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Cancer Investigation, 33:241–245, 2015

ISSN: 0735-7907 print / 1532-4192 online


Copyright 
C 2015 Informa Healthcare USA, Inc.
DOI: 10.3109/07357907.2015.1024318

ORIGINAL ARTICLE

A Randomized Phase II Study of Erlotinib Plus Nab-Paclitaxel Versus


Erlotinib Alone as Second-Line Therapy for Chinese Patients with
Advanced EGFR Wild-Type Non-Small-Cell Lung Cancer
Yong Zhang, Chao Gao, Wei Qu, Yongsheng Gao, Shouhui Zhu, Shuo Zhang, Wei He,
and Yonghua Yu
Department of Radiation Oncology, Shandong Tumor Hospital and Institute, Jinan, China
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7.9 months in erlotinib-treated patients (9). Thus, given the


ABSTRACT
positive result from this study and several other clinic trials,
Erlotinib is a standard second-line therapy for patients with erlotinib has been approved as both first-line and second-line
advanced non-small-cell lung cancer (NSCLC). However, its chemotherapy for patients with NSCLC who have EGFR mu-
efficacy for those patients with epidermal growth factor tated tumors (10–12).
receptor (EGFR) wild-type (WT) tumors is undecided. In this However, most NSCLC patients rather have EGFR wild-
randomized phase II study, NSCLC patients with EGFR-WT type (WT) tumors, than EGFR-mutated tumors. It is not clear
tumors, who had been treated with platinum-based whether erlotinib is efficient in treating NSCLC patients with
chemotherapy but still developed disease progression, were EGFR-WT tumors, as conflicting results were shown in the
assigned to receive second-line treatment of erlotinib plus studies (13–15).
For personal use only.

nab-paclitaxel or erlotinib alone. We found PFS and OS were Nanoparticle albumin bound (nab-) paclitaxel is an
significantly improved by erlotinib plus nab-paclitaxel. The albumin-bound formulation of paclitaxel, thus can be used
adverse events were also well tolerable. as solvent-free option for the first-line chemotherapy for
patients with advanced NSCLC. Clinic trials of first-line
Keywords: NSCLC, EGFR, Erlotinib, Nab-paclitaxel
chemotherapy have shown that, while combined with car-
boplatin, nab-paclitaxel resulted in significantly better sur-
INTRODUCTION vivals in patients with advanced NSCLC, than solvent-based
Lung cancer is one of the most frequently diagnosed cancers paclitaxel (16–18). Nab-paclitaxel was also demonstrated to
in the world, accounting for ∼15% of the total new cancer be effective in second-line chemotherapy for patients with
cases and ∼20% of the cancer related deaths every year (1). pancreatic cancer (19, 20), bladder cancer (21), or gastric can-
Non-small-cell lung cancer (NSCLC) is the most common cer (22). However, no study has been reported on using nab-
lung cancer form, accounting for more than 75% of the to- paclitaxel as second-line treatment options for patients with
tal cases (2). Patients with NSCLC, once diagnosed, are often NSCLC.
at advanced stages (3). The standard first-line treatment for In the present randomized phase II study, we assessed the
those patients is platinum doublet chemotherapy (4, 5), yet efficacy and safety of erlotinib plus nab-paclitaxel, compared
disease progression is unavoidable. with erlotinib alone, as second-line treatment for patients
For the patients with NSCLC who experience failure of with NSCLC who have EGFR-WT tumors.
first-line chemotherapy, three drugs, docetaxel, pemetrexed,
and erlotinib, have been approved for second-line treatment
MATERIALS AND METHODS
(6–9). While all three drugs appear to be effectively prolong-
ing patients’ progression free survival or overall survival (OS) Study Protocol and Treatment Plan
in second-line treatment, erlotinib, a small molecular epider- In this randomized phase II study, all studies and treatments
mal growth factor receptor (EGFR) tyrosine kinase inhibitor, were performed in the Department of Radiation Oncology
is shown to be specifically efficient in treating NSCLC pa- at Shandong Tumor Hospital and Institute, Jinan, China. All
tients with EGFR mutated tumors. Study showed that median procedures were approved by the Medical Ethics and Clin-
survival was improved from 3.7 months in placebo patients to ical Study Review Committee at the Tumor Hospital and

Yong Zhang and Chao Gao contributed equally to this work.


Correspondence to: Yonghua Yu, MD, Department of Radiation Oncology, Shandong Tumor Hospital and Institute, 440 JiYan Road, Jinan
250117, China. E-mail: yonghua yu@aol.com
Received 20 October 2014; accepted 25 February 2015.


 Y. Zhang et al.

Institute. All patients had written consent forms. They had Table 1. The Demographics and Disease Characteristics of the
recurrence or progression after failing first-line platinum- Patients with Advanced NSCLC who have EGFR-WT Tumors
based chemotherapy. EGFR mutations were examined by Erlotinib/Nab- Erlotinib Alone
genotyping through amplification-refractory mutation sys- Characteristic Paclitaxel (N = 45) (N = 43)
tem (ARMS) protocol (23). The patients with EGFR muta- Age (years)
tions were then excluded from the study. The clinical stages Median 55.3 54.6
were classified according to the Revision of International Sys- Range 29–72 25–71
Sex, no. (%)
tem for Staging Lung Cancer (24). The primary endpoints in Male 23 (51%) 24 (56%)
the present study were progression-free survival (PFS), the Female 22 (49%) 19 (44%)
secondary endpoints were OS, response rates (RR), safety, ECOG performance status, no. (%)
and drug tolerability. 0.1 42 (93%) 41 (95%)
Patients were randomly assigned to receive erlotinib 2 3 (7%) 2 (5%)
Histology no. (%)
plus nab-paclitaxel or erlotinib alone. Randomization was Squamous 7 (16%) 6 (14%)
stratified among sex, Eastern Cooperative Oncology Group Adenocarcinoma 34 (76%) 35 (81%)
(ECOG) performance status and smoking history. Patients Large-cell carcinoma 1 (1%) 1(1%)
were given orally administered erlotinib at a dose of 150 mg Bronchoalveolar 1 (1%) 0 (0%)
every day. If patients experienced grade 3 or 4 toxicities, dose Others 2 (7%) 1 (1%)
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Smoking history, no. (%)


was reduced to 100 mg. Nab-paclitaxel was intravenously ad- Current and former 35 (78%) 31 (72%)
ministered at 100 mg/m2 on days 1 and 8, every 21 days. Never 10 (22%) 12 (28%)
If patients experienced grade 3 or 4 toxicities, dose was re- Best response to first-line chemotherapy, no. (%)
duced to 75 mg/m2 . In addition, patients with grade 3 or 4 Complete response 0 (0%) 0 (0%)
toxicities were also given vitamin B12 and dexamethasone Partial response 17 (38%) 20 (47%)
Stable disease 15 (30%) 18 (42%)
to counter toxicities. Treatment continued until disease pro- Progressive disease 13 (29%) 13 (30%)
gression, death, or a request by patients or their families to
terminate. Further treatments were consulted by the physi-
cians and patients, thus not recorded in the present study.
unstratified log-rank test; significance level 10%). PFS and
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Patients OS were estimated by Kaplan–Meier models. Statistical com-


Between March 2012 and February 2014, 88 eligible patients parisons between patients were conducted with a con-sided
with advanced NSCLC were enrolled in the Department of log-rank test. The hazard ratio (HR) was estimated with a
Radiation Oncology at Shandong Tumor Hospital and Insti- Cox proportional-hazards model, with 95% confidence in-
tute in Jinan, China. They were randomly assigned to two tervals (95% CIs) and p values.
treatment groups, erlotinib plus nab-paclitaxel group of 45
patients and erlotinib alone group of 43 patients. Patients RESULTS
were included if they were between 18 and 75 years, had an
ECOG performance status of 0–2, had stage III to IV ad- Patients and Treatment
vanced NSCLC, had EGFR-WT tumors, had been previously From March 2012 to February 2014, 88 patients with ad-
received platinum-based chemotherapy but failed, had ≥3 vanced NSCLC were enrolled in the Department of Radia-
months life-expectancy, had adequate bone marrow func- tion Oncology at Shandong Tumor Hospital and Institute in
tion (platelet count > 1011 /L, neutrophil count > 109 /L, and Jinan, China, of whom 45 were assigned to erlotinib plus nab-
hemoglobin > 90 g/L), had adequate liver and renal func- paclitaxel group and 43 to erlotinib alone group. The baseline
tions. characteristics were matched between two groups (Table 1).
The exclusion criteria were if patients had been pregnant, In both groups, more than 90% of the patients had ECOG
had previously received any EGFR inhibitor treatment, had performance status of 0 or 1, more than 70% of the patients
any major surgery within 6 months or any uncontrollable were current or former smokers, and the majority of the pa-
concurrent diseases. tients had adenocarcinoma. The cut-off date was February

Efficacy and Safety Assessments Table 2. Post-Study Treatment


The primary end point was progression free survival (PFS)
Erlotinib/Nab-Paclitaxel Erlotinib Alone
every 6 weeks as per Response Evaluation Criteria In Solid (N = 45) (N = 43)
Tumors (RECIST) criteria (WHO, version 1.0). The sec-
ondary endpoints were OS, RR, including complete and par- No. % No. %
tial responses, and safety every 12 weeks. Total 33 73 31 72
Pemetrexed 14 31 20 47
Statistical Analysis Gemcitabine 1 2 2 4
Vinorelbine 0 0 1 2
Based on a planned sample size of 88 patients, this study Docetaxel 18 40 8 19
was designed to have 85% power to detect an improvement Erlotinib 0 0 0 0
in median PFS from 3 months to 5.5 months (two-sided

Cancer Investigation
Erlotinib/nab-paclitaxe for NSCLC 
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Figure 1. (A) Progression-free survival and (B) overall survival were assessed by Kaplan–Meier curves for both groups.

20, 2014. The post-study treatment was listed in Table 2, as in erlotinib plus nab-paclitaxel group than in erlotinib alone
31% of the patients in the erlotinib plus nab-paclitaxel group group (25% for erlotinib plus nab-paclitaxel vs. 42% for er-
received pemetrexed, and 40% of them received docetaxel. lotinib alone, p < .05).
Among the patients in erlotinib alone patients, 47% of them
received pemetrexed, and 19% of them received docetaxel. Safety
The common AEs are listed in Table 4. The overall drug-
Efficacy related AEs were comparable between two groups (75% vs.
Due to disease progression or death, treatments (including 71%) without significant differences. The most common AEs
those during study and after study) were discontinued in 69% in erlotinib plus nab-paclitaxel group were rash (44%), fa-
(31/45) of the patients in erlotinib plus nab-paclitaxel group, tigue (31%), and headache (22%), whereas the most common
and 81% (35/43) of the patients in erlotinib alone group. The AEs in erlotinib alone group were fatigue (42%), rash (35%),
median PFS was 5.6 months (95% CI, 1.7–10.1 months) in and diarrhea (14%). The majority of the AEs in both groups
erlotinib plus nab-paclitaxel group, and 4.3 months (95% CI, were mild (grade 1 or 2). Some of the exceptions were, (1)
1.4–7.8 months) in erlotinib alone group, representing a 23% 22% of the patients in erlotinib plus nab-paclitaxel group, and
reduction in disease progression (hazard ratio, 0.24; 95% CI, 7% of the patients in erlotinib alone group had grade 3 or 4
0.14–0.74 [p < .05]) (Figure 1(A)). The median OS was 7.6
months (95% CI, 4.9–11.4 months) in erlotinib plus nab-
Table 3. Responses of the Patients
paclitaxel group, versus 5.2 months (95% CI, 3.0–9.8 months)
in erlotinib alone group, representing a 32% reduction in dis- Erlotinib/Nab-Paclitaxel Erlotinib Alone
(N = 45) (N = 43)
ease progression (hazard ratio, 0.68; 95% CI, 0.25–0.81 [p <
.05]) (Figure 1(B)). No. % No. %
The RR of patients were listed in Table 3. No patients Complete response 0 0 0 0
reached complete response. However, significantly more pa- Partial response∗ 15 33 8 19
tients had partial response in erlotinib plus nab-paclitaxel Stable disease 18 40 15 35
Progressive disease∗ 11 25 18 42
group than in erlotinib alone group (33% for erlotinib plus
Unknown 1 2 2 4
nab-paclitaxel vs. 19% for erlotinib alone, p < .05). Further- ∗
p < .05.
more, significantly fewer patients had progressive diseases

Copyright 
C 2015 Informa Healthcare USA, Inc.
 Y. Zhang et al.

Table 4. Adverse Events (AEs) for the Patients


Erlotinib/Nab-Paclitaxel (N = 45) Erlotinib Alone (N = 43)

AEs All Grades, No. (%) Grade 3 and 4, No. (%) All grades, No. (%) Grade 3 and 4, No. (%)
Rash 20 (44%) 10 (22%) 15 (35%) 3 (7%)
Diarrhea 8 (18%) 3 (7%) 6 (14%) 0 (0%)
Dry skin 5 (11%) 2 (4%) 3 (7%) 0 (0%)
Paronychia 5 (11%) 1 (2%) 2 (5%) 0 (0%)
Pruritus 3 (7%) 0 (0%) 2 (5%) 0 (0%)
Anorexia 5 (11%) 1 (2%) 5 (12%) 2 (5%)
Nausea 4 (9%) 0 (0%) 3 (7%) 0 (0%)
Constipation 2 (4%) 0 (0%) 2 (5%) 0 (0%)
Fatigue 14 (31%) 5 (11%) 18 (42%) 3 (7%)
Infection 1 (2%) 0 (0%) 2 (5%) 0 (0%)
Alopecia 5 (11%) 0 (0%) 3 (7%) 0 (0%)
Insomnia 7 (16%) 1 (2%) 4 (9%) 0 (0%)
Headache 10 (22%) 0 (0%) 5 (12%) 0 (0%)
Leukopenia 5 (11%) 1 (2%) 4 (9%) 1 (2%)
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rash, (2) 11% of the patients in erlotinib plus nab-paclitaxel plan for patients with advanced NSCLC who have EGFR-WT
group, and 7% of the patients in erlotinib alone group had tumors.
grade 3 or 4 fatigue. The most obvious difference between the two clinical tri-
als is the ethical background, as TAILOR trial was conducted
in Italy and the other phase II trial was in China (15, 25). If
DISCUSSIONS that is the case, the interpretation to the disparity between
In the present study, erlotinib plus nab-paclitaxel was com- these two trials could be that second-line chemotherapy is
pared with erlotinib alone as the second-line chemotherapy superior to erlotinib in treating western patients than Chi-
for NSCLC patients with EGFR-WT tumors. One may argue nese patients with NSCLC and EGFR-WT tumors. In our
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that, to better examine efficiency and safety of this new treat- study, we focused on Chinese patients and demonstrated that
ment, a controlled second-line therapy, such as nab-paclitaxel a combination second-line treatment plan including erlotinib
alone shall be conducted. We agree with this strategy in and chemotherapy regimen, nab-paclitaxel, resulted in bet-
general, but chose not to do so for the following reasons. ter PFS and OS than erlotinib alone in Chinese patients with
First, the majority of patients in the present study already NSCLC who have EGFR-WT tumors. These results are very
received first-line paclitaxel chemotherapy but still had dis- encouraging, since nab-paclitaxel has not been fully studied
ease progression. A repeated application of paclitaxel in as second-line treatment option for patients with advanced
second-line treatment would do little to improve patients’ NSCLC.
prognosis. In the present study, the median PFS reported in the er-
Second, there have been two recent clinical trials eval- lotinib alone group was 4.3 months, similar to the median
uating the efficacy and safety of erlotinib as second-line PFS of 4.1 months in previous phase II clinical trial (15).
chemotherapy for patients with advanced NSCLC who also This result suggests that the even the number of patients in
had EGFR-WT tumors, and the conclusions from those the present study (total of 88 patients, 45 with erlotinib plus
two studies are conflicting (15, 25). In the TAILOR trial, nab-paclitaxel vs. 43 with erlotinib alone), is smaller than the
Garassino and colleagues analyzed 222 patients, 110 to re- number of patients in previous trial (total of 123 patients,
ceive docetaxel versus 112 to receive erlotinib, from 52 Italian 62 with pemetrexed vs. 61 with erlotinib), the conclusion
hospitals with advanced NSCLC and WT EGFR tumors (25). of present study is unlikely to be confounded the sampling
They discovered that median OS was 8.2 months with doc- size. Thus, our results show better PFS and OS in erlotinib
etaxel versus 5.4 months with erlotinib, and median PFS was plus nab-paclitaxel group than in erlotinib along group (for
2.9 months with docetaxel versus 2.4 months with erlotinib. PFS, 5.6 months vs. 4.2 months, p < .05; for OS, 7.6 months
They concluded that docetaxel was significantly better than vs. 5.2 months, p < .05) would very likely to be the case
erlotinib in treating NSCLC patients with EGFR-WT tumors. even in a future study involving substantially larger patient
However, in another randomized phase II trial, Li and col- pool.
leagues examined erlotinib versus pemetrexed in second-line Also in the present study, the responses of AEs were com-
therapy for patients with advanced EGFR-WT and FISH- parable between two groups. The most common AEs in both
positive lung adenocarcinoma (15). They did not find signifi- groups included rash, fatigue, and diarrhea, which is in line
cant differences in PFS or OS between two treatment groups. with previous study showing these are the frequently oc-
Thus, the seemingly conflicting results from these two stud- curred toxicity among patients receive erlotinib (9, 12, 15,
ies suggest that more studies are needed. For that purpose, we 25). As expected, since nab-paclitaxel is superior to paclitaxel
chose to include erlotinib in the current study so we may have in solvent free form, the related AEs were very mild for pa-
better chance to identify the optimal second-line treatment tients receive erlotinib plus nab-paclitaxel.

Cancer Investigation
Erlotinib/nab-paclitaxe for NSCLC 

Overall, our study demonstrates that second-line treat- Erlotinib versus standard chemotherapy as first-line treatment
ment option of combining erlotinib and nab-paclitaxel is ef- for European patients with advanced EGFR mutation-positive
non-small-cell lung cancer (EURTAC): A multicentre, open-
ficient and safe for patients with advanced NSCLC who have label, randomised phase 3 trial. Lancet Oncol 2012;13(3):239–
EGFR-WT tumors. 246.
13. Garassino MC, Marsoni S, Floriani I. Testing epidermal growth
factor receptor mutations in patients with non-small-cell lung
DECLARATION OF INTEREST cancer to choose chemotherapy: The other side of the coin. J Clin
Oncol 2011;29(28):3835–3837; author reply 3837–3839.
The authors report no conflicts of interest. The authors alone 14. Laurie SA, Goss GD. Role of epidermal growth factor receptor in-
are responsible for the content and writing of the paper. The hibitors in epidermal growth factor receptor wild-type non-small-
study is supported by Shandong province science and tech- cell lung cancer. J Clin Oncol 2013;31(8):1061–1069.
nology development plan NO. 2014GSF118176. 15. 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
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