Open, randomized, multi-center phase II study comparing efficacy and tolerability of Erlotinib vs. Carboplatin/Vinorelbin in elderly patients (>70 years of age) with untreated non-small cell lung cancer
Introduction
Non-small cell lung cancer is a frequent cancer in the elderly population, with a peak in prevalence at the age of 74 to 79 years in men (approx. 400 cases per 100,000 people) and 80 to 84 years in women (100 cases per 100,000 people) in Germany [1].
Elderly patients did receive less systemic therapy compared to younger patients presumably because of concerns regarding toxicity. In one series, 75% of patients older than 66 years did not receive systemic therapy at all for advanced disease [2].
It could be shown, however, that elderly patients do benefit from systemic chemotherapy compared to best supportive care alone in terms of overall survival (relative risk [RR] of death 0.65; confidence interval [CI] 0.45–0.93) and quality of life [3].
Inhibition of the epidermal-growth factor receptor (EGFR) has become an established therapeutical approach in non-small cell lung cancer (NSCLC), especially in patients with a tumor harboring an activating mutation in the EGFR-gene.
Tyrosine-kinase inhibitors of EGFR (EGFR-TKI) were originally tested in larger populations without initial knowledge of the EGFR-mutational status and including squamous-cell cancers (a so called “all-comer” population). In these trials, EGFR-TKI proved to be superior to best supportive care in pre-treated patients [4], [5] and non-inferior to standard second-line chemotherapy [6]. Later, it was frequently stated, that this benefit in an unselected population was driven by undetected EGFR-mutated patients. However, in subgroup analyses, it could be shown that this benefit was observed in patients with squamous-cell cancers and heavy smokers as well—patient groups, where the presence of an activating EGFR-mutation is very unlikely. Subgroup analyses of an Erlotinib maintenance trial even showed efficacy in EGFR-wild type patients [7], [8].
EGFR-TKI lack hematologic toxicity, one of the greatest concerns in conventional chemotherapy, so it is a reasonable option for elderly patients who are at higher risk for comorbidity and thus complications from chemotherapy. Earlier phase-II studies suggested that Erlotinib might be effective in this setting. In a single-arm study, 53 patients received Erlotinib until disease progression. The non-progression rate at six weeks was 52.8% and the response rate was 22.7% [9].
This trial was undertaken to determine, whether the orally available EGFR-TKI Erlotinib is non-inferior to combination chemotherapy with Carboplatin and Vinorelbine in elderly patients.
Section snippets
Trial design
This study was planned as a randomised, multicenter phase II trial with the primary endpoint of progression-free survival (PFS). Secondary endpoints were overall survival (OS), quality of life (QoL) and response rate (RR).
The experimental group received 150 mg of Erlotinib daily orally until disease progression or inacceptable toxicity. The control group received Carboplatin AUC 5 on day one and Vinorelbine (25 mg/m2) on day one and eight of a 21 day cycle intravenous for a maximum of six cycles.
Patient recruitment
284 patients were screened and randomized. 144 patients were randomized to treatment arm A, 140 patients were randomized to treatment arm B (full-analysis-set). Nine patients (arm A: 1 patient, arm B: eight patients) did not start study treatment and were excluded from the safety-analysis-set (n = 275). Forty-six patients (arm A: 19 patients, arm B: 27 patients) were excluded from the per-protocol-analysis-set (n = 238) because of one or more of the following: insufficient study drug exposure
Discussion
In this trial we could not demonstrate non-inferiority of Erlotinib compared to a standard chemotherapy with Carboplatin and Vinorelbine. The EGFR-TKI arm was inferior in terms of the primary endpoint, PFS as well as RR. However, there was no difference in overall survival.
Another trial with a similar design (albeit not restricted to the elderly), the “Tarceva or chemotherapy” (TORCH)-study was also negative regarding Erlotinib as first-line treatment in NSCLC: In this study, treatment-naïve
Conflict of interest statements
DFH received Honoraria for Speeches and Travel reimbursements from Hoffmann-la Roche, Eli Lilly, Pfizer, Novartis, BMS and Boehringer Ingelheim. He is a Member of Advisory Boards for Hoffmann-la Roche, Pfizer, Eli Lilly and Boehringer Ingelheim.
WK is a Member of an Advisory Board for Eli-Lilly
MT Received Honoraria for Speeches from Astra Zeneca and Pfizer. He is a Member of Advisory Boards for Hoffmann-la Roche, Astra Zeneca, Eli-Lilly, Novartis and Pfizer.
MR received Honoraria for Speeches and
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Cited by (0)
- 1
On behalf of the AIO Working Group for Thoracic Oncology.