Intercalated erlotinib/chemotherapy shows mixed results in NSCLC

By Joanna Lyford, Senior medwireNews Reporter

A study comparing erlotinib alone with erlotinib intercalated with chemotherapy has failed to demonstrate a clear advantage of the combination strategy when used to treat relapsed patients with non-small-cell lung cancer (NSCLC), Dutch researchers report.

Nevertheless, the investigators say that intercalated therapy deserves further study in view of promising secondary analyses and its theoretical benefits, preferably with chemotherapy being continued beyond four cycles, as in their study.

The phase II study by Joachim Aerts (Amphia Hospital, Breda, the Netherlands) and team investigated a possible synergistic effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and chemotherapy given in an intercalated manner, in order to achieve pharmacodynamic separation.

They recruited 231 patients with advanced NSCLC who had progressive disease despite chemotherapy. Patients were randomly assigned to receive treatment with erlotinib 150 mg/day as monotherapy or an intercalated regimen of erlotinib 150 mg/day on days 2 to 16 every 21 days with docetaxel 75 mg/m² (for squamous histology) or pemetrexed 500 mg/m² (for nonsquamous) on day 1 for four cycles.

The median follow-up duration was 19 months, during which time 78 (77%) patients died, mostly due to disease progression.

Writing in the Annals of Oncology, Aerts et al report that median progression-free survival was 4.9 months with erlotinib monotherapy and 6.1 months with combination treatment. This difference was not statistically significant although there was a trend in favor of combination treatment, with an adjusted hazard ratio (HR) of 0.76.

Overall survival was 5.5 months with monotherapy and 7.8 months with combination therapy; this difference was statistically significant with an adjusted HR of 0.67. Rates of disease control were also significantly greater with combination therapy versus monotherapy (54% vs 39%).

Subgroup analysis found that the advantage of combination therapy on overall survival was restricted to patients with nonsquamous tumors; the treatment effect did not differ between patients with wild-type EGFR and those with unknown EGFR status, however.

Toxicity was significantly greater in the combination therapy group, with a frequency of grade 2 or higher adverse events of 55% versus just 19% in the monotherapy group. There were no treatment-related deaths.

The authors say that although their study failed to demonstrate a significant benefit of combination treatment on the primary endpoint, there was a significant benefit on overall survival.

“The intermittent dosing schedule of erlotinib is designed to overcome the potential antagonism between cytotoxic chemotherapy and EGFR TKIs,” the authors remark.

They add: “To optimize the synergistic effect, it can be hypothesized that chemotherapy should be continued beyond four cycles.”

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