Med Oncol (2015) 32:216 DOI 10.1007/s12032-015-0660-5
ORIGINAL PAPER
A phase II open-label clinical study of comparing nab-paclitaxel with pemetrexed as second-line chemotherapy for patients with stage IIIB/IV non-small-cell lung cancer Zhefeng Liu1 • Zhimin Wei1 • Yi Hu1 • Feng Gao3 • Lu Hao2 • Ping Fang1 Shengjie Sun1 • Jinyu Li1 • Shunchang Jiao1
•
Received: 6 June 2015 / Accepted: 19 June 2015 / Published online: 14 July 2015 Ó Springer Science+Business Media New York 2015
Abstract Current choices of second-line chemotherapy regimens for patients with advanced non-small-cell lung cancer (NSCLC) are extremely limited. We applied a new strategy of using nab-paclitaxel as single chemotherapy regimen in second-line setting for patients with unsuccessful first-line chemotherapy. The efficacy and safety were compared with patients who received standard second-line regimen pemetrexed. Patients with stage IIIB/IV NSCLC and unsuccessful first-line platinum-based chemotherapy were randomly divided into two arms. Arm I received pemetrexed 500 mg/m2 intravenously (i.v.) on day 1 of 3-week cycle. Arm II received nab-paclitaxel 150 mg/m2 i.v. on days 1 and 8 of 3-week cycle. The primary endpoint was overall survival (OS). One hundred and eleven patients were randomly assigned to receive pemetrexed (n = 56) and nab-paclitaxel (n = 55). Median OSs were 9.4 months (95 % CI 7.1–12.5 months) for pemetrexed and 9.9 months (95 % CI 8.2–11.9 months) for nab-paclitaxel. Median PFS was 4.6 months (95 % CI 2.7–6.1 months) for pemetrexed and 5.1 months (95 % CI 3.9–7.4 months) for nab-paclitaxel. While no CR was reported for either treatment, PRs ? SDs were seen in 32/56 (57.1 %) patients in pemetrexed arm and 36/55
& Shunchang Jiao [email protected] 1
Department of Oncology, General Hospital of Chinese PLA, 28 Fuxing Road, Beijing 100853, China
2
Department of Medical Statistics, General Hospital of Chinese PLA, 28 Fuxing Road, Beijing 100853, China
3
Health Division of Guard Bureau, General Staff Department of Chinese PLA, 81 Nanchang Street, Beijing 100017, China
(65.5 %) patients in nab-paclitaxel arm. Grade 3 and grade 4 adverse events were comparable between two treatment arms. New second-line chemotherapy single-regimen nabpaclitaxel showed equivalent efficacy and toxicity profiles as pemetrexed in treating patients with NSCLC. Keywords Nab-paclitaxel Pemetrexed NSCLC Chemotherapy
Introduction Lung cancer is one of the most commonly diagnosed cancers in both male and female patients [1]. In the USA in 2014, the number of lung cancer new cases was estimated to be around quarter million, and the expected numbers of lung cancer mortality were close to 160,000 [1]. More than 80 % of the lung cancer cases can be accounted as non-small-cell lung cancer (NSCLC), which includes squamous-cell carcinoma, large cell carcinoma, and adenocarcinoma. Given the fact that most patients diagnosed with NSCLC are already at advanced stages and often progressing after first-line treatment, standard treatment strategy usually involves second-line chemotherapy [2, 3]. While combination chemotherapy failed to improve patients’ prognosis [4], clinic trials showed that several single chemotherapy regimens, including erlotinib, pemetrexed, docetaxel, and gefitinib, could improve patients’ survivals in second-line chemotherapy settings [5–8]. In a randomized clinic trial, docetaxel, at dosage of 75 mg/m2, improved overall survival from 4.6 to 7.5 months, while comparing with supportive care in second-line treatment [7]. In another randomized trial, erlotinib improved patients’ overall survival from 4.7 months (placebo) to 6.7 months in secondor third-line chemotherapy [6]. Gefitinib and pemetrexed,
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while comparing with docetaxel, showed comparable clinical outcomes [5, 8], but with better toxic profiles [5]. Nanoparticle albumin bound (nab) paclitaxel (nab-paclitaxel) is the solvent-free, 130-nm format of paclitaxel. It has shown superior safety and efficiency in treating patients with breast caner or pancreatic cancer [9, 10]. In first-line chemotherapy for patients with NSCLC, nab-paclitaxel also showed improvements on patients’ survival and adverse events while combining with platinum compounds such as cisplatin or carboplatin [11–13]. Interestingly, two new studies demonstrated that patients with NSCLC could also benefit from nab-paclitaxel either as single regimen or in combination with erlotinib in secondline chemotherapy [14, 15]. However, since those reports are fairly new with limited sample sizes, more clinic data are needed to explore optimal treatment strategy for the application of nab-paclitaxel in second-line NSCLC chemotherapy (Fig. 1).
Med Oncol (2015) 32:216
Patients and methods Patients Between December 2008 and January 2014, there were one hundred and eleven eligible patients participating in this study at the General Hospital of Chinese PLA in Beijing, China. Patients were included in the study if they were between 22 and 75 years old, had histologically or surgically confirmed advanced (stage IIIB/IV) NSCLC, had at least one measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) [16], had first-line platinum-based chemotherapy but still had progressing disease, had a life expectancy no shorter than 3 months, and had adequate renal, hepatic, or bone marrow functions. Patients were excluded if they had received prior treatments involving nab-paclitaxel or pemetrexed, were pregnant, had immunotherapy or radiotherapy within 1 month before enrollment, had major surgeries within 6 months before enrollment, or had other incurable diseases or tumor metastasis. The protocol of the study was designed based on the principles of Good Clinical Practice included in the Declaration of Helsinki, the WHO Good Clinical Practice Guidelines. In addition, all patients signed consent forms, and Ethics Committees at the General Hospital of Chinese PLA reviewed and approved all experimental paradigms, including treatment plan and clinic data collection, prior to the study enrollment.
Study design and treatment plan
Fig. 1 a Overall survivals and b progression-free survivals were plotted according to Kaplan–Meier method for NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
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This is a randomized, open-label phase II clinical study. One hundred and eleven eligible patients with stage IIIB/IV NSCLC and unsuccessful first-line platinum-based chemotherapy were randomly divided into two arms. Arm I (n = 55) received pemetrexed 500 mg/m2 intravenously (i.v.) on day 1 of 3-week cycle. Arm II (n = 56) received nabpaclitaxel 150 mg/m2 i.v. on days 1 and 8 of 3-week cycle. In addition, patients in both arms were provided with 4 mg dexamethasone plus 1 mg vitamin B12 to reduce toxicities. The treatments were continuously carried out until disease progression, intolerable toxicities, or discontinuation request. The primary endpoint was overall survival (OS), which was defined as time from the onset of treatment to death. Progression-free survival (PFS) was defined as time from the onset of treatment to progressive disease or death, whichever occurs earlier. Responses were assessed based on the guideline of RECIST (version 1.1) [16]. Toxicities or adverse events were estimated based on the guideline of National Cancer Institute’s Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) [17].
Med Oncol (2015) 32:216
Statistical analysis In our study, we compared the survivals and response rates between two second-line chemotherapy regimens, nab-paclitaxel and pemetrexed. The predefined overall hazard ratio of nab-paclitaxel versus pemetrexed was determined to be 0.6. Thus, considering the deviation proportion from positive assessment, a total number of 94 patients were assessed to be sufficient to provide 0.8 power with twosided significance level of 10 %. Kaplan–Meier methods were used to evaluate PFS and OS. Their statistic comparisons were performed with a log-rank test with 95 % confidence intervals (95 % CIs) and P values.
Results Patients Between December 2008 and January 2014, there were one hundred and eleven eligible patients participating in this study at the General Hospital of Chinese PLA in Beijing, China. They were randomly assigned to receive pemetrexed treatment (arm I, n = 56) or nab-paclitaxel treatment (arm II, n = 55) in an estimated 1:1 ratio. It showed that patients’ baseline characteristics were well balanced between two arms (Table 1). The median ages were 51.1 years for patients in arm I of pemetrexed treatment and 52.5 years for patients in arm II of nab-paclitaxel treatment. In arm I, thirty-four (60.7 %) patients were male. In arm II, thirty-seven (67.3 %) patients were male. Forty-five (80.4 %) patients had ECOG PS between 0 and 1 in arm I and forty (72.7 %) of them in arm II. For firstline chemotherapy, four (7.1 %) patients achieved either complete response (CR) or response (PR) in arm I and seven (12.7 %) of them in arm II. Efficacy The cutoff date of current study was February 17, 2015. Median OSs were 9.4 months (95 % CI 7.1–12.5 months) for pemetrexed and 9.9 months (95 % CI 8.2–11.9 months) for nab-paclitaxel. The difference of OSs between two treatment arms was not statistically significant (hazard ratio 1.23; 95 % CI 0.78–1.59; P = 0.712). Median PFSs were 4.6 months (95 % CI 2.7–6.1 months) for pemetrexed and 5.1 months (95 % CI 3.9–7.4 months) for nab-paclitaxel. Again, the difference of PFSs between two treatment arms was not statistically significant either (hazard ratio 1.12; 95 % CI 0.69–1.31; P = 0.848). The clinical responses for patients in two arms were compared (Table 2). No complete response was recorded in either of the treatment arms. PRs were seen in six (10.7 %) patients in pemetrexed arm
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and eight (14.5 %) patients in nab-paclitaxel arm. Stable diseases (SDs) were seen in 25 (44.6 %) patients in pemetrexed arm and 28 (50.9 %) patients in nab-paclitaxel arm. Progressive diseases (PDs) were seen in 22 (39.3 %) patients in pemetrexed arm and 15 (27.3 %) patients in nab-paclitaxel arm. Safety For safety profile, we compared grade 3 and grade 4 adverse events (AEs) between two treatment arms (Table 3). Overall, the incidence rates of severe toxicity were low in both arms. In arm I of pemetrexed treatment, the most occurred grade 3 and grade 4 AEs were rash (n = 4, 7.1 %), nausea (n = 2, 3.6 %), paronychia (n = 2, 3.6 %), anorexia (n = 2, 3.6 %), and thrombocytopenia (n = 2, 3.6 %). In arm II of nab-paclitaxel treatment, the most occurred grade 3 and grade 4 AEs were nausea (n = 3, 5.5 %), fever (n = 2, 3.6 %), anemia (n = 2, 3.6 %), and thrombocytopenia (n = 2, 3.6 %). Thus, it showed that nab-paclitaxel had a comparable tolerability as pemetrexed among patients with advanced NSCLC.
Discussion In our study, we conducted a randomized open-label phase II clinical investigation to directly compare the efficacy and safety profiles of nab-paclitaxel to pemetrexed as single regimen in second-line chemotherapy for patients with advanced NSCLC. Median OSs were 9.4 months (95 % CI 7.1–12.5 months) for pemetrexed and 9.9 months (95 % CI 8.2–11.9 months) for nab-paclitaxel. Median PFSs were 4.6 months (95 % CI 2.7–6.1 months) for pemetrexed and 5.1 months (95 % CI 3.9–7.4 months) for nab-paclitaxel. Statistical analysis confirmed that difference in OSs (hazard ratio 1.23; 95 % CI 0.78–1.59; P = 0.712) and PFSs (hazard ratio 1.12; 95 % CI 0.69–1.31; P = 0.848) was insignificant. In addition, the clinical responses were comparable between two treatment arms. PRs were 10.7 % for pemetrexed and 14.5 % for nab-paclitaxel. SDs were 44.6 % for pemetrexed arm and 50.9 % for nab-paclitaxel. Thus, these results demonstrated equivalent efficacy between pemetrexed and nab-paclitaxel, suggesting that nab-paclitaxel might be considered as a new second-line chemotherapy regimen in treatment patients with advanced NSCLC. While comparing the data of our study to previous ones, it seems like patients’ survivals for both pemetrexed and nab-paclitaxel are slightly better in our study than the survivals’ data in other studies. For pemetrexed, we observed OS of 9.4 months and PFS of 4.6 months in second-line chemotherapy for patients with advanced
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216 Page 4 of 6 Table 1 Baseline characteristics of NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
Med Oncol (2015) 32:216
Characteristics
Arm I, pemetrexed (n = 56)
Arm II, nab-paclitaxel (n = 55)
No.
No.
%
%
Age, years Median
51.1
52.5
Range
27–73
29–74
Sex Male
34
60.7
37
67.3
Female
22
39.3
18
32.7
0–1
45
80.4
40
72.7
2
11
19.6
15
27.3
Current Former
48 7
85.7 12.5
50 5
90.9 9.1
Never
1
1.8
0
0.0
32
57.1
27
49.1
Adenocarcinoma
23
41.1
27
49.1
Large cell carcinoma
1
1.8
1
1.8
ECOG PS
Smoking history
NSCLC histology Squamous-cell carcinoma
First-line chemotherapy responses CR/PR
4
7.1
7
12.7
SD
24
42.9
21
38.2
PD/unknown
28
50.0
27
49.1
ECOG PS Eastern Cooperative Oncology Group performance status; CR complete response; PR partial response; SD stable disease; PD progressive disease
Table 2 Clinical response of NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
Responses
CR
Arm I, pemetrexed (n = 56)
Arm II, nab-paclitaxel (n = 55)
No.
No.
0
% 0.0
%
0
0.0
PR
6
10.7
8
14.5
SD
25
44.6
28
50.9
PD
22
39.3
15
27.3
N/A
3
5.4
4
7.3
CR complete response; PR partial response; SD stable disease; PD progressive disease
NSCLC. In an international phase III trial, Hanna reported that pemetrexed achieved OS of 8.3 months and PFS of 2.9 months for NSCLC patients receiving second-line chemotherapy [5]. In another randomized phase II trial, Li reported that for NSCLC patients with wild-type EGFR lung adenocarcinoma, pemetrexed achieved PFS of 3.9 months in second-line setting [18]. For nab-paclitaxel, we observed OS of 9.9 months and PFS of 5.1 months in second-line chemotherapy for patients with advanced NSCLC. In a recent single-arm phase II clinical trial, Hu [15] reported that nab-paclitaxel achieved 6.8 months of OS and 3.5 months of PFS. There are several possible explanations. First, in Hanna’s [5] report, more than five
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hundred patients were pooled from ten countries and regions, and the baseline characteristics were well mixed among large number of patients. In our study, one hundred and eleven patients were all from one country. Therefore, study sample size or patients’ ethnic backgrounds may contribute to the difference in observed survivals. Second, patients seemed younger in our study, with median ages between 51 and 53 years (Table 1). The patients were around 55 years old in Li’s and Hi’s reports [15, 18] or close to 60 years old in Hanna’s report [5]. Therefore, the overall health conditions may contribute to better survivals in our study. Third, all patients in current study received 4 mg dexamethasone plus 1 mg vitamin B12. In other
Med Oncol (2015) 32:216 Table 3 Adverse events (AEs) of NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
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Grade 3 and grade 4 AEs
Arm I, pemetrexed (n = 56)
Arm II, nab-paclitaxel (n = 55)
No.
%
No.
%
Nausea
2
3.6
3
5.5
Rash
4
7.1
2
3.6
Fever
1
1.8
2
3.6
Headache
1
1.8
1
1.8
Fatigue
0
0
0
0
Anemia
1
1.8
2
3.6
Constipation
0
0
1
1.8
Insomnia
0
0
0
0
Paronychia
2
3.6
1
1.8
Neutropenia
0
0
1
1.8
Anorexia Alopecia
2 1
3.6 1.8
1 1
1.8 1.8
Thrombocytopenia
2
3.6
2
3.6
Leukopenia
1
1.8
0
0
studies, only partial patients received supplements [5]. Thus, other supportive treatment might help improving patients’ prognosis. In conclusion, current clinical study demonstrated that nab-paclitaxel had clinically equivalent efficacy and safety of being second-line chemotherapy single regimen to treat patients with advanced NSCLC.
7.
8.
Compliance with Ethical Standards Conflict of interest
None. 9.
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216 Page 6 of 6 erlotinib alone as second-line therapy for Chinese patients with advanced EGFR wild-type non-small-cell lung cancer. Cancer Investig. 2015;33(6):241–5. doi:10.3109/07357907.2015.1024318. 15. Hu W, Zhang Z. A phase II clinical study of using nab-paclitaxel as second-line chemotherapy for Chinese patients with advanced non-small cell lung cancer. Med Oncol. 2015;32(6):498. 16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.
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Med Oncol (2015) 32:216 17. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN. CTCAE v3. 0: development of a comprehensive grading system for the adverse effects of cancer treatment. In: Seminars in radiation oncology. Elsevier; 2003. p. 176–181. 18. Li N, Ou W, Yang H, Liu QW, Zhang SL, Wang BX, Wang SY. A randomized phase 2 trial of erlotinib versus pemetrexed as second-line therapy in the treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Cancer. 2014;120(9):1379–86.
ORIGINAL PAPER
A phase II open-label clinical study of comparing nab-paclitaxel with pemetrexed as second-line chemotherapy for patients with stage IIIB/IV non-small-cell lung cancer Zhefeng Liu1 • Zhimin Wei1 • Yi Hu1 • Feng Gao3 • Lu Hao2 • Ping Fang1 Shengjie Sun1 • Jinyu Li1 • Shunchang Jiao1
•
Received: 6 June 2015 / Accepted: 19 June 2015 / Published online: 14 July 2015 Ó Springer Science+Business Media New York 2015
Abstract Current choices of second-line chemotherapy regimens for patients with advanced non-small-cell lung cancer (NSCLC) are extremely limited. We applied a new strategy of using nab-paclitaxel as single chemotherapy regimen in second-line setting for patients with unsuccessful first-line chemotherapy. The efficacy and safety were compared with patients who received standard second-line regimen pemetrexed. Patients with stage IIIB/IV NSCLC and unsuccessful first-line platinum-based chemotherapy were randomly divided into two arms. Arm I received pemetrexed 500 mg/m2 intravenously (i.v.) on day 1 of 3-week cycle. Arm II received nab-paclitaxel 150 mg/m2 i.v. on days 1 and 8 of 3-week cycle. The primary endpoint was overall survival (OS). One hundred and eleven patients were randomly assigned to receive pemetrexed (n = 56) and nab-paclitaxel (n = 55). Median OSs were 9.4 months (95 % CI 7.1–12.5 months) for pemetrexed and 9.9 months (95 % CI 8.2–11.9 months) for nab-paclitaxel. Median PFS was 4.6 months (95 % CI 2.7–6.1 months) for pemetrexed and 5.1 months (95 % CI 3.9–7.4 months) for nab-paclitaxel. While no CR was reported for either treatment, PRs ? SDs were seen in 32/56 (57.1 %) patients in pemetrexed arm and 36/55
& Shunchang Jiao [email protected] 1
Department of Oncology, General Hospital of Chinese PLA, 28 Fuxing Road, Beijing 100853, China
2
Department of Medical Statistics, General Hospital of Chinese PLA, 28 Fuxing Road, Beijing 100853, China
3
Health Division of Guard Bureau, General Staff Department of Chinese PLA, 81 Nanchang Street, Beijing 100017, China
(65.5 %) patients in nab-paclitaxel arm. Grade 3 and grade 4 adverse events were comparable between two treatment arms. New second-line chemotherapy single-regimen nabpaclitaxel showed equivalent efficacy and toxicity profiles as pemetrexed in treating patients with NSCLC. Keywords Nab-paclitaxel Pemetrexed NSCLC Chemotherapy
Introduction Lung cancer is one of the most commonly diagnosed cancers in both male and female patients [1]. In the USA in 2014, the number of lung cancer new cases was estimated to be around quarter million, and the expected numbers of lung cancer mortality were close to 160,000 [1]. More than 80 % of the lung cancer cases can be accounted as non-small-cell lung cancer (NSCLC), which includes squamous-cell carcinoma, large cell carcinoma, and adenocarcinoma. Given the fact that most patients diagnosed with NSCLC are already at advanced stages and often progressing after first-line treatment, standard treatment strategy usually involves second-line chemotherapy [2, 3]. While combination chemotherapy failed to improve patients’ prognosis [4], clinic trials showed that several single chemotherapy regimens, including erlotinib, pemetrexed, docetaxel, and gefitinib, could improve patients’ survivals in second-line chemotherapy settings [5–8]. In a randomized clinic trial, docetaxel, at dosage of 75 mg/m2, improved overall survival from 4.6 to 7.5 months, while comparing with supportive care in second-line treatment [7]. In another randomized trial, erlotinib improved patients’ overall survival from 4.7 months (placebo) to 6.7 months in secondor third-line chemotherapy [6]. Gefitinib and pemetrexed,
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216 Page 2 of 6
while comparing with docetaxel, showed comparable clinical outcomes [5, 8], but with better toxic profiles [5]. Nanoparticle albumin bound (nab) paclitaxel (nab-paclitaxel) is the solvent-free, 130-nm format of paclitaxel. It has shown superior safety and efficiency in treating patients with breast caner or pancreatic cancer [9, 10]. In first-line chemotherapy for patients with NSCLC, nab-paclitaxel also showed improvements on patients’ survival and adverse events while combining with platinum compounds such as cisplatin or carboplatin [11–13]. Interestingly, two new studies demonstrated that patients with NSCLC could also benefit from nab-paclitaxel either as single regimen or in combination with erlotinib in secondline chemotherapy [14, 15]. However, since those reports are fairly new with limited sample sizes, more clinic data are needed to explore optimal treatment strategy for the application of nab-paclitaxel in second-line NSCLC chemotherapy (Fig. 1).
Med Oncol (2015) 32:216
Patients and methods Patients Between December 2008 and January 2014, there were one hundred and eleven eligible patients participating in this study at the General Hospital of Chinese PLA in Beijing, China. Patients were included in the study if they were between 22 and 75 years old, had histologically or surgically confirmed advanced (stage IIIB/IV) NSCLC, had at least one measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) [16], had first-line platinum-based chemotherapy but still had progressing disease, had a life expectancy no shorter than 3 months, and had adequate renal, hepatic, or bone marrow functions. Patients were excluded if they had received prior treatments involving nab-paclitaxel or pemetrexed, were pregnant, had immunotherapy or radiotherapy within 1 month before enrollment, had major surgeries within 6 months before enrollment, or had other incurable diseases or tumor metastasis. The protocol of the study was designed based on the principles of Good Clinical Practice included in the Declaration of Helsinki, the WHO Good Clinical Practice Guidelines. In addition, all patients signed consent forms, and Ethics Committees at the General Hospital of Chinese PLA reviewed and approved all experimental paradigms, including treatment plan and clinic data collection, prior to the study enrollment.
Study design and treatment plan
Fig. 1 a Overall survivals and b progression-free survivals were plotted according to Kaplan–Meier method for NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
123
This is a randomized, open-label phase II clinical study. One hundred and eleven eligible patients with stage IIIB/IV NSCLC and unsuccessful first-line platinum-based chemotherapy were randomly divided into two arms. Arm I (n = 55) received pemetrexed 500 mg/m2 intravenously (i.v.) on day 1 of 3-week cycle. Arm II (n = 56) received nabpaclitaxel 150 mg/m2 i.v. on days 1 and 8 of 3-week cycle. In addition, patients in both arms were provided with 4 mg dexamethasone plus 1 mg vitamin B12 to reduce toxicities. The treatments were continuously carried out until disease progression, intolerable toxicities, or discontinuation request. The primary endpoint was overall survival (OS), which was defined as time from the onset of treatment to death. Progression-free survival (PFS) was defined as time from the onset of treatment to progressive disease or death, whichever occurs earlier. Responses were assessed based on the guideline of RECIST (version 1.1) [16]. Toxicities or adverse events were estimated based on the guideline of National Cancer Institute’s Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) [17].
Med Oncol (2015) 32:216
Statistical analysis In our study, we compared the survivals and response rates between two second-line chemotherapy regimens, nab-paclitaxel and pemetrexed. The predefined overall hazard ratio of nab-paclitaxel versus pemetrexed was determined to be 0.6. Thus, considering the deviation proportion from positive assessment, a total number of 94 patients were assessed to be sufficient to provide 0.8 power with twosided significance level of 10 %. Kaplan–Meier methods were used to evaluate PFS and OS. Their statistic comparisons were performed with a log-rank test with 95 % confidence intervals (95 % CIs) and P values.
Results Patients Between December 2008 and January 2014, there were one hundred and eleven eligible patients participating in this study at the General Hospital of Chinese PLA in Beijing, China. They were randomly assigned to receive pemetrexed treatment (arm I, n = 56) or nab-paclitaxel treatment (arm II, n = 55) in an estimated 1:1 ratio. It showed that patients’ baseline characteristics were well balanced between two arms (Table 1). The median ages were 51.1 years for patients in arm I of pemetrexed treatment and 52.5 years for patients in arm II of nab-paclitaxel treatment. In arm I, thirty-four (60.7 %) patients were male. In arm II, thirty-seven (67.3 %) patients were male. Forty-five (80.4 %) patients had ECOG PS between 0 and 1 in arm I and forty (72.7 %) of them in arm II. For firstline chemotherapy, four (7.1 %) patients achieved either complete response (CR) or response (PR) in arm I and seven (12.7 %) of them in arm II. Efficacy The cutoff date of current study was February 17, 2015. Median OSs were 9.4 months (95 % CI 7.1–12.5 months) for pemetrexed and 9.9 months (95 % CI 8.2–11.9 months) for nab-paclitaxel. The difference of OSs between two treatment arms was not statistically significant (hazard ratio 1.23; 95 % CI 0.78–1.59; P = 0.712). Median PFSs were 4.6 months (95 % CI 2.7–6.1 months) for pemetrexed and 5.1 months (95 % CI 3.9–7.4 months) for nab-paclitaxel. Again, the difference of PFSs between two treatment arms was not statistically significant either (hazard ratio 1.12; 95 % CI 0.69–1.31; P = 0.848). The clinical responses for patients in two arms were compared (Table 2). No complete response was recorded in either of the treatment arms. PRs were seen in six (10.7 %) patients in pemetrexed arm
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and eight (14.5 %) patients in nab-paclitaxel arm. Stable diseases (SDs) were seen in 25 (44.6 %) patients in pemetrexed arm and 28 (50.9 %) patients in nab-paclitaxel arm. Progressive diseases (PDs) were seen in 22 (39.3 %) patients in pemetrexed arm and 15 (27.3 %) patients in nab-paclitaxel arm. Safety For safety profile, we compared grade 3 and grade 4 adverse events (AEs) between two treatment arms (Table 3). Overall, the incidence rates of severe toxicity were low in both arms. In arm I of pemetrexed treatment, the most occurred grade 3 and grade 4 AEs were rash (n = 4, 7.1 %), nausea (n = 2, 3.6 %), paronychia (n = 2, 3.6 %), anorexia (n = 2, 3.6 %), and thrombocytopenia (n = 2, 3.6 %). In arm II of nab-paclitaxel treatment, the most occurred grade 3 and grade 4 AEs were nausea (n = 3, 5.5 %), fever (n = 2, 3.6 %), anemia (n = 2, 3.6 %), and thrombocytopenia (n = 2, 3.6 %). Thus, it showed that nab-paclitaxel had a comparable tolerability as pemetrexed among patients with advanced NSCLC.
Discussion In our study, we conducted a randomized open-label phase II clinical investigation to directly compare the efficacy and safety profiles of nab-paclitaxel to pemetrexed as single regimen in second-line chemotherapy for patients with advanced NSCLC. Median OSs were 9.4 months (95 % CI 7.1–12.5 months) for pemetrexed and 9.9 months (95 % CI 8.2–11.9 months) for nab-paclitaxel. Median PFSs were 4.6 months (95 % CI 2.7–6.1 months) for pemetrexed and 5.1 months (95 % CI 3.9–7.4 months) for nab-paclitaxel. Statistical analysis confirmed that difference in OSs (hazard ratio 1.23; 95 % CI 0.78–1.59; P = 0.712) and PFSs (hazard ratio 1.12; 95 % CI 0.69–1.31; P = 0.848) was insignificant. In addition, the clinical responses were comparable between two treatment arms. PRs were 10.7 % for pemetrexed and 14.5 % for nab-paclitaxel. SDs were 44.6 % for pemetrexed arm and 50.9 % for nab-paclitaxel. Thus, these results demonstrated equivalent efficacy between pemetrexed and nab-paclitaxel, suggesting that nab-paclitaxel might be considered as a new second-line chemotherapy regimen in treatment patients with advanced NSCLC. While comparing the data of our study to previous ones, it seems like patients’ survivals for both pemetrexed and nab-paclitaxel are slightly better in our study than the survivals’ data in other studies. For pemetrexed, we observed OS of 9.4 months and PFS of 4.6 months in second-line chemotherapy for patients with advanced
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216 Page 4 of 6 Table 1 Baseline characteristics of NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
Med Oncol (2015) 32:216
Characteristics
Arm I, pemetrexed (n = 56)
Arm II, nab-paclitaxel (n = 55)
No.
No.
%
%
Age, years Median
51.1
52.5
Range
27–73
29–74
Sex Male
34
60.7
37
67.3
Female
22
39.3
18
32.7
0–1
45
80.4
40
72.7
2
11
19.6
15
27.3
Current Former
48 7
85.7 12.5
50 5
90.9 9.1
Never
1
1.8
0
0.0
32
57.1
27
49.1
Adenocarcinoma
23
41.1
27
49.1
Large cell carcinoma
1
1.8
1
1.8
ECOG PS
Smoking history
NSCLC histology Squamous-cell carcinoma
First-line chemotherapy responses CR/PR
4
7.1
7
12.7
SD
24
42.9
21
38.2
PD/unknown
28
50.0
27
49.1
ECOG PS Eastern Cooperative Oncology Group performance status; CR complete response; PR partial response; SD stable disease; PD progressive disease
Table 2 Clinical response of NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
Responses
CR
Arm I, pemetrexed (n = 56)
Arm II, nab-paclitaxel (n = 55)
No.
No.
0
% 0.0
%
0
0.0
PR
6
10.7
8
14.5
SD
25
44.6
28
50.9
PD
22
39.3
15
27.3
N/A
3
5.4
4
7.3
CR complete response; PR partial response; SD stable disease; PD progressive disease
NSCLC. In an international phase III trial, Hanna reported that pemetrexed achieved OS of 8.3 months and PFS of 2.9 months for NSCLC patients receiving second-line chemotherapy [5]. In another randomized phase II trial, Li reported that for NSCLC patients with wild-type EGFR lung adenocarcinoma, pemetrexed achieved PFS of 3.9 months in second-line setting [18]. For nab-paclitaxel, we observed OS of 9.9 months and PFS of 5.1 months in second-line chemotherapy for patients with advanced NSCLC. In a recent single-arm phase II clinical trial, Hu [15] reported that nab-paclitaxel achieved 6.8 months of OS and 3.5 months of PFS. There are several possible explanations. First, in Hanna’s [5] report, more than five
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hundred patients were pooled from ten countries and regions, and the baseline characteristics were well mixed among large number of patients. In our study, one hundred and eleven patients were all from one country. Therefore, study sample size or patients’ ethnic backgrounds may contribute to the difference in observed survivals. Second, patients seemed younger in our study, with median ages between 51 and 53 years (Table 1). The patients were around 55 years old in Li’s and Hi’s reports [15, 18] or close to 60 years old in Hanna’s report [5]. Therefore, the overall health conditions may contribute to better survivals in our study. Third, all patients in current study received 4 mg dexamethasone plus 1 mg vitamin B12. In other
Med Oncol (2015) 32:216 Table 3 Adverse events (AEs) of NSCLC patients receiving second-line chemotherapy of pemetrexed or nab-paclitaxel
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Grade 3 and grade 4 AEs
Arm I, pemetrexed (n = 56)
Arm II, nab-paclitaxel (n = 55)
No.
%
No.
%
Nausea
2
3.6
3
5.5
Rash
4
7.1
2
3.6
Fever
1
1.8
2
3.6
Headache
1
1.8
1
1.8
Fatigue
0
0
0
0
Anemia
1
1.8
2
3.6
Constipation
0
0
1
1.8
Insomnia
0
0
0
0
Paronychia
2
3.6
1
1.8
Neutropenia
0
0
1
1.8
Anorexia Alopecia
2 1
3.6 1.8
1 1
1.8 1.8
Thrombocytopenia
2
3.6
2
3.6
Leukopenia
1
1.8
0
0
studies, only partial patients received supplements [5]. Thus, other supportive treatment might help improving patients’ prognosis. In conclusion, current clinical study demonstrated that nab-paclitaxel had clinically equivalent efficacy and safety of being second-line chemotherapy single regimen to treat patients with advanced NSCLC.
7.
8.
Compliance with Ethical Standards Conflict of interest
None. 9.
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