A multi-center, Phase II trial of nab-paclitaxel and gemcitabine in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy

Abstract

Background

Nanoparticle albumin-bound paclitaxel (nab-PTX) plus gemcitabine (GEM) significantly improved overall survival in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between GEM and nab-PTX was recently demonstrated in a mouse model. We planned to assess the efficacy and safety of the combination of nab-PTX + GEM in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Methods

Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m²) + GEM (1000 mg/m²) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS).

Results

Of the 28 patients enrolled, all were evaluable for response and toxicity. The median age was 68 years (range 47–79), and 23 were male and 5 female. The histologic subtypes were: adenocarcinoma in 19 patients, and squamous cell carcinoma in 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were second line and 4 patients were third line. The median number of cycles administered was 4 (range 1–10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6–4.1). Adverse events were generally tolerable except grade 3 interstitial pneumonia with in 4 patients (14.3%).

Conclusion

The efficacy of nab-PTX in combination with GEM in advanced second or third-line NSCLC patients was limited and the frequent occurrence of interstitial pneumonia was unacceptable.

Introduction

Recent progress in the treatment of advanced non-small cell lung cancer (NSCLC) has been remarkable. The development of immunotherapy resulted in a paradigm shift in NSCLC therapy.^1–3 Now, platinum-doublet plus immune checkpoint inhibitors (ICIs) therapy is standard in the first-line therapy for patients with advanced NSCLC. But, probably most of the patients will become worse and need to have next chemotherapy. In the second-line therapy, cytotoxic chemotherapy is still considered a key treatment for patients with advanced NSCLC. And even if disease progression does occur, many patients will still have a good performance status (PS) and can be considered for further active cytotoxic treatment. Docetaxel (DTX) plus ramucirumab (RAM) is one of second-line standard therapy, but some patients cannot receive RAM therapy because it is not adapted for RAM use.⁴

An albumin-bound formulation of PTX, nanoparticle albumin-bound paclitaxel (nab-PTX), can be administered more safely and with higher efficacy than solvent-based paclitaxel (sb-PTX).⁵ It is superior to sb-PTX because it can be administered to patients who are hypersensitive to solvents or alcohol, and it allows for shorter infusion times without necessitating steroid prophylaxis. Nab-PTX and CBDCA (nab-PC group) demonstrated a significantly higher ORR than PTX and CBDCA (sb-PC group) (33% vs 25%) in a Phase III trial in advanced NSCLC.⁶ In addition, a safety profile of nab-PTX was well tolerated. The nab-PC regimen produced less severe neuropathy, neutropenia, myalgia, and arthralgia compared with sb-PC group.

Recently, in patients with metastatic pancreatic adenocarcinoma, nab-PTX plus gemcitabine (GEM) was shown to significantly improve overall survival, although GEM has been the standard first-line treatment since 1997.⁷ Moreover, the significant activity and favorable toxicity profile of the nab-PTX plus GEM combination was documented in patients with metastatic breast cancer.⁸

To study the efficacy and safety of nab-PTX plus GEM combination therapy for advanced NSCLC, we conducted a multi-center Phase II trial of nab-paclitaxel (100 mg/m²) + gemcitabine (1000 mg/m²) on days 1 and 8 of each 3-week cycle for NSCLC patients who had been treated previously with platinum-based chemotherapy.

Materials and methods

Patients and treatment

Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) PS of 0–1, as well as adequate kidney, liver and bone marrow function were eligible. Patients were also required to have measurable legions as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria were: previous treatment with nab-PTX, PTX or GEM; interstitial pneumonia recognized on chest-computed tomography (CT) scan. Treatment consisted of nab-paclitaxel (100 mg/m²) + gemcitabine (1000 mg/m²) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred, as assessed by the investigator.

Before enrollment, this study was approved by the ethics committee of Kobe University and each institution as a multicenter Phase II trial. The trial has been registered under University Medical Hospital Information Network (UMIN) Clinical Trials Registry Identifier UMIN 000017010. The protocol was approved through institutional ethical review boards each of the participating institutes, and all patients were provided written informed consent before treatment. The study was conducted in accordance with the ethical principles in the Declaration of Helsinki.

Clinical analyses

The primary endpoint was progression-free survival (PFS). Overall response (ORR), the disease control ratio (DCR), overall survival (OS) and adverse events also were evaluated as secondary endpoints. CT scans of the chest and the abdomen, and magnetic resonance imaging (MRI) studies or CT scans of the brain, and positron emission tomography (PET)-CT studies were performed for tumor assessment within 28 days of initiation of the study treatment. Tumor measurements were assessed with CT scans. CT scans were repeated with every 2 cycles until PD. Tumor assessments were done at baseline, then every 2 cycles until PD. Objective tumor responses were based on the RECIST version1.1. Toxicity evaluations were based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0.

Statistical analyses

The study was designed as a prospective, multicenter, single-arm Phase II study. In light of the previous data, we assumed that PFS of 4.0 months in eligible patients would indicate potential usefulness, while PFS of 2.0 months would be the lower limit. A total of 25 assessable patients were required with one-sided significance level of 5% and power of 80%. Taking ineligible patients into account, the sample size was set at 28. PFS and OS were analyzed using Kaplan–Meier method to estimate the median points with 95% CIs. Objective RR and DCR rates were calculated. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan, version 1.37), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 3.3.2).⁹

Results

From May 2015 to May 2017, a total of 28 patients from 3 institutions were enrolled in the study, and all of these subjects were evaluated for their therapeutic responses and drug toxicity. Baseline characteristics of the subjects are summarized in Table 1. The median age was 68 years (range 47–79 years), 23 subjects (82.1%) were male, and 17 (60.7%) had a PS of 1. The histopathology subtypes diagnosed included 19 adenocarcinomas (67.9%) and 9 squamous cell carcinomas (32.1%). Twenty-four patients (85.7%) were given second-line treatment and 4 (14.3%) were given third-line treatment.

Table 1.

Patient characteristics

Patient characteristics		Total number =28
Age (median, range)		68 (47–79)
Sex	Female	5 (18%)
Male	23 (82%)
ECOG PS	0	11 (39.2%)
1	17 (75.6%)
Smoking history	Never smoker	5 (18%)
Current or ex-smoker	23 (82%)
Histology	Adenocarcinoma	19 (68%)
Squamous cell carcinoma	9 (32%)
Clinical stage	Stage IIIA	1 (4%)
	Stage IIIB	5 (18%)
	Stage IV	18 (64%)
Postoperative recurrence	4 (14%)
EGFR mutation status	Deletion in exon19	5 (18%)
	Exon 21 L858R	3 (11%)
Wild-type/Unknown	18/2 (64%/7%)
Number of prior regimens	1 regimen	24(86%)
2 regimens	4 (14%)
Prior chemotherapy	CDDP + VNR	1 (4%)
	CDDP + PEM ± BEV	10 (36%)
	CDDP + S-1	3 (11%)
	CBDCA + PEM ± BEV	5 (18%)
	CBDCA + S-1	6 (21%)
DTX	3 (11%)

The median number of cycles administered was 4 (range 1–10). The median follow-up time was 9.5 months (range 2.0–22.6 months). The overall response rate was 17.9% (Table 2). The disease control rate was 67.9%. Median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6–4.1) (Figure 1A). The median overall survival was 11.7 months (95% CI, 8.0–19.3 months) (Figure 1B).

Table 2.

Tumor response

Response	Number of patients	%
CR	0	0
PR	5	17.8
SD	14	50.0
PD	9	32.2
RR	5	17.8
DCR	19	67.9

Abbreviations: RR, response rate; DCR, disease control rate.

Figure 1.

(A) Kaplan–Meier plots of progression-free survival. (B) Kaplan–Meier plots of overall survival.

The adverse events that occurred are shown in Table 3. Five subjects (17.9%) had grade 4 neutropenia, 4 (14.3%) had grade 3 anemia and 3 (10.7%) had grade 3 thrombocytopenia, but none of the subjects developed febrile neutropenia. No treatment-related deaths occurred. Non-hematologic toxic effects included interstitial pneumonia (IP, grade 3) in 4 subjects (14.3%), neuropathy (with grade 1) in 2 (7.1%) and infections (with grade 3) in 2 subjects (7.1%).

Table 3.

Adverse events

Adverse event	All grades (%)	G3 (%)	G4 (%)
Leukopenia	85.7	28.6	0
Neutropenia	71.4	28.6	17.9
Anemia	64.3	14.3	0
Thrombocytopenia	64.3	10.7	0
Albumin decreased	35.7	0	0
ALT increased	46.4	10.7	0
AST increased	42.9	7.1	0
Total bilirubin increased	14.3	0	0
Creatinin increased	14.3	0	0
Interstitial pneumonia	14.3	14.3	0
Febrile neutropenia	0	0	0
Fatigue	71.4	3.6	0
Decreased appetite	60.7	7.1	0
Nausea	25	3.6	0
Vomiting	10.7	3.6	0
Diarrhea	10.7	0	0
Constipation	42.9	0	0
Fever	50	0	0
Infection	17.9	7.1	0
Peripheral neuropathy	46.4	7.1	0
Arthralgia	21.4	0	0
Mucositis/Stomatitis	14.3	0	0
Pruritus	17.9	0	0
Rash	14.3	0	0
Alopecia	46.4	0	0
Allergic reaction	10.7	0	0

Discussion

This Phase II study failed to show significant therapeutic efficacy by the combination nab-PTX with GEM as second- or third-line therapy in patients with advanced NSCLC. However, this is the first report of examination of the combination nab-PTX with GEM in NSCLC. Non-platinum combinations had been considered as alternative regimens for those who cannot tolerate platinum-based chemotherapy in the first-line setting.^10–12 Kosmidis et al showed that non-platinum combinations of PTX and GEM had similar efficacy and safety compared to platinum doublet chemotherapy (median time to progression; 6.3 months vs 6.1 months) and the toxicity profile was similar for both. Gillenwater et al also reported that weekly PTX and GEM was an active and well-tolerated combination for advanced NSCLC in first-line settings.¹³ Moreover, nab-PTX can be administered more safely and with higher efficacy than sb-PTX.⁵ Contrary to expectations, the PFS of this present study was similar to that of DTX monotherapy.^14,15 Our study did not meet the primary endpoint. There might be a difference between first-line treatment and second- or third-line treatment. For example, PFS of DTX monotherapy was reported 5.5 months in first line¹⁶ and 2–2.5 months in second line.^14,15

In patients with pancreatic adenocarcinoma, this nab-PTX plus GEM combination therapy has been taken in place of single GEM with significantly improved overall survival and significant activity in patients with metastatic breast cancer as well.^7,8 There is also a possibility of a difference in effect in the various carcinomas.

Regarding safety, the incidence of IP was high. Severe IP with GEM is reported to occur in 0–5% of the patients with solid tumors and up to 13.8% in NSCLC pretreated patients.¹⁷ It was reported that combination nab-PTX + GEM treatment increases intratumoral GEM levels as a result of a marked decrease in the activity of primary GEM metabolizing enzymes.¹⁸ It might be suggested that IP appeared more frequently as the concentration of GEM increased. On the other hand, the prevalence of IP in pancreatic cancer patients treated with nab-PTX + GEM was reported as only 4%.⁷ The varying incidence of IP in lung cancer and pancreatic cancer might reflect the presence of lung disorders or some inflammation such as emphysema in lung cancer patients.

In analysis of ICIs, although it was the examination of the patient to whom the ICIs were administered, pneumonitis occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease than in those without (5.4% vs 3.1%).¹⁹

We excluded patients whose IPs are recognized on chest CT scan. But, all four patients who developed IP had lung abnormalities, such as 4 findings like bronchitis and 1 severe emphysema. These abnormal findings in the background lung except lung cancer may suggest a possible risk factor for IP occurrence.

Conclusion

The efficacy of nab-PTX in combination with GEM in advanced second- or third-line NSCLC patients was limited and the high rate of development of interstitial pneumonia was unacceptable.

Data availability

The overview of this trial has been registered under UMIN Clinical Trials Registry Identifier (UMIN 000017010). Individual patient data are confidential and thus they cannot be made publicly available.

Disclosure

Dr Nobuyuki Katakami reports personal fees from MSD, AstroZeneca, Ono Pharma, Taiho Pharma, Daiichi-Sankyo Pharma, Chugai Pharma, Eli Lilly, Boehringer-Ingelheim and Pfizer, outside the submitted work. Dr Yoshihiro Nishimura reports grants from Taiho Pharmaceutical Co., Ltd and Eli Lilly Japan K.K., during the conduct of the study. The authors report no other conflicts of interest in this work.