The IMPRESS trial found no benefit for continuing treatment with the epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor gefitinib (Iressa, discontinued in the United States) plus chemotherapy vs chemotherapy alone in patients with EGFR-mutated non–small cell lung cancer (NSCLC) who had disease progression on treatment with gefitinib. Progression was defined according to RECIST criteria in the IMPRESS trial, and not by clinical symptoms or metastatic spread.

Hotly Debated Issue

“This study resolves a hotly debated issue, and the results demonstrated that EGFR tyrosine kinase inhibitors should not be continued beyond progression. The standard treatment at progression remains platinum-based chemotherapy,” stated lead author Tony S.K. Mok, MD, Professor of Clinical Oncology at the Chinese University of Hong Kong, and the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.¹

EGFR tyrosine kinase inhibitors are the standard first-line treatment for patients with EGFR-positive NSCLC. Gefitinib is the EGFR tyrosine kinase inhibitor of choice in Asia and Europe, whereas erlotinib is used in the United States.

Most patients who initially respond to first-line therapy with an EGFR tyrosine kinase inhibitor experience disease progression with “acquired resistance.” At that time, there are two options: to discontinue the EGFR tyrosine kinase inhibitor or to continue it and combine it with platinum-based doublet chemotherapy, Dr. Mok explained.

Key Data

The IMPRESS trial included patients who achieved response greater than 4 months on standard gefitinib and then had disease progression less than 4 weeks prior to randomization. The study enrolled 265 patients from 71 centers in Europe and Asia Pacific. Patients were randomly assigned to cisplatin/pemetrexed (Alimta) plus gefitinib vs cisplatin/pemetrexed plus placebo.

At baseline, 65% were female and mean age was about 60. There was an imbalance in brain metastases, with 33% in the gefitinib arm and 23% in the chemotherapy arm. Also, the rate of complete responses to first-line treatment was higher in the chemotherapy arm: 76% for those receiving cisplatin/pemetrexed vs 68% for those receiving cisplatin/pemetrexed plus gefitinib.

Overall response rate was 31.6% for gefitinib vs 34.1% for chemotherapy alone, and the disease control rate was 84.2% vs 78.2%, respectively. Median progression-free survival (the primary endpoint) was identical in both groups: 5.4 months. No significant difference between treatment arms was found in any subgroup.

Overall Survival Findings

Overall survival data are immature, with only 33% of required events. Nevertheless, “because of a potential detrimental effect [of gefitinib], we feel obligated to share survival data with the audience,” Dr. Mok said. “Survival from the time of randomization is 14.8 months with gefitinib vs 17.2 months with chemotherapy. The hazard ratio is 1.62, and the difference is potentially significant,” he noted.

One possible explanation for this finding could be fewer brain metastases in the control arm, but a post hoc analysis found that there was still no benefit for gefitinib.

No significant difference between treatment arms was observed in rates of adverse events, serious adverse events, and events leading to death.

“IMPRESS is the only randomized phase III trial to compare continuation of gefitinib in combination with chemotherapy vs chemotherapy alone in patients with advanced ­EGFR-mutation positive NSCLC with resistance to first-line gefitinib. This study does not support continuation of gefitinib after disease progression by RECIST criteria on first-line gefitinib,” Dr. Mok stated. ■

Disclosure: Dr. Mok reported no potential conflicts of interest.

Reference

1. Mok TSK, Nakagawa W, Kim S, et al: Gefitinib/chemotherapy versus chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer after progression on first-line gefitinb: The phase III, randomized IMPRESS study. ESMO 2014 Congress. Abstract LBA2_PR. Presented September 28, 2014.