Jpn J Clin Oncol 2013;43(12)1184 – 1189 doi:10.1093/jjco/hyt159 Advance Access Publication 29 October 2013
A Phase II Study of Pemetrexed in Chemotherapy-naı¨ve Elderly Patients Aged ≥75 years with Advanced Non-squamous Non-small-cell Lung Cancer (HANSHIN Oncology Group 003) Yoshihiro Hattori1, Masahiro Iwasaku2, Miyako Satouchi1,*, Akihiro Nishiyama2, Yohei Korogi2, Kojiro Otsuka3, Shiro Fujita4, Nobuyuki Katakami4, Masahide Mori5, Kazumi Nishino6, Satoshi Morita7 and Shunichi Negoro8 1
*For reprints and all correspondence: Miyako Satouchi, Department of Thoracic Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi-shi, Hyogo 673-8558, Japan. E-mail: [email protected] Received June 29, 2013; accepted September 27, 2013
Objective: Pemetrexed has relatively mild toxicity and possibly can be administered long term to patients with non-small-cell lung cancer. We conducted a Phase II trial to evaluate the efficacy and safety of pemetrexed in chemotherapy-naı¨ve elderly patients with advanced nonsquamous non-small-cell lung cancer. Methods: In this multicenter Phase II trial, we recruited elderly patients with non-squamous non-small-cell lung cancer. Patients with previously untreated Stage IIIB or IV non-squamous non-small-cell lung cancer, 75 years, Eastern Cooperative Oncology Group performance status 0–1 and adequate organ functions were eligible. Patients received pemetrexed (500 mg/m2) intravenously on Day 1 every 3 weeks until disease progression. The primary endpoint was objective response rate. Results: Forty-seven patients were enrolled from August 2009 to July 2011, and 46 patients were eligible. The median age was 79 years (range 75 – 91 years), 57% were males, 37% had never smoked, 87% had adenocarcinoma, 74% had Stage IV and 33% had epidermal growth factor receptor tyrosine kinase-activating mutation. The median number of cycles was 4 (1–20). The objective response rate was 13.3% (95% confidence interval; 5.1 – 26.8%), the disease control rate was 66.7% (95% confidence interval 51.0 – 80.0%), the median progression-free survival was 4.9 months (95% confidence interval 3.0 –6.1 months) and the median overall survival was 18.2 months (95% confidence interval 13.2 – 23.5 months). One Grade 5 infection (pneumonia) was observed. Conclusions: This study did not meet the primary endpoint. Pemetrexed monotherapy is not recommended in chemotherapy-naı¨ve elderly patients aged 75 years with advanced nonsquamous non-small-cell lung cancer. Key words: pemetrexed – non-small-cell lung cancer – chemotherapy-naı¨ve – elderly – Phase II study
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, 2Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, 3Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, 4 Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, 5Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, 6Department of Respiratory Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 7Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama and 8Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
Jpn J Clin Oncol 2013;43(12)
INTRODUCTION
PATIENTS AND METHODS Patients with histologically or cytologically confirmed nonsquamous NSCLC without large-cell neuroendocrine carcinoma were classified as Stage IIIB not amenable to curative radiotherapy and Stage IV or recurrent disease after surgery. Eligible patients met the following criteria: no prior chemotherapy regimen; measurable disease; an Eastern Cooperative Oncology Group performance status (PS) of 0 – 1; 75 years; an estimated life expectancy of at least 3 months and adequate bone marrow, renal and hepatic function.
Patients with interstitial pneumonia or pulmonary fibrosis detectable on computed tomography (CT) scan, uncontrolled pleural effusions or symptomatic brain metastases were deemed to be ineligible. The protocol was approved through institutional ethical review boards, and all patients provided written informed consent before treatment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. TREATMENT PLAN Patients received 500 mg/m 2 pemetrexed in a 10-min intravenous infusion on Day 1 of a 21-day cycle. Cycles were repeated until disease progression, unacceptable toxicity or until the patient or the investigator requested therapy discontinuation. Patients were instructed to take 500 mg folic acid orally each day, beginning 1 week before the first dose of pemetrexed and continuing on a daily basis until 3 weeks after the last dose of pemetrexed. A vitamin B12 injection (1000 mg) was intramuscularly administered 1 week before the first dose of pemetrexed and was repeated approximately every 9 weeks until 3 weeks after the last dose of pemetrexed. The subsequent cycles were begun if a patient presented a PS of 0 – 2, neutrophil count of 1500/ml, platelet count of 75 000/ml, aspartate aminotransferase/alanine aminotransferase (AST/ALT) lower than 2.5 times the upper limit of each facility, total bilirubin ,1.5 times the upper limit of each facility, creatinine 1.5 mg/dl and/or other non-hematologic toxicities of a grade no more than 2. A 2-week delay in initiating the subsequent course was allowed. Otherwise, the patient was withdrawn from the study. Patients were scheduled to receive pemetrexed until the administration was not possible anymore. In regard to the dose modification of pemetrexed in the subsequent cycles, if, during the previous course, the patient presented Grade 4 leukopenia, FN, thrombocytopenia characterized by a platelet count of no more than 25 000/ml, nonhematologic toxicities at a grade of at least 3 or a delay in starting a subsequent course by .8 days, the dose of pemetrexed was reduced to 400 mg/m2. Any patient with a grade of non-hematologic toxicity of at least 4 or interstitial pneumonia grade of at least 2 was withdrawn from the study. Patients received full supportive care. The baseline assessment included a history and physical examination, complete blood cell count, comprehensive blood chemistries, chest X-ray, CT scan of the chest and the upper abdomen and magnetic resonance imaging or CT scan of the brain. Tumor measurements were assessed with a monthly CT scan. Objective tumor responses were based on the Response Evaluation Criteria in Solid Tumors (RECISTs) version 1.1. The objective response rate (ORR), which was the primary endpoint, was confirmed by an extramural review. Toxicity evaluations were based on the National Cancer Institute-Common Toxicity Criteria, version 3.0.
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The incidence of lung cancer among elderly is on a constant rise (1), and this trend is expected to continue. This correlates with an increasing need for developing chemotherapy that is effective in treating advanced lung cancer among elderly without being very toxic. The elderly, though, represents a non-uniform population characterized by compromised organ functions, a high incidence of complications and large differences among individuals. There are few prospective trials in patients 75 years with advanced non-small-cell lung cancer (NSCLC), however, and a significant paucity of evidence. The standard therapy for elderly is vinorelbine, gemcitabine and docetaxel based on an ELVIS Group study comparing vinorelbine with a best supportive care (2), a Gridelli et al.’s (3) Phase III study comparing vinorelbine, gemcitabine and gemcitabine/vinorelbine combination therapy and a WJTOG9904 Phase III study in Japan comparing docetaxel and vinorelbine (4). Pemetrexed is a novel multitargeted antifolate that inhibits three enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, and it displays cytotoxic activity against several solid tumors, including NSCLC (5). Hanna et al. (6) conducted a Phase III study (JMEI study) comparing pemetrexed with docetaxel in second-line chemotherapy on relapsed advanced NSCLC patients previously treated with chemotherapy. Non-inferiority was not observed in the progression-free survival (PFS) (2.9 versus 2.9 months) or overall survival (OS) (8.3 versus 7.9 months) (hazard ratio ¼ 0.99) between pemetrexed and docetaxel. The report cited the tendency of pemetrexed to display significantly milder toxicities than docetaxel in terms of Grade 3 and 4 adverse events (AEs), such as neutropenia (5.3 versus 40.2%) and febrile neutropenia (FN) (1.9 versus 12.7%), elevating pemetrexed to the status of standard treatment for relapsed NSCLC as mildly toxic second-line chemotherapy. Moreover, the clinical study findings on pemetrexed to date have suggested the possibility of histological efficacy differences (7), as it is recommended for use on non-squamous NSCLC. Based on this, we designed a Phase II study to examine the efficacy and safety of pemetrexed (which is considered to be very safe, i.e. display milder toxicity) on elderly patients 75 years with advanced non-squamous NSCLC.
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Pemetrexed in elderly (75 years) advanced NSCLC
STATISTICAL ANALYSIS
Characteristics
n ¼ 46
Median age, years (range)
79 (75– 91)
Gender, n (%) Female
20 (43)
Male
26 (57)
ECOG PS, n (%) 0
21 (46)
1
25 (54)
Smoking status, n (%) Never
17 (37)
Ever
29 (63)
Histology, n (%) Adenocarcinoma NSCLC (unclassified)
RESULTS
40 (87) 6 (13)
Stage, n (%)
PATIENTS AND TREATMENT
IIIB
10 (22)
Forty-seven patients were registered between August 2009 and July 2011. One of the patients was deemed a postscreening failure after being found to have undergone adjuvant chemotherapy after registration, resulting in 46 patients ultimately receiving the protocol treatment. The median follow-up period was 14 months, and the baseline patient characteristics are shown in Table 1. The number of men/women and the number of PS 0 and 1 were approximately the same, slightly more smokers than never smokers, 87% had adenocarcinoma and 74% were Stage IV. Sixteen of the patients were epidermal growth factor receptor (EGFR) mutation-positive (15 of such displayed active mutations), 23 patients were EGFR mutation-negative and the mutation status was unknown for seven patients. The median number of treatment cycles was four (range 1 – 16 cycles), seven of the patients (15%) could have received treatment for at least 10 cycles and one of the patients received 20 cycles of treatment. It was found that the lesion assessed after initiation of the protocol treatment in one of the 46 patients who received the protocol treatment was included within the radiation field. As such, safety was assessed for 46 patients, and the efficacy was assessed for 45 patients (excluding one post-screening failure patient). The observation period ended as of July 2012, which concluded the study.
IV
34 (74)
EFFICACY The ORR was 13.3% (95% CI 5.1 – 26.8%), and the disease control rate was 66.7% (95% CI 51.0 – 80.0%) (Table 2). The median PFS was 4.9 months (95% CI 3.0 – 6.1 months) (Fig. 1A), and the median survival time (MST) was 18.2 months (95% CI 13.2 – 23.5 months) (Fig. 1B). Moreover, the median PFS among the EGFR mutation-positive and -negative
Recurrence
2 (4)
EGFR mutation status, n (%) Exon 19 or 21 Other mutations Wild Unknown
15 (33) 1 (2) 23 (50) 7 (15)
ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor.
Table 2. Tumor response in evaluable patients according to RECISTs n ¼ 45 Objective response Complete response, n (%)
0 (0.0)
Partial response, n (%)
6 (13.3)
Stable disease, n (%)
24 (53.4)
Progressive disease, n (%)
11 (24.4)
Not evaluable, n (%) Objective response rate (%)
4 (8.9) 13.3
95% CI, %
5.1– 26.8
Disease control rate (%)
66.7
95% CI, %
51.0–80.0
RECISTs, Response Evaluation Criteria in Solid Tumors; 95% CI, 95% confidence interval.
patients was 5.7 months (95% CI 3.4 – 6.2 months) and 4.7 months (95% CI 1.6 – 6.2 months) (Fig. 2A), respectively. The MST among the EGFR mutation-positive and -negative
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In light of the previous data (2 – 4), we assumed that a 25% response rate (RR) in the pemetrexed regimen in eligible patients would indicate potential usefulness, while 10% of RR would be the lower limit of interest. Based on this assumption, the number of patients needed to provide the 80% power for a one-sided 0.05 level of Type I error was calculated to be 38. Taking ineligible patients into account, the sample size was set at 45 in our study. Efficacy and safety analyses were planned for patients who received at least one dose of the treatment. The ORR was calculated and its 95% confidence interval (CI) was estimated. PFS and OS were analyzed using the Kaplan – Meier method to estimate the median points with 95% CIs. All statistical analyses were performed with SAS for Windows, release 9.3 (SAS Institute, Cary, NC, USA).
Table 1. Patient characteristics
Jpn J Clin Oncol 2013;43(12)
patients was 20.2 months (95% CI, 8.3 months to not reached) and 13.7 months (95% CI, 9.4 months to not reached) (Fig. 2B), respectively.
Figure 2. (A) The Kaplan – Meier curve for PFS by epidermal growth factor receptor (EGFR) mutation status and (B) the Kaplan – Meier curve for OS by EGFR mutation status.
treatments received were cytotoxic chemotherapy in 14 patients, EGFR-tyrosine kinase inhibitors (TKIs) in 13 patients and crizotinib in one patient.
TOXICITY AEs were assessed for 46 patients who had undergone the protocol treatment (Table 3). Grade 3 or 4 hematologic toxicities were observed in three patients with leukopenia, 18 with neutropenia, five with anemia and three with thrombocytopenia. While one patient received RBC and platelet transfusion, respectively, there were no cases of FN. In regard to non-hematologic toxicities, there was one case each of Grade 4 ALT and AST elevation. There was one treatment-related death—an 81-year-old man who presented pneumonia without neutropenia on Day 19 of the second cycle. POST-STUDY TREATMENT Progression was observed in 42 of the 45 patients deemed to be eligible for treatment in the study, and 28 (67%) patients received post-study treatment (Table 4). The respective
DISCUSSION Our study was designed to examine the efficacy and safety of pemetrexed, which is considered to have a relatively mild level of toxicity and promises efficacy as front-line treatment for elderly with advanced non-squamous NSCLC. This is a rare prospective study conducted only on patients aged 75 years. The 13.3% ORR did not reach the expected ORR of 25%. And, at a 95% CI, the minimum ORR was 5.1%, which failed to exceed the threshold ORR of 10%. There were not enough data from our prospective study limited to patients aged 75 years in order to establish the primary endpoint, so the expected response and threshold rates were established, using the WJTOG9904 study’s RR as a reference. This study, however, targeted patients aged 70 years and included at least one-third of Stage IIIB patients, suggesting a population that could have been more favorable than the population
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Figure 1. (A) The Kaplan – Meier curve for progression-free survival (PFS) and (B) for overall survival (OS).
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Pemetrexed in elderly (75 years) advanced NSCLC
Table 3. Toxicity grades associated with chemotherapy (n ¼ 46) Grade 1/2
Grade 3
Grade 4
Table 4. Post-progression therapy n ¼ 42
Grade 5
Hematologic toxicity, n (%)
Cytotoxic chemotherapy
14
Leukopenia
23 (50)
1 (2)
2 (4)
0 (0)
Vinorelbine
3
Neutropenia
9 (20)
14 (30)
4 (9)
0 (0)
Carboplatin/paclitaxel/bevacizumab
2
Anemia
41 (89)
4 (9)
1 (2)
0 (0)
Docetaxel
2
Thrombocytopenia
22 (48)
1 (2)
2 (4)
0 (0)
Amrubicin
2
Febrile neutropenia
0 (0)
0 (0)
0 (0)
0 (0)
S-1
2
Gemcitabine
1
Non-hematologic toxicity, n (%) AST increased
26 (57)
1 (2)
1 (2)
0 (0)
Carboplatin/paclitaxel
1
ALT increased
18 (39)
0 (0)
1 (2)
0 (0)
Carboplatin/etoposide
1
Creatinine increased
11 (24)
0 (0)
0 (0)
0 (0)
Hyponatremia
13 (28)
2 (4)
0 (0)
0 (0)
Active EGFR mutation
13 11
9 (20)
1 (2)
0 (0)
0 (0)
Gefitinib
6
Hypercalcemia
20 (44)
0 (0)
0 (0)
0 (0)
Erlotinib
5
Fatigue
25 (54)
5 (11)
0 (0)
0 (0)
Other EGFR mutation, gefitinib
1
Nausea
15 (33)
1 (2)
0 (0)
0 (0)
Unknown, erlotinib
1
Vomiting
7 (15)
0 (0)
0 (0)
0 (0)
Constipation
15 (33)
0 (0)
0 (0)
0 (0)
Crizotinib
Rash
No chemotherapy
12 (26)
2 (4)
0 (0)
0 (0)
Mucositis/stomatitis
6 (13)
0 (0)
0 (0)
0 (0)
Sensory neuropathy
3 (7)
0 (0)
0 (0)
0 (0)
Infection
3 (7)
2 (4)
0 (0)
1 (2)
Interstitial pneumonia
0 (0)
0 (0)
0 (0)
0 (0)
AST, aspartate aminotransferase; ALT, alanine aminotransferase.
targeted in our study. This also suggests that the expected and threshold RR based on only one clinical study may have been set excessively high. In regard to pemetrexed for elderly 75 years, the ORR in our study is more favorable than other reports, including the 4.5% with pemetrexed used as front-line treatment in a randomized Phase II study reported by Gridelli et al. (8) or 5.5% among elderly (70 years) according to the subset analysis in a JMEI study, in which the second-line use of pemetrexed was reported by Weiss et al. (9). A characteristic of this treatment is that the toxicity is minor even when conducted on elderly. In regard to hematologic toxicities, 39% of the patients presented Grade 3 or 4 neutropenia. FN, which is usually a problem in patients who have undergone docetaxel or carboplatin/paclitaxel, was not observed in our study. This suggests that pemetrexed is better than other drugs as a treatment for 75 years elderly patients. In regard to non-hematologic toxicities, one of the conceivable characteristic AEs of pemetrexed was fatigue. In our study, there were 65% all-grade cases and 11% Grade 3 cases of it. This is a very difficult AE for elderly patients 75 years to cope with. Grade 3 or 4 fatigue was observed in 5% of patients in the pemetrexed group in the JMEI study and in 7.5% among the elderly subset (70 years) in the same study.
ALK-TKI
1 1 14
EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors; ALK-TKI, anaplastic lymphoma kinase-tyrosine kinase inhibitor.
Fatigue tends to be amplified among elderly, so it was considered to be an AE that requires special caution when treated with pemetrexed. In regard to the serious AEs, there was one case each of Grade 4 AST and ALT elevation. One treatment-related death was observed due to pneumonia, but it was not interstitial pneumonia. The median number of treatment cycles was 4, though seven of the patients (15%) could have received treatment for at least 10 cycles. Moreover, one of the patients received 20 cycles of treatment. Furthermore, it has been reported that 47.5% of the patients in the WJTOG9904 study and 34% in the JCOG0803/WJOG4307L study received post-study treatment, with both of these studies being conducted on patients aged 70 years. Meanwhile, 28 (67%) of the 42 patients in whom the progression was confirmed in this study, which targeted patients 75 years, received post-study treatment. Yet, the PFS in this study was similar to that observed in the MILES study, WJTOG study, that reported by Gridelli et al. (8) in a study using pemetrexed, as well as the others including JCOG0803/WJOG4307L studies using docetaxel (10). This result did not meet our expectations. The OS was very favorable. One of the conceivable reasons for the favorable OS was that there were 15 (33% of the whole) EGFR mutationpositive patients, and the MST for the EGFR mutationpositive group (20.2 months) was better than that in the mutation-negative group (13.7 months) (P ¼ 0.354). The MST for the EGFR mutation-negative group, however, did not
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Hypokalemia
EGFR-TKIs
Jpn J Clin Oncol 2013;43(12)
Acknowledgements The authors are grateful to the participating patients and to the members of the HANSHIN Oncology Group.
Funding This study was supported by Foundation for Biomedical Research and Innovation.
Conflict of interest statement None declared.
References 1. Kaneko S, Ishikawa KB, Yoshimi I, et al. Projection of lung cancer mortality in Japan. Cancer Sci 2003;94:919–23. 2. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999;91:66 –72. 3. Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003;95:362– 72. 4. Kudoh S, Takeda K, Nakagawa K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol 2006;24:3657 –63. 5. Adjei AA. Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. Clin Cancer Res 2004;10:4276s – 80s. 6. Hanna N, Shepherd FA, Fossella FV, 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;22:1589 –97. 7. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 2009;14:253– 63. 8. Gridelli C, Kaukel E, Gregorc V, et al. Single-agent pemetrexed or sequential pemetrexed/gemcitabine as front-line treatment of advanced non-small cell lung cancer in elderly patients or patients ineligible for platinum-based chemotherapy: a multicenter, randomized, phase II trial. J Thorac Oncol 2007;2:221 –9. 9. Weiss GJ, Langer C, Rosell R et al. Elderly patients benefit from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of pemetrexed compared with docetaxel in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2006;24:4405 –11. 10. Abe T, Yokoyama A, Takeda K, et al. Randomized phase III trial comparing weekly docetaxel (D)-cisplatin (P) combination with triweekly D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): an intergroup trial of JCOG0803/WJOG4307L. ASCO Meeting Abstracts 2011;29:7509. 11. Quoix E, Zalcman G, Oster JP, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 2011;378:1079–88.
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meet our expectations, either. These findings may suggest that pemetrexed monotherapy lacks efficacy as a first-line treatment in this population. In recent years, there have been reports of studies that investigate the potential of platinum-based combination therapy used in front-line treatment on elderly. According to a report by Quoix et al. (11), combination therapy with carboplatin and weekly paclitaxel improved OS significantly better than gemcitabine or vinorelbine. They also reported, though, that combination therapy increases toxicity, i.e. careful attention should be paid to the higher incidence of treatment-related death among the combination therapy group (4.4%) over that in the monotherapy group (1.3%). Furthermore, the JCOG0803/WJOG4307L study failed to show that the MST of the weekly docetaxel – cisplatin group (13.3 months, 95% CI 10.8 – 19.4 months) exceeds that of the docetaxel group (14.8 months, 95% CI 11.9 – 24.1 months). Based on the foregoing, we thought that it is premature to consider the platinum doublet as standard treatment for 75 years elderly patients. Our study did not meet its primary endpoint, and thus pemetrexed monotherapy should not be recommended to elderly patients aged 75 years with advanced NSCLC. Docetaxel monotherapy remains the standard, and further studies are necessary in this patient population.
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A Phase II Study of Pemetrexed in Chemotherapy-naı¨ve Elderly Patients Aged ≥75 years with Advanced Non-squamous Non-small-cell Lung Cancer (HANSHIN Oncology Group 003) Yoshihiro Hattori1, Masahiro Iwasaku2, Miyako Satouchi1,*, Akihiro Nishiyama2, Yohei Korogi2, Kojiro Otsuka3, Shiro Fujita4, Nobuyuki Katakami4, Masahide Mori5, Kazumi Nishino6, Satoshi Morita7 and Shunichi Negoro8 1
*For reprints and all correspondence: Miyako Satouchi, Department of Thoracic Oncology, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi-shi, Hyogo 673-8558, Japan. E-mail: [email protected] Received June 29, 2013; accepted September 27, 2013
Objective: Pemetrexed has relatively mild toxicity and possibly can be administered long term to patients with non-small-cell lung cancer. We conducted a Phase II trial to evaluate the efficacy and safety of pemetrexed in chemotherapy-naı¨ve elderly patients with advanced nonsquamous non-small-cell lung cancer. Methods: In this multicenter Phase II trial, we recruited elderly patients with non-squamous non-small-cell lung cancer. Patients with previously untreated Stage IIIB or IV non-squamous non-small-cell lung cancer, 75 years, Eastern Cooperative Oncology Group performance status 0–1 and adequate organ functions were eligible. Patients received pemetrexed (500 mg/m2) intravenously on Day 1 every 3 weeks until disease progression. The primary endpoint was objective response rate. Results: Forty-seven patients were enrolled from August 2009 to July 2011, and 46 patients were eligible. The median age was 79 years (range 75 – 91 years), 57% were males, 37% had never smoked, 87% had adenocarcinoma, 74% had Stage IV and 33% had epidermal growth factor receptor tyrosine kinase-activating mutation. The median number of cycles was 4 (1–20). The objective response rate was 13.3% (95% confidence interval; 5.1 – 26.8%), the disease control rate was 66.7% (95% confidence interval 51.0 – 80.0%), the median progression-free survival was 4.9 months (95% confidence interval 3.0 –6.1 months) and the median overall survival was 18.2 months (95% confidence interval 13.2 – 23.5 months). One Grade 5 infection (pneumonia) was observed. Conclusions: This study did not meet the primary endpoint. Pemetrexed monotherapy is not recommended in chemotherapy-naı¨ve elderly patients aged 75 years with advanced nonsquamous non-small-cell lung cancer. Key words: pemetrexed – non-small-cell lung cancer – chemotherapy-naı¨ve – elderly – Phase II study
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, 2Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, 3Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, 4 Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, 5Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, 6Department of Respiratory Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 7Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama and 8Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan
Jpn J Clin Oncol 2013;43(12)
INTRODUCTION
PATIENTS AND METHODS Patients with histologically or cytologically confirmed nonsquamous NSCLC without large-cell neuroendocrine carcinoma were classified as Stage IIIB not amenable to curative radiotherapy and Stage IV or recurrent disease after surgery. Eligible patients met the following criteria: no prior chemotherapy regimen; measurable disease; an Eastern Cooperative Oncology Group performance status (PS) of 0 – 1; 75 years; an estimated life expectancy of at least 3 months and adequate bone marrow, renal and hepatic function.
Patients with interstitial pneumonia or pulmonary fibrosis detectable on computed tomography (CT) scan, uncontrolled pleural effusions or symptomatic brain metastases were deemed to be ineligible. The protocol was approved through institutional ethical review boards, and all patients provided written informed consent before treatment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. TREATMENT PLAN Patients received 500 mg/m 2 pemetrexed in a 10-min intravenous infusion on Day 1 of a 21-day cycle. Cycles were repeated until disease progression, unacceptable toxicity or until the patient or the investigator requested therapy discontinuation. Patients were instructed to take 500 mg folic acid orally each day, beginning 1 week before the first dose of pemetrexed and continuing on a daily basis until 3 weeks after the last dose of pemetrexed. A vitamin B12 injection (1000 mg) was intramuscularly administered 1 week before the first dose of pemetrexed and was repeated approximately every 9 weeks until 3 weeks after the last dose of pemetrexed. The subsequent cycles were begun if a patient presented a PS of 0 – 2, neutrophil count of 1500/ml, platelet count of 75 000/ml, aspartate aminotransferase/alanine aminotransferase (AST/ALT) lower than 2.5 times the upper limit of each facility, total bilirubin ,1.5 times the upper limit of each facility, creatinine 1.5 mg/dl and/or other non-hematologic toxicities of a grade no more than 2. A 2-week delay in initiating the subsequent course was allowed. Otherwise, the patient was withdrawn from the study. Patients were scheduled to receive pemetrexed until the administration was not possible anymore. In regard to the dose modification of pemetrexed in the subsequent cycles, if, during the previous course, the patient presented Grade 4 leukopenia, FN, thrombocytopenia characterized by a platelet count of no more than 25 000/ml, nonhematologic toxicities at a grade of at least 3 or a delay in starting a subsequent course by .8 days, the dose of pemetrexed was reduced to 400 mg/m2. Any patient with a grade of non-hematologic toxicity of at least 4 or interstitial pneumonia grade of at least 2 was withdrawn from the study. Patients received full supportive care. The baseline assessment included a history and physical examination, complete blood cell count, comprehensive blood chemistries, chest X-ray, CT scan of the chest and the upper abdomen and magnetic resonance imaging or CT scan of the brain. Tumor measurements were assessed with a monthly CT scan. Objective tumor responses were based on the Response Evaluation Criteria in Solid Tumors (RECISTs) version 1.1. The objective response rate (ORR), which was the primary endpoint, was confirmed by an extramural review. Toxicity evaluations were based on the National Cancer Institute-Common Toxicity Criteria, version 3.0.
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The incidence of lung cancer among elderly is on a constant rise (1), and this trend is expected to continue. This correlates with an increasing need for developing chemotherapy that is effective in treating advanced lung cancer among elderly without being very toxic. The elderly, though, represents a non-uniform population characterized by compromised organ functions, a high incidence of complications and large differences among individuals. There are few prospective trials in patients 75 years with advanced non-small-cell lung cancer (NSCLC), however, and a significant paucity of evidence. The standard therapy for elderly is vinorelbine, gemcitabine and docetaxel based on an ELVIS Group study comparing vinorelbine with a best supportive care (2), a Gridelli et al.’s (3) Phase III study comparing vinorelbine, gemcitabine and gemcitabine/vinorelbine combination therapy and a WJTOG9904 Phase III study in Japan comparing docetaxel and vinorelbine (4). Pemetrexed is a novel multitargeted antifolate that inhibits three enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, and it displays cytotoxic activity against several solid tumors, including NSCLC (5). Hanna et al. (6) conducted a Phase III study (JMEI study) comparing pemetrexed with docetaxel in second-line chemotherapy on relapsed advanced NSCLC patients previously treated with chemotherapy. Non-inferiority was not observed in the progression-free survival (PFS) (2.9 versus 2.9 months) or overall survival (OS) (8.3 versus 7.9 months) (hazard ratio ¼ 0.99) between pemetrexed and docetaxel. The report cited the tendency of pemetrexed to display significantly milder toxicities than docetaxel in terms of Grade 3 and 4 adverse events (AEs), such as neutropenia (5.3 versus 40.2%) and febrile neutropenia (FN) (1.9 versus 12.7%), elevating pemetrexed to the status of standard treatment for relapsed NSCLC as mildly toxic second-line chemotherapy. Moreover, the clinical study findings on pemetrexed to date have suggested the possibility of histological efficacy differences (7), as it is recommended for use on non-squamous NSCLC. Based on this, we designed a Phase II study to examine the efficacy and safety of pemetrexed (which is considered to be very safe, i.e. display milder toxicity) on elderly patients 75 years with advanced non-squamous NSCLC.
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Pemetrexed in elderly (75 years) advanced NSCLC
STATISTICAL ANALYSIS
Characteristics
n ¼ 46
Median age, years (range)
79 (75– 91)
Gender, n (%) Female
20 (43)
Male
26 (57)
ECOG PS, n (%) 0
21 (46)
1
25 (54)
Smoking status, n (%) Never
17 (37)
Ever
29 (63)
Histology, n (%) Adenocarcinoma NSCLC (unclassified)
RESULTS
40 (87) 6 (13)
Stage, n (%)
PATIENTS AND TREATMENT
IIIB
10 (22)
Forty-seven patients were registered between August 2009 and July 2011. One of the patients was deemed a postscreening failure after being found to have undergone adjuvant chemotherapy after registration, resulting in 46 patients ultimately receiving the protocol treatment. The median follow-up period was 14 months, and the baseline patient characteristics are shown in Table 1. The number of men/women and the number of PS 0 and 1 were approximately the same, slightly more smokers than never smokers, 87% had adenocarcinoma and 74% were Stage IV. Sixteen of the patients were epidermal growth factor receptor (EGFR) mutation-positive (15 of such displayed active mutations), 23 patients were EGFR mutation-negative and the mutation status was unknown for seven patients. The median number of treatment cycles was four (range 1 – 16 cycles), seven of the patients (15%) could have received treatment for at least 10 cycles and one of the patients received 20 cycles of treatment. It was found that the lesion assessed after initiation of the protocol treatment in one of the 46 patients who received the protocol treatment was included within the radiation field. As such, safety was assessed for 46 patients, and the efficacy was assessed for 45 patients (excluding one post-screening failure patient). The observation period ended as of July 2012, which concluded the study.
IV
34 (74)
EFFICACY The ORR was 13.3% (95% CI 5.1 – 26.8%), and the disease control rate was 66.7% (95% CI 51.0 – 80.0%) (Table 2). The median PFS was 4.9 months (95% CI 3.0 – 6.1 months) (Fig. 1A), and the median survival time (MST) was 18.2 months (95% CI 13.2 – 23.5 months) (Fig. 1B). Moreover, the median PFS among the EGFR mutation-positive and -negative
Recurrence
2 (4)
EGFR mutation status, n (%) Exon 19 or 21 Other mutations Wild Unknown
15 (33) 1 (2) 23 (50) 7 (15)
ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor.
Table 2. Tumor response in evaluable patients according to RECISTs n ¼ 45 Objective response Complete response, n (%)
0 (0.0)
Partial response, n (%)
6 (13.3)
Stable disease, n (%)
24 (53.4)
Progressive disease, n (%)
11 (24.4)
Not evaluable, n (%) Objective response rate (%)
4 (8.9) 13.3
95% CI, %
5.1– 26.8
Disease control rate (%)
66.7
95% CI, %
51.0–80.0
RECISTs, Response Evaluation Criteria in Solid Tumors; 95% CI, 95% confidence interval.
patients was 5.7 months (95% CI 3.4 – 6.2 months) and 4.7 months (95% CI 1.6 – 6.2 months) (Fig. 2A), respectively. The MST among the EGFR mutation-positive and -negative
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In light of the previous data (2 – 4), we assumed that a 25% response rate (RR) in the pemetrexed regimen in eligible patients would indicate potential usefulness, while 10% of RR would be the lower limit of interest. Based on this assumption, the number of patients needed to provide the 80% power for a one-sided 0.05 level of Type I error was calculated to be 38. Taking ineligible patients into account, the sample size was set at 45 in our study. Efficacy and safety analyses were planned for patients who received at least one dose of the treatment. The ORR was calculated and its 95% confidence interval (CI) was estimated. PFS and OS were analyzed using the Kaplan – Meier method to estimate the median points with 95% CIs. All statistical analyses were performed with SAS for Windows, release 9.3 (SAS Institute, Cary, NC, USA).
Table 1. Patient characteristics
Jpn J Clin Oncol 2013;43(12)
patients was 20.2 months (95% CI, 8.3 months to not reached) and 13.7 months (95% CI, 9.4 months to not reached) (Fig. 2B), respectively.
Figure 2. (A) The Kaplan – Meier curve for PFS by epidermal growth factor receptor (EGFR) mutation status and (B) the Kaplan – Meier curve for OS by EGFR mutation status.
treatments received were cytotoxic chemotherapy in 14 patients, EGFR-tyrosine kinase inhibitors (TKIs) in 13 patients and crizotinib in one patient.
TOXICITY AEs were assessed for 46 patients who had undergone the protocol treatment (Table 3). Grade 3 or 4 hematologic toxicities were observed in three patients with leukopenia, 18 with neutropenia, five with anemia and three with thrombocytopenia. While one patient received RBC and platelet transfusion, respectively, there were no cases of FN. In regard to non-hematologic toxicities, there was one case each of Grade 4 ALT and AST elevation. There was one treatment-related death—an 81-year-old man who presented pneumonia without neutropenia on Day 19 of the second cycle. POST-STUDY TREATMENT Progression was observed in 42 of the 45 patients deemed to be eligible for treatment in the study, and 28 (67%) patients received post-study treatment (Table 4). The respective
DISCUSSION Our study was designed to examine the efficacy and safety of pemetrexed, which is considered to have a relatively mild level of toxicity and promises efficacy as front-line treatment for elderly with advanced non-squamous NSCLC. This is a rare prospective study conducted only on patients aged 75 years. The 13.3% ORR did not reach the expected ORR of 25%. And, at a 95% CI, the minimum ORR was 5.1%, which failed to exceed the threshold ORR of 10%. There were not enough data from our prospective study limited to patients aged 75 years in order to establish the primary endpoint, so the expected response and threshold rates were established, using the WJTOG9904 study’s RR as a reference. This study, however, targeted patients aged 70 years and included at least one-third of Stage IIIB patients, suggesting a population that could have been more favorable than the population
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Figure 1. (A) The Kaplan – Meier curve for progression-free survival (PFS) and (B) for overall survival (OS).
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Table 3. Toxicity grades associated with chemotherapy (n ¼ 46) Grade 1/2
Grade 3
Grade 4
Table 4. Post-progression therapy n ¼ 42
Grade 5
Hematologic toxicity, n (%)
Cytotoxic chemotherapy
14
Leukopenia
23 (50)
1 (2)
2 (4)
0 (0)
Vinorelbine
3
Neutropenia
9 (20)
14 (30)
4 (9)
0 (0)
Carboplatin/paclitaxel/bevacizumab
2
Anemia
41 (89)
4 (9)
1 (2)
0 (0)
Docetaxel
2
Thrombocytopenia
22 (48)
1 (2)
2 (4)
0 (0)
Amrubicin
2
Febrile neutropenia
0 (0)
0 (0)
0 (0)
0 (0)
S-1
2
Gemcitabine
1
Non-hematologic toxicity, n (%) AST increased
26 (57)
1 (2)
1 (2)
0 (0)
Carboplatin/paclitaxel
1
ALT increased
18 (39)
0 (0)
1 (2)
0 (0)
Carboplatin/etoposide
1
Creatinine increased
11 (24)
0 (0)
0 (0)
0 (0)
Hyponatremia
13 (28)
2 (4)
0 (0)
0 (0)
Active EGFR mutation
13 11
9 (20)
1 (2)
0 (0)
0 (0)
Gefitinib
6
Hypercalcemia
20 (44)
0 (0)
0 (0)
0 (0)
Erlotinib
5
Fatigue
25 (54)
5 (11)
0 (0)
0 (0)
Other EGFR mutation, gefitinib
1
Nausea
15 (33)
1 (2)
0 (0)
0 (0)
Unknown, erlotinib
1
Vomiting
7 (15)
0 (0)
0 (0)
0 (0)
Constipation
15 (33)
0 (0)
0 (0)
0 (0)
Crizotinib
Rash
No chemotherapy
12 (26)
2 (4)
0 (0)
0 (0)
Mucositis/stomatitis
6 (13)
0 (0)
0 (0)
0 (0)
Sensory neuropathy
3 (7)
0 (0)
0 (0)
0 (0)
Infection
3 (7)
2 (4)
0 (0)
1 (2)
Interstitial pneumonia
0 (0)
0 (0)
0 (0)
0 (0)
AST, aspartate aminotransferase; ALT, alanine aminotransferase.
targeted in our study. This also suggests that the expected and threshold RR based on only one clinical study may have been set excessively high. In regard to pemetrexed for elderly 75 years, the ORR in our study is more favorable than other reports, including the 4.5% with pemetrexed used as front-line treatment in a randomized Phase II study reported by Gridelli et al. (8) or 5.5% among elderly (70 years) according to the subset analysis in a JMEI study, in which the second-line use of pemetrexed was reported by Weiss et al. (9). A characteristic of this treatment is that the toxicity is minor even when conducted on elderly. In regard to hematologic toxicities, 39% of the patients presented Grade 3 or 4 neutropenia. FN, which is usually a problem in patients who have undergone docetaxel or carboplatin/paclitaxel, was not observed in our study. This suggests that pemetrexed is better than other drugs as a treatment for 75 years elderly patients. In regard to non-hematologic toxicities, one of the conceivable characteristic AEs of pemetrexed was fatigue. In our study, there were 65% all-grade cases and 11% Grade 3 cases of it. This is a very difficult AE for elderly patients 75 years to cope with. Grade 3 or 4 fatigue was observed in 5% of patients in the pemetrexed group in the JMEI study and in 7.5% among the elderly subset (70 years) in the same study.
ALK-TKI
1 1 14
EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors; ALK-TKI, anaplastic lymphoma kinase-tyrosine kinase inhibitor.
Fatigue tends to be amplified among elderly, so it was considered to be an AE that requires special caution when treated with pemetrexed. In regard to the serious AEs, there was one case each of Grade 4 AST and ALT elevation. One treatment-related death was observed due to pneumonia, but it was not interstitial pneumonia. The median number of treatment cycles was 4, though seven of the patients (15%) could have received treatment for at least 10 cycles. Moreover, one of the patients received 20 cycles of treatment. Furthermore, it has been reported that 47.5% of the patients in the WJTOG9904 study and 34% in the JCOG0803/WJOG4307L study received post-study treatment, with both of these studies being conducted on patients aged 70 years. Meanwhile, 28 (67%) of the 42 patients in whom the progression was confirmed in this study, which targeted patients 75 years, received post-study treatment. Yet, the PFS in this study was similar to that observed in the MILES study, WJTOG study, that reported by Gridelli et al. (8) in a study using pemetrexed, as well as the others including JCOG0803/WJOG4307L studies using docetaxel (10). This result did not meet our expectations. The OS was very favorable. One of the conceivable reasons for the favorable OS was that there were 15 (33% of the whole) EGFR mutationpositive patients, and the MST for the EGFR mutationpositive group (20.2 months) was better than that in the mutation-negative group (13.7 months) (P ¼ 0.354). The MST for the EGFR mutation-negative group, however, did not
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Hypokalemia
EGFR-TKIs
Jpn J Clin Oncol 2013;43(12)
Acknowledgements The authors are grateful to the participating patients and to the members of the HANSHIN Oncology Group.
Funding This study was supported by Foundation for Biomedical Research and Innovation.
Conflict of interest statement None declared.
References 1. Kaneko S, Ishikawa KB, Yoshimi I, et al. Projection of lung cancer mortality in Japan. Cancer Sci 2003;94:919–23. 2. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999;91:66 –72. 3. Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003;95:362– 72. 4. Kudoh S, Takeda K, Nakagawa K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol 2006;24:3657 –63. 5. Adjei AA. Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. Clin Cancer Res 2004;10:4276s – 80s. 6. Hanna N, Shepherd FA, Fossella FV, 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;22:1589 –97. 7. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 2009;14:253– 63. 8. Gridelli C, Kaukel E, Gregorc V, et al. Single-agent pemetrexed or sequential pemetrexed/gemcitabine as front-line treatment of advanced non-small cell lung cancer in elderly patients or patients ineligible for platinum-based chemotherapy: a multicenter, randomized, phase II trial. J Thorac Oncol 2007;2:221 –9. 9. Weiss GJ, Langer C, Rosell R et al. Elderly patients benefit from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of pemetrexed compared with docetaxel in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2006;24:4405 –11. 10. Abe T, Yokoyama A, Takeda K, et al. Randomized phase III trial comparing weekly docetaxel (D)-cisplatin (P) combination with triweekly D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): an intergroup trial of JCOG0803/WJOG4307L. ASCO Meeting Abstracts 2011;29:7509. 11. Quoix E, Zalcman G, Oster JP, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 2011;378:1079–88.
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meet our expectations, either. These findings may suggest that pemetrexed monotherapy lacks efficacy as a first-line treatment in this population. In recent years, there have been reports of studies that investigate the potential of platinum-based combination therapy used in front-line treatment on elderly. According to a report by Quoix et al. (11), combination therapy with carboplatin and weekly paclitaxel improved OS significantly better than gemcitabine or vinorelbine. They also reported, though, that combination therapy increases toxicity, i.e. careful attention should be paid to the higher incidence of treatment-related death among the combination therapy group (4.4%) over that in the monotherapy group (1.3%). Furthermore, the JCOG0803/WJOG4307L study failed to show that the MST of the weekly docetaxel – cisplatin group (13.3 months, 95% CI 10.8 – 19.4 months) exceeds that of the docetaxel group (14.8 months, 95% CI 11.9 – 24.1 months). Based on the foregoing, we thought that it is premature to consider the platinum doublet as standard treatment for 75 years elderly patients. Our study did not meet its primary endpoint, and thus pemetrexed monotherapy should not be recommended to elderly patients aged 75 years with advanced NSCLC. Docetaxel monotherapy remains the standard, and further studies are necessary in this patient population.
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