19] examined over 60 studies. Insufficient information in most reports made it impossible to weigh the relative importance of those factors possibly having an impact on second-line treatment or new drug testing. In the current study, entry was restricted to patients with demonstrated disease progression within a short interval following first-line treatment. This disease progression factor, along with the nature of front-line therapy, is likely to be of paramount importance in refining treatment decisions for second-line NSCLC. Six of the seven responses achieved in this study were seen in patients who had previously responded to first-line treatment. No significant correlation was noted between response to ALIMTA and types of agents used in first-line therapy, although five patients were in the group who had not received prior platinum. Likewise, disease stabilization was achieved in patients who either responded or had stable disease during first-line therapy. Only a small number of patients with progressive disease during first-line therapy had stable disease during treatment with ALIMTA.

In conclusion, ALIMTA has shown activity in two studies in chemonaive NSCLC patients. In addition, this antifolate has now demonstrated activity as a second-line agent, at least in patients who have not been pretreated with (cis)platinum-containing chemotherapy, with moderate toxicity. Because the mechanism of action allows the agent to be non-cross-resistant with the currently used cytotoxic agents, ALIMTA may be a useful second-line NSCLC agent. A phase III study comparing ALIMTA with docetaxel as second-line therapy for NSCLC has been planned on the basis of the results reported here and will finish accrual in the summer of 2002.


    Acknowledgements
 
This study was supported by a grant (USA6/27/01) from Eli Lilly & Co., Indianapolis, IN, USA.


    Footnotes
 
+ Correspondence to: Dr P. E. Postmus, Department of Pulmonary Diseases, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel: +31-30-4444782; Fax: +31-20-4444328; E-mail: pe.postmus{at}vumc.nl Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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