Pemetrexed for Heavily Pretreated Patients With Advanced Non-small ...

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Jul 19, 2009 - safety of pemetrexed for heavily pretreated, advanced NSCLC. ... The median number of cycles of pemetrexed therapy was four (range, 1–11).
J Formos Med Assoc 2010;109(5):338–344

Contents lists available at ScienceDirect

Volume 109 Number 5 May 2010

Journal of the Formosan Medical Association

ISSN 0929 6646

Journal of the

Formosan Medical Association Clinical implications of HBV variants GRP78 protein as a biomarker of oral cancer in Taiwan Pemetrexed in heavily pretreated patients with advanced NSCLC Sex differences in geriatric depression

Journal homepage: http://www.jfma-online.com

Formosan Medical Association Taipei, Taiwan

Original Article

Pemetrexed for Heavily Pretreated Patients With Advanced Non-small Cell Lung Cancer Jih-Hsiang Lee,1,2 Chong-Jen Yu,3 Kuan-Yu Chen,3 Jin-Yuan Shih,3 Yu-Lin Lin,1 Chih-Hsin Yang1,2,4* Background/Purpose: The efficacy and safety of chemotherapy as third- or higher-line therapy for advanced non-small cell lung cancer (NSCLC) are unclear. The purpose of this study was to evaluate the efficacy and safety of pemetrexed for heavily pretreated, advanced NSCLC. Methods: We retrospectively reviewed advanced NSCLC patients who received pemetrexed and more than two prior chemotherapy regimens. The tumor responses were evaluated by the Response Evaluation Criteria of Solid Tumors. Progression-free survival and overall survival were calculated by the Kaplan–Meier method. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 3.0. Results: A total of 95 patients (53 men and 42 women) were included. The median age was 63 years (range, 29–83). Seventy (73.7%) patients had adenocarcinoma. The median number of prior systemic therapies was three (range, 2–7). The median number of cycles of pemetrexed therapy was four (range, 1–11). Seven (7.4%) patients achieved a partial response, and 33 (34.7%) had stable disease. The median progression-free survival was 116 days, and the median overall survival was 382 days. A trend toward increased progressionfree survival was observed for patients who had non-squamous compared with squamous NSCLC. Conclusion: Pemetrexed has modest efficacy for heavily pretreated NSCLC patients. Key Words: drug therapy, non-small cell lung carcinoma, pemetrexed, retrospective studies

Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide.1 Systemic therapy, either chemotherapy or targeted therapy, is the main treatment strategy for advanced NSCLC.2,3 Platinum-based doublet chemotherapy is often prescribed as first-line therapy for NSCLC, followed by single agent docetaxel4,5 or pemetrexed6 at the time of progression. Gefitinib was approved in Asia and Europe, especially for

NSCLC harboring epidermal growth factor receptor mutation.7 Erlotinib was used as second or third line therapy in Asia and United States.3,8 Currently, there is no standard third-line chemotherapy for NSCLC.9 Pemetrexed is a novel multi-targeted antifolate which inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyltransferase.10 Pemetrexed has become a

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Department of Oncology, 2National Center of Excellence for Clinical Trial and Research, and 3Department of Internal Medicine, National Taiwan University Hospital; 4Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan. Received: April 9, 2009 Revised: July 19, 2009 Accepted: August 10, 2009

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*Correspondence to: Dr Chih-Hsin Yang, Department of Oncology, National Taiwan University Hospital, 7 Zhongshan South Road, Taipei, Taiwan. E-mail: [email protected]

J Formos Med Assoc | 2010 • Vol 109 • No 5

Pemetrexed in heavily pretreated NSCLC

standard first- or second-line therapies for NSCLC patients11 and has recently been approved as maintenance treatment after first-line chemotherapy.12 For chemotherapy-naïve NSCLC patients, the overall survival for pemetrexed plus cisplatin or carboplatin is not inferior to that with gemcitabine plus cisplatin13 or carboplatin;14 the incidence of hematological toxicity with pemetrexed-based treatment is less than with gemcitabine-based treatment.13,14 As second-line therapy, pemetrexed and docetaxel offer comparable efficacy to NSCLC patients who have progressed on first-line chemotherapy.6 Pemetrexed has the advantage of low hematological toxicity compared with docetaxel. As a result of its low toxicity, single-agent pemetrexed is the ideal choice for heavily pretreated NSCLC patients, and the objective of this study was to evaluate its efficacy and safety in these patients.

the patient’s death. Overall survival was defined as the duration between initiation of pemetrexed treatment and the patient’s death. The adverse effects in the medical records were coded according to the Common Terminology Criteria for Adverse Event version 3.0.

Patient characteristics A total of 95 patients (53 men and 42 women) met the enrollment criteria for our analysis. Their characteristics are listed in Table 1. The median number of therapy regimens prior to pemetrexed treatment was three for all patients, and two for those for whom epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) were not regarded as one line of therapy. The prior therapies are listed in Table 2.

Treatment

Materials and Methods Study design and patient selection We searched the complete National Taiwan University Cancer Registry for NSCLC patients who had received pemetrexed therapy, and reviewed their pharmacy records from July 1, 2005 to December 31, 2006. The inclusion criteria for this study were NSCLC patients who received at least two lines of prior systemic therapy (chemotherapy or targeted therapy) and at least one chemotherapy regimen. Patients who had enrolled in other pemetrexed-related clinical trials were excluded from the analysis. Recorded items included sex, age, smoking history, histopathological type of NSCLC, prior systemic therapy regimens, and other demographic factors. The dose, schedule, number of cycles, and dose modification of pemetrexed were recorded. A dose delay was defined as an interval of > 4 weeks between two pemetrexed treatments. Tumor response was retrospectively evaluated according to the Response Evaluation Criteria in Solid Tumors. Progression-free survival was defined as the time from initiation of pemetrexed to the date of documented progressive disease or J Formos Med Assoc | 2010 • Vol 109 • No 5

All patients received a full dose of vitamin B12 and folic acid supplement before and during pemetrexed treatment. All patients except one received the recommended 500 mg/m2 pemetrexed as an Table 1. Patient characteristics (n = 95)* Variables Age (yr)

63 (29–83)

Sex Male Female

53 (55.8) 42 (44.2)

Smoking status Smoker Non-smoker

38 (40.0) 57 (60.0)

Histopathology Adenocarcinoma Squamous cell carcinoma Others†

70 (73.7) 12 (12.6) 13 (13.7)

ECOG performance status 0 1 2 3 4

2 (2.1) 53 (55.9) 36 (37.9) 3 (3.2) 1 (1.1)

*Data presented as median (range) or n (%); †include poorlydifferentiated or unclassified non-small cell lung cancer. ECOG = Eastern Cooperative Oncology Group.

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Table 2. Numbers and regimens of prior therapies Number of prior therapies* 1 2 3 4 5 6

0:14 23:53 47:16 15:10 9:2 1:0



Chemotherapy Cisplatin Carboplatin Gemcitabine Docetaxel Vinorelbine Uracil/Tegafur Paclitaxel Etoposide Epirubicin Bevacizumab Cetuximab

89 (93.7) 5 (5.3) 86 (90.5) 69 (72.6) 26 (27.4) 14 (14.7) 13 (13.7) 11 (11.6) 6 (6.3) 1 (1.1) 1 (1.1)

EGFR TKIs Gefitinib Erlotinib

76 (80.0) 70 (73.7) 13 (13.7)

*Data presented as TKI included: TKI excluded; or †n (%). EGFR TKIs = epidermal growth factor receptor tyrosine kinase inhibitor.

initial dose. Seventy-five (78.9%) patients received the same dose in the following cycles. Eighteen (18.9%) patients received an escalated dose of pemetrexed in the following cycles, with a maximum of 787 mg/m2. Dose reduction was carried out for one patient because of grade 3 hematological toxicity. One patient received 333 mg/m2 (500 mg) per cycle. One patient received cisplatin along with pemetrexed therapy, and three received uracil/tegafur accompanied with pemetrexed. A median four cycles of pemetrexed were prescribed (range, 1–11).

Statistical analysis Statistical analyses were carried out using SPSS version 17.0 (SPSS, Chicago, IL, USA). The Kaplan– Meier method was used to estimate overall survival and progression-free survival. Log-rank test was used to compare survival of patients with different clinicopathological factors. All p values were 340

two-sided and a value of < 0.05 was considered as statistically significant.

Results Efficacy Seven (7.4%) patients achieved a partial response and 33 (34.7%) had stable disease as best response. The overall disease control rate (partial response plus stable disease) was 42.1%. Fortyeight (50.5%) patients had progressive disease after pemetrexed treatment. Seven (7.4%) patients did not have adequate imaging studies to evaluate treatment response. With a median follow-up of 253 days, the median progression-free survival was 116 days (range, 8–432 days). The median overall survival was 382 days (range, 8–575 days) (Figure 1). Many patients received EGFR-TKIs before pemetrexed administration. Therefore, we tested whether prior EGFR-TKIs influenced the treatment outcome of pemetrexed. The median progression-free survival of patients who received prior EGFR-TKIs and those who did not was 114 and 65 days, respectively (p = 0.36). The overall survival was 382 and 339 days, respectively (p = 0.72) (Figure 2). We performed subgroup analysis according to NSCLC histological type. The progression-free survival for non-squamous NSCLC was 116 days compared with 40 days for squamous NSCLC (p = 0.14). The overall survival was 382 days for non-squamous NSCLC and 295 days for squamous NSCLC (p = 0.74).

Toxicity The toxicity of pemetrexed included anemia, leukopenia, gastrointestinal infection, abnormal liver function, and respiratory discomfort. Table 3 lists the toxicities that were grade 3 or higher. Infection was the most common serious toxicity and accounted for three possible treatment-related deaths (2 from pneumonia and 1 from septic shock). Elevation of alanine transaminase was noted in 26 patients (27.4%), but only four of them (4.2%) were grade 3 or higher. One woman J Formos Med Assoc | 2010 • Vol 109 • No 5

Pemetrexed in heavily pretreated NSCLC

A

B

1.0

1.0

0.8 Cumulative survival

Cumulative survival

0.8

0.6

0.4

0.6

0.4

0.2

0.2

0.0

0.0 0

0

100 200 300 400 Progression-free survival (d)

100

200 300 400 Overall survival (d)

500

600

Figure 1. Kaplan–Meier curves of (A) progression-free survival and (B) overall survival. Vertical lines indicate censored observation.

A

B

1.0

1.0

0.8 Cumulative survival

Cumulative survival

0.8

0.6

0.4

0.6

0.4

0.2

0.2

0.0

0.0 0

100 200 300 400 Progression-free survival (d)

0

100 200 300 400 Progression-free survival (d)

Figure 2. Kaplan–Meier curves stratified by prior epidermal growth factor receptor tyrosine kinase inhibitor exposure. (A) Progression-free survival (p = 0.36) and (B) overall survival (p = 0.72). Solid line, EGFR-TKIs exposure prior to pemetrexed therapy; dashed line, no EGFR-TKI exposure prior to pemetrexed therapy. Vertical lines indicate censored observations. EGFR-TKIs = Epidermal growth factor receptor tyrosine kinase inhibitors.

died of a catheter-related complication (perforation of the superior vena cava).

Discussion In our study, the response rate for pemetrexed in heavily pretreated NSCLC patients was 7.4%, progression-free survival was 3.8 months, and J Formos Med Assoc | 2010 • Vol 109 • No 5

overall survival was 12.5 months. According to the results of two large randomized controlled trials, the response rate for best supportive care for NSCLC patients who had received more than two lines of therapy was < 1.3%, progression-free survival was 1.8–2.6 months, and overall survival was 4.7–5.1 months.8,15 Compared with historical controls, our study suggested that pemetrexed offers some benefit to heavily pretreated NSCLC patients. 341

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Table 3. Serious adverse events during pemetrexed treatment Adverse event

Grade 3

Grade 4

Grade 5

Hematological Anemia Leukopenia

2 1

0 0

0 0

Gastrointestinal Diarrhea Nausea Vomiting

2 1 1

1 0 0

0 0 0

Infectious Pneumonia Sepsis

1 0

4 1

2 1

Hepatobiliary ALT

3

1

0

Respiratory ILD Dyspnea

0 1

1 4

0 0

Vascular Venous injury

0

0

1

ALT = Alanine transaminase; ILD = interstitial lung disease.

The role of third- or higher-line chemotherapy for NSCLC patients is still controversial. To date, as far as we are aware, there has been no prospective phase II or III trial to evaluate the safety and efficacy of cytotoxic agents as third- or higher-line therapy. In a small retrospective study, Ozdogan et al suggested that third-line chemotherapy is feasible for selected NSCLC patients.16 However, the improvement in survival beyond that with second-line chemotherapy was only modest.17 Many patients did not receive third-line treatment because of a decline in performance status. Therefore, treatment efficacy, tolerability, and other factors such as convenience should be considered when preparing to prescribe cytotoxic agents to heavily pretreated NSCLC patients.2 As second-line therapy, pemetrexed has less toxicity than docetaxel and has similar efficacy, even for elderly patients.6,18 A retrospective study has shown that second- or third-line therapy with pemetrexed is safe and might offer better progression-free survival in patients with good 342

performance status.19 Our study suggested that pemetrexed was well tolerated as third- or higherline therapy for NSCLC, even though 42% patients had an Eastern Cooperative Oncology Group performance status of ≥ 2. In the present study, 97.9% of patients received the recommended (500 mg/ m2) or higher dose of pemetrexed. Schedule delay was necessary in only 17.9% patients, which was similar to that in a previous trial in which pemetrexed was administrated as second-line therapy.20 To the best of our knowledge, our study is the largest, although retrospective, case series to evaluate the safety and efficacy of a cytotoxic agent in heavily pretreated NSCLC patients. The role of pemetrexed as third- or higher-line therapy in NSCLC should be confirmed by prospective studies. The overall survival in our study was 12.5 months, which was longer than that in a previous trial in which pemetrexed was administrated as second-line therapy for NSCLC.6 The overall response rate in our study was only 7.4%, and 50.5% of patients had progressive disease after pemetrexed therapy. The progression-free survival in our study was 3.8 months, which is similar to that in other studies.6,20,21 It is possible that ethnic difference, but not pemetrexed therapy, might be responsible for the differences in overall survival. Asian NSCLC patients might live longer than their Caucasian counterparts. This has also been demonstrated in the subgroup analysis of a randomized phase III trial, which evaluates the efficacy of cetuximab for therapy-naïve NSCLC patients and in which the median survival of Asian and Caucasian NSCLC patients was 19.5 and 9.6 months, respectively. As for pemetrexed, a randomized phase III trial of pemetrexed as second-line therapy in Caucasian patients with NSCLC showed that the median survival was 6.7–6.9 months.20 However, a similarly designed randomized trial conducted in Japan showed that the overall survival of pretreated NSCLC patients who received pemetrexed was 12.6–16.0 months.21 Therefore, ethnic difference is a plausible explanation for the long survival time observed in the present study. Salvage therapy with J Formos Med Assoc | 2010 • Vol 109 • No 5

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EGFR-TKIs after pemetrexed failure has also been postulated to be responsible for the ethnic difference.22 The overall survival in our study, however, was comparable to the that in the above Japanese study,21 even though 80% of our patients received EGFR-TKIs prior to pemetrexed therapy (Table 2). There was no difference in progression-free survival and overall survival with regard to prior EGFR-TKI exposure (Figure 2). Factors other than EGFR-TKI exposure seemed to contribute to the long survival time. A study of the underlying mechanism responsible for this difference is warranted. Our study had several limitations. First, selection bias could have been introduced into the retrospective study because patients with rapidly progressive NSCLC might not have had the choice to receive third-line therapy. However, this selection bias might have existed in all studies that have explored the role of third-line therapy. Second, some toxicity might have been evaluated or recorded inadequately and retrospectively. Some data were not collected regularly and comprehensively, therefore, the incidence of toxicity might have been underestimated. For example, grade 3 or more elevation alanine transaminase developed in 4.2% of our patients, whereas this toxicity developed in 8.1–20.0% of patients in many other prospective studies.21,23–25 In order to evaluate patient tolerance and overall toxicity more precisely, dose-reduction and scheduledelay rates were used as surrogates. Only one patient received a reduced dose of pemetrexed because of toxicity, and 78 (82.1%) received treatment as scheduled. The dose-reduction and schedule-delay rates in our study were similar to those in a prospective randomized phase III trial,20 although more patients with poor performance status were enrolled in our study. Therefore, we believed that the administration of pemetrexed in our study was as safe as in other prospective studies. In summary, the results of the present retrospective study suggest that pemetrexed has modest efficacy and an acceptable toxicity profile in heavily pretreated NSCLC patients. J Formos Med Assoc | 2010 • Vol 109 • No 5

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