Original Research
Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non–small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study

https://doi.org/10.1016/j.ejca.2020.02.022Get rights and content

Highlights

  • Prognosis of patients with advanced non–small-cell lung cancer (NSCLC) is poor.

  • Few options beyond platinum-based chemo and immunotherapy in non-squamous (ns) NSCLC.

  • Phase III trial of bevacizumab-paclitaxel (wPB) or docetaxel in 2nd/3rd line nsNSCLC.

  • wPB improved progression-free survival and objective response rate.

  • Safety profile was manageable and Quality of Life was preserved with wPB.

Abstract

Purpose

Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non–small-cell lung cancer (nsNSCLC).

Methods

In this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671.

Results

One hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44–0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8–30·3) and 5·5% (95% CI: 0·0–11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group).

Conclusion

Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population.

Clinical trials registration number

ClinicalTrials.gov Identifier: NCT01763671.

Section snippets

Evidence before this study

  • -

    Limited efficacy of systemic treatments for patients with advanced non–small-cell lung cancer (NSCLC) beyond first-line therapy

  • -

    Bevacizumab has activity in non-squamous NSCLC (nsNSCLC) and was approved in first-line therapy combined with chemotherapy by Food and Drug Administration (FDA) and European Medicines Agency (EMA)

  • -

    Bevacizumab add-on to weekly paclitaxel first-line therapy has almost doubled the response rate and the progression-free survival (PFS), with a favourable safety profile in

Background

During the last decades, new combined therapies have contributed to improve outcomes in patients with advanced NSCLC in the first-line setting. More recently, immune checkpoint inhibitors (ICIs) given alone or in combination with chemotherapy have been shown to prolong survival compared with chemotherapy given alone in selected patients [[1], [2], [3], [4], [5]]. However, the vast majority of patients experience further disease progression which requires subsequent therapy [6]. Drugs usually

Study design

This double-arm, randomised, open-label, multicentre, phase III clinical trial was conducted in patients with pre-treated advanced nsNSCLC. Patients were allowed to crossover to the other arm after disease progression over the study. This study was approved by a local ethics committee (CPP Nord-Ouest III, France) and complied with French legislation, Good Clinical Practices and the principles outlined in the latest version of the Declaration of Helsinki. After approvals, the study was

Patients' disposal and characteristics

A total of 166 randomised patients [wPAC-BEV group: 111 (67%), DOC group: 55 (33%)] were included between May 31, 2013 and August 13, 2014. Among this ITT population, two patients withdrew before their first wPAC-BEV cycle, leading to a safety population based on 164 patients (Fig. 1).

Patients' characteristics were balanced between treatment groups (Table 1). The majority of patients (69%) received only one previous line of chemotherapy and 31% had been previously exposed to bevacizumab

Discussion

Weekly paclitaxel combined with bevacizumab as second- or third-line therapy demonstrated superiority over docetaxel in terms of PFS, the primary end-point, with a 38% risk reduction in disease progression, and ORR (22·5% and 5·5%, respectively) in a population of patients with advanced nsNSCLC. No superiority of paclitaxel plus bevacizumab was observed on OS. However, the optional crossover design of the study may have impacted this result as more docetaxel-treated patients crossed over after

Contributors

The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Funding

The study is supported by Roche (supplying bevacizumab and unrestricted grant).

Role of the funding source

The study was sponsored by Intergroupe Francophone de Cancérologie Thoracique (IFCT). Roche (Boulogne Billancourt, France) supplied bevacizumab and a complementarygrant but had no role in the study design, conduct of the study and data analysis and had no other involvement in the study. The study was also supported by the French National Cancer Institute(INCa) and French League Against Cancer.

Conflict of interest statement

A.B.C. has reported receiveing honoraria from Roche, AstraZeneca, Bristol-Myers Squibb, BoehringerIngelheim, MSD, Novartis and Pfizer and travel grants from Roche, AstraZeneca, BoehringerIngelheim, Novartis and Pfizer. C.A.V. has reported receiving grants, personal fees and non-financial support from Roche. O.M. has received personal fees from BMS, BoehringerIngelheim, Astra Zeneca, Novartis and Hoffman-Roche. F.B. has received personal fees from Astra Zeneca, BMS, BoehringerIngelheim, Clovis

Acknowledgements

The authors thank AUXESIA (M-O. Barbaza) for writing and editing support.

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