Elsevier

Lung Cancer

Volume 67, Issue 1, January 2010, Pages 86-92
Lung Cancer

Cetuximab and gemcitabine in elderly or adult PS2 patients with advanced non-small-cell lung cancer: The cetuximab in advanced lung cancer (CALC1-E and CALC1-PS2) randomized phase II trials

https://doi.org/10.1016/j.lungcan.2009.03.021Get rights and content

Abstract

Background

Two parallel randomized phase 2 trials were performed to choose the optimal way of combining cetuximab with gemcitabine in the first-line treatment of elderly (CALC1-E) and adult PS2 (CALC1-PS2) patients with advanced NSCLC.

Methods

Stage IV or IIIB NSCLC patients, aged ≥70 years with PS 0–2 for CALC1-E or aged <70 with PS2 for CALC1-PS2, not selected for EGFR expression, were eligible. Patients were randomized to concomitant (gemcitabine, for a maximum of 6 cycles, plus cetuximab until progression) or sequential (gemcitabine, for a maximum of 6 cycles, followed by cetuximab) strategy. A selection design, with 1-year survival rate as the primary endpoint, was applied, requiring 58 elderly and 42 PS2 patients.

Results

All planned patients were randomized. In sequential arms, 34.5% and 60.0% patients were not able to receive cetuximab after gemcitabine in CALC1-E and CALC1-PS2, respectively. Survival rates (95% CI) at 1-year for concomitant and sequential arms were 41.4% (23.5–61.1) and 31.0% (15.3–50.8) in CALC1-E and 27.3% (10.7–50.2) and 35.0% (15.4–59.2) in CALC1-PS2. In both studies, survival curves crossed at about 10 months and the worse arm until that time became the better one at 1-year. Toxicity was similar across treatment groups. In concomitant arm of CALC1-E (but not of CALC1-PS2), survival was longer for patients who developed skin toxicity within the first two cycles of treatment.

Conclusion

In both groups of patients, sequential strategy cannot be proposed for future trials because of low compliance. Inconsistency of survival outcomes makes also concomitant treatment not a candidate for further testing in unselected elderly and PS2 NSCLC patients.

Introduction

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in Western countries [1]. At diagnosis, the majority of patients have metastatic disease, two thirds of them are older than 65, while about 15% have a performance status (PS) 2 [2].

Single-agent chemotherapy with vinorelbine or gemcitabine can be recommended for elderly advanced NSCLC patients [3], [4], [5], [6]. For PS2 patients there is no widely accepted standard treatment; evidences on the efficacy of platinum-based treatment are contrasting, due to high risk of toxicity, and single-agent chemotherapy is among accepted standards of treatment [7], [8], [9]. Therefore, for both elderly and PS2 patients new treatment strategies to improve their prognosis are needed.

Signalling pathways involved in cell proliferation, apoptosis, angiogenesis, and metastasis are being investigated as possible therapeutic targets [10], [11], [12]. Cetuximab is a chimeric human–mouse anti-EGFR monoclonal antibody that blocks cell proliferation and cell cycle progression, inhibits tumor-induced angiogenesis, and enhances apoptosis [13]. A potentiation of the antitumoral activity by adding cetuximab to chemotherapy has been suggested, partly due to the increased expression of EGFR induced by cytotoxic drugs, prompting studies of combination of cetuximab with platinum-based therapy and with docetaxel [14], [15], [16], [17].

However, the most appropriate strategy to combine cetuximab with chemotherapy in elderly or PS2 patients is not defined. A reasonable approach is the concomitant administration of cetuximab and chemotherapy that might yield synergistic effects, with acceptable tolerability [18]. Another option is to give cetuximab sequentially after the end of chemotherapy, avoiding eventual negative interaction between EGFR inhibition and chemotherapy that is suggested in some preclinical models [19].

The aim of the CALC1 project was to select the most promising modality for combining cetuximab with gemcitabine (concomitant vs sequential) as first-line treatment, in two separate phase 2 studies in elderly and PS2 patients with advanced NSCLC.

Section snippets

Study design

We conducted two parallel multicenter randomized phase 2 studies in elderly (CALC1-E) and adult PS2 (CALC1-PS2) patients (hereby reported as PS2 for simplicity) with advanced NSCLC, to select a concomitant (gemcitabine plus cetuximab) or sequential (gemcitabine followed by cetuximab) strategy to be evaluated in phase 3 trials (ClinicalTrials.gov ID: NCT00330746). Rate of patients alive at 1 year was the primary endpoint. The two studies had a similar selection design [20], with a 90%

Elderly patients (CALC1-E)

From November 2005 to June 2006, 58 elderly patients were randomized to concomitant or sequential treatment (29 patients for each arm). The majority were male (72.1%), with PS 0–1 (87.9%), stage IV (81%), former or current smoker (84.5%). Stage IIIB and never smokers were slightly more frequent in the sequential arm (Table 1).

In the concomitant arm all patients received cetuximab; 5 patients remained in maintenance after the end of chemotherapy. Median number of cetuximab administrations was 8

Discussion

CALC1 aimed to select the best combination of cetuximab and gemcitabine (concomitant or sequential) in elderly and PS2 patients with advanced NSCLC. The study showed that sequential strategy cannot be proposed for future trials because of low compliance, but the inconsistency of survival outcomes also makes concomitant treatment possibly not a candidate for further testing in unselected elderly and PS2 NSCLC patients.

The interpretation of results, indeed, is difficult for several reasons: the

Conflicts of interest

C. Gridelli and F. Ciardiello disclose consultant or advisory relationship with Merck-Serono.

C. Verusio discloses travel grants by Merck-Serono.

A. Morabito, V. Gebbia, M. Mencoboni, F. Carrozza, M.G. Viganò, R. Bollina, R. Mattioli, M.R. Valerio, G. Valmadre, P. Maione, A. Rossi, T. Cascone, F. Morgillo, M. Di Maio, M.C. Piccirillo, C. Gallo, F. Perrone have no conflict of interest to disclose.

Acknowledgments

The study was supported by: Merck-Serono, Italy, that supplied cetuximab and contributed a grant for trial coordination, without being involved in plan, conduction and analysis of the study; Health Minister finalized project FSN 2004. The Clinical Trials Unit of National Cancer Institute of Napoli and Medical Statistic Unit of Second University of Napoli are partially supported by the no-profit “Associazione Italiana per la Ricerca sul Cancro” (AIRC).

The authors thank: all the patients who

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    1

    Contributed equally.

    2

    On behalf of the CALC1 (Cetuximab in Advanced Lung Cancer study) Investigators (see Appendix A for the complete list of coauthors).

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