Elsevier

European Journal of Cancer

Volume 75, April 2017, Pages 73-82
European Journal of Cancer

Original Research
Gemcitabine–erlotinib versus gemcitabine–erlotinib–capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group

https://doi.org/10.1016/j.ejca.2016.12.032Get rights and content

Highlights

  • Gemcitabine + erlotinib (GE) have a survival benefit in first-line mPC.

  • The addition of capecitabine to GE did not significantly increase PFS versus GE.

  • The presence of skin rash strongly predicted a survival benefit.

Abstract

Background

Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC.

Patients and methods

Previously untreated mPC patients were randomised to receive G (1000 mg/m2, days 1, 8, 15) + E (100 mg/day, days 1–28) + C (1660 mg/m2, days 1–21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety.

Results

120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine–erlotinib–capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58–1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72–1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26–0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33–0.77; p = 0.0014).

Conclusion

PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy.

The study was registered with ClinicalTrials.gov: NCT01303029.

Introduction

Pancreatic cancer is the eighth most common cancer in Europe, accounting for 3% of cancers in 2012 [1]. Survival is poor; 1-year survival has been estimated at 21% and less than 10% of pancreatic cancer patients survive for more than 5 years [2].

Since 1997, gemcitabine therapy has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer (mPC) [3]. Whereas many phase II studies evaluating combination chemotherapies in patients with advanced pancreatic cancer have shown promising results, most subsequent phase III studies have not shown significantly improved survival [for review see 4]. However, in 2007, the combination of gemcitabine plus erlotinib (GE) was shown to modestly, but statistically significantly, improve survival compared with gemcitabine alone, which was the primary objective of the study [5]. A phase III trial conducted by a French consortium study group in patients with metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) score of 0–1 found that the combination of 5-FU, folinic acid, oxaliplatin and irinotecan (FOLFIRINOX) was associated with a median increase in overall survival (OS) of 4.3 months compared with gemcitabine [6]. The MPACT study randomised 842 patients with mPC and a Karnofsky Index above 70% to either gemcitabine or gemcitabine plus nab-paclitaxel and reported significantly increased OS (8.5 versus 6.7 months) and progression-free survival (PFS) (5.5 versus 3.7 months) with the combination [7].

In addition, the combination of gemcitabine and capecitabine has shown to be more effective than gemcitabine alone in patients with mPC and a good performance status [8], and a phase II study has shown the triplet combination of gemcitabine–erlotinib–capecitabine (GEC) to be effective and tolerable in this setting [9]. Hence, the aim of the present study was to compare the safety and effectiveness of the first-line treatment with the triple combination of GEC with GE doublet therapy in patients with mPC.

Section snippets

Study design and patients

This was a phase IIb, open-label, randomised, two-arm, active comparator study. Patients with histologically or cytologically confirmed, measurable, metastatic pancreatic adenocarcinoma, aged ≥18 years and with an ECOG performance status 0–2 were eligible for inclusion in the study. Patients were required to have adequate bone marrow, liver and renal function and to be able to take oral medication.

Exclusion criteria included the history of another primary neoplasm in the 5 years before study

Results

Between April 2011 and February 2013, 120 patients were recruited at 23 centres in Spain; 60 patients were randomised to the GE arm and 60 to the GEC arm. All patients were eligible for inclusion in the efficacy analyses. Two patients did not receive any treatment; therefore, the safety population comprised 118 patients (Fig. 1).

Patient characteristics for the ITT population are shown in Table 1. For both the ITT and PP populations, the two treatment groups were generally comparable although

Discussion

The results of this phase IIb study by the Spanish TTD Group have shown that triplet chemotherapy with GEC was no more effective than doublet GE in patients with advanced pancreatic cancer. This is the first randomised study to examine the efficacy of triplet therapy containing erlotinib with an erlotinib-based doublet regimen.

Treatment with GEC was less effective than expected based on the results of the previous phase II study by Oh et al [9], who reported a PFS of 6.5 months and an OS of

Funding

This study was funded by Roche Pharma, Spain. The editorial support was provided by Miller Medical Communications Ltd, funded by Roche Pharma, Spain.

Conflict of interest statement

F. Rivera has an advisory relationship and has received honoraria and research funding from Roche and Celgene; T. García has received honoraria and travel expenses to medical meetings from Roche; E. Aranda has received honoraria for an advisory role from Amgen, Bayer, Celgene, Merck, Roche and Sanofi; M. Benavides and E. Aranda have received honoraria for advisory roles from Amgen, Bayer, Celgene, Merck, Roche and Sanofi. The other authors have no conflicts of interest.

Acknowledgements

The physicians listed below cared for the patients in this study. The authors thank them for their co-operation and support:

Study Chairs: M. Benavides (H. R. U. de Málaga) and A. Irigoyen (C.H. Toledo).

J. Gallego (H. G. U. de Elche), C. Guillén Ponce (H. Ramón y Cajal), R. Vera (H. de Navarra), V. Iranzo (H. G. U. de Valencia), I. Alés (H. R. U. de Málaga), S. Arévalo (H. de Donostia), A. Pisa (C. S. Parc Taulí), M. Martín (H. Santa Creu i Sant Pau), A. Salud (H. Lleida Arnau de Vilanova), E.

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