Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non–small cell lung cancer

doi:10.1016/j.lungcan.2018.09.014

Lung Cancer

Volume 125, November 2018, Pages 136-141

https://doi.org/10.1016/j.lungcan.2018.09.014 Get rights and content

Highlights

•
Nab-paclitaxel at 50 mg/m² in concurrent phase was determined to be the RD.
•
Common toxicities of grade 3 or 4 in concurrent phase was leukopenia and neutropenia.
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The ORR was 76.8% and mPFS was 11.8 months in 56 patients treated at the RD.
•
Our results reveal encouraging feasibility and activity for this regimen.

Abstract

Objectives

Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC).

Patients and methods

In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m²) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL^–1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation.

Results

In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m², which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2–85.9%), median progression-free survival was 11.8 months (60% CI, 10.6–16.2 months; 95% CI, 8.2–20.8 months), and median overall survival was not reached.

Conclusion

Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m² and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.

Introduction

Lung cancer is the leading cause of cancer death worldwide [1], with stage III, locally advanced non–small cell lung cancer (NSCLC) accounting for ∼25% of all lung cancer cases [2]. The standard of care for such patients is platinum-based doublet chemotherapy with concurrent radiotherapy (chemoradiation) [3]. A recent phase III study showed that administration of durvalumab, an antibody to programmed cell death–ligand 1 (PD-L1), as a consolidative therapy after chemoradiation conferred a significant increase in progression-free survival (PFS) compared with a placebo control in patients with locally advanced NSCLC [4]. However, cytotoxic agents still play an important role in chemoradiation, and there is a demand for more effective and less toxic regimens.

Weekly solvent-based paclitaxel (sb-paclitaxel) plus carboplatin with concurrent radiotherapy is regarded as a standard treatment option for locally advanced NSCLC because of its favorable toxicity profile and efficacy [[5], [6], [7]]. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free, 130-nm particle form of paclitaxel. Compared with sb-paclitaxel, nab-paclitaxel yielded a 10-fold higher mean maximal circulating concentration of free paclitaxel and delivered a 33% higher drug concentration to tumors in preclinical xenograft models [8]. A phase III study found a significantly higher objective response rate (ORR) for weekly nab-paclitaxel at 100 mg/m² plus carboplatin at an area under the concentration-time curve (AUC) of 6 mg mL^–1 min once every 3 weeks compared with sb-paclitaxel at 200 mg/m² plus carboplatin at an AUC of 6 once every 3 weeks in patients with metastatic NSCLC [9]. The combination of nab-paclitaxel and carboplatin (nab-P/C) with concurrent radiotherapy thus seems a reasonable approach to the treatment of locally advanced NSCLC. Given that the optimal dosing and schedule for nab-P/C differ from those for sb-P/C, however, a dose-finding study for the combination of nab-P/C and concurrent radiotherapy has been needed. We performed the present phase I/II study of nab-P/C and concurrent radiotherapy to determine the recommended dose (RD) and to evaluate the safety and efficacy of this regimen in patients with locally advanced NSCLC.

Section snippets

Patient eligibility

Patients between 20 and 74 years of age with histologically or cytologically confirmed, unresectable NSCLC of stage IIIA or IIIB (based on the American Joint Committee on Cancer [AJCC] staging system 7th edition) were eligible for the study. Eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease, no previous chemotherapy or radiotherapy, no previous cancer surgery, a percentage of normal lung receiving at least 20 Gy (V20) of

Dose escalation

Eleven patients were enrolled in the phase I study, two of whom were excluded from analysis because of protocol violation (they did not receive the prescribed dose of nab-paclitaxel in the concurrent phase). Nine patients (eight men, one woman) with a median age of 61 years (range, 45 to 69 years) were deemed evaluable for DLT (Fig. 1). Six of these patients had a baseline ECOG performance status of 0, four had stage IIIA disease, and five had adenocarcinoma. DLT was not observed in the first

Discussion

Weekly sb-paclitaxel at 40–50 mg/m² plus carboplatin at an AUC of 2 combined with concurrent radiotherapy is regarded as a standard treatment for locally advanced NSCLC as a result of its favorable toxicity profile and efficacy [[5], [6], [7]]. However, many such treated patients eventually develop distant metastasis or local recurrence, resulting in poor prognosis. Chemoradiation regimens that are more effective are therefore needed to improve treatment outcome. A phase III study revealed a

Funding

This study was supported by Taiho Pharmaceutical Co. Ltd. under a study contract.

Conflicts of interest

H. Yamaguchi has received grants from MSD, Astellas Pharma, Kyorin Pharmaceutical, Shionogi, Daiichi Sankyo, Taisho Toyama Pharmaceutical, Sumitomo Dainippon Pharma, Pfizer, and Boehringer Ingelheim Japan. K. Hirano has received personal fees from AstraZeneca KK, Chugai Pharmaceutical, Eli Lilly, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Novartis. M. Satouchi has received grants and personal fees from Chugai Pharmaceutical, Eli Lilly Japan, AstraZeneca

Acknowledgments

We thank all patients and investigators who participated in this study.

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Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non–small cell lung cancer

Highlights

Abstract

Objectives

Patients and methods

Results

Conclusion

Introduction

Section snippets

Patient eligibility

Dose escalation

Discussion

Funding

Conflicts of interest

Acknowledgments

Respir. Med.

Global cancer statistics

CA Cancer J. Clin.

Therapeutic management options for stage III non-small cell lung cancer

World J. Clin. Oncol.

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer

N. Engl. J. Med.

Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: west Japan Thoracic Oncology Group WJTOG0105

J. Clin. Oncol.

Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol

J. Clin. Oncol.