No statistically significant improvement in progression-free survival from continued treatment with gefitinib after the development of resistance

The IMPRESS study is the first randomised phase III trial confirming that continuation of gefitinib in addition to pemetrexed/cisplatin is of no clinical benefit for patients with non-small cell lung cancer (NSCLC) and acquired resistance to gefitinib. These results were reported during the Presidential Symposium 1 at ESMO 2014 Congress by Prof. Tony Mok of the Clinical Oncology Department, The Chinese University of Hong Kong, Hong Kong, China.

The phase III, double-blind IRESSA Mutation Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS) evaluated the efficacy and safety of continuing gefitinib plus pemetrexed/cisplatin vs placebo plus pemetrexed/cisplatin in NSCLC patients with acquired resistance to first-line gefitinib. The study included 265 patients from 71 centres in Europe and the Asia Pacific region who received the chemotherapy regimen plus either gefitinib or placebo.

Most patients with EGFR mutation-positive non-small cell lung cancer respond to first-line EGFR tyrosine kinase inhibitors, but later acquire resistance. Optimal management for patients with acquired resistance has yet to be defined, and options include:

• Discontinuing EGFR TKI therapy and commencing platinum-based doublet chemotherapy
• Continuing EGFR TKI therapy in combination with platinum-based doublet chemotherapy.

The primary objective of the trial at hand was to show whether there would be a difference in PFS when gefitinib is continued in this situation. As such, this study was designed to resolve a greatly debated issue: whether tyrosine kinase inhibitors should be continued beyond progression. The researchers had hoped that the study would show an improvement in progression-free survival because they expected that the inhibition of TKI-sensitive cancer cells with continuation of gefitinib and inhibition of resistant cells with chemotherapy would optimize the treatment outcome. However, the study has proved otherwise. Patients with EGFR mutation-positive NSCLC whose cancer has developed resistance to gefitinib experience no statistically significant improvement in progression-free survival (PFS) from continued treatment with gefitinib in addition to chemotherapy (PFS for gefitinib vs. placebo: median PFS 5.4 months for both arms; HR[95%CI]: 0.86 [0.65-1.13], p = 0.273).

At the time of presentation, the overall survival (OS) date were immature, although there was a suggestion of better OS in the placebo group (HR[95%CI]: 1.62 [1.05-2.52], p = 0.029). No treatment differences were found in ORR/DCR.

The most common adverse events in the safety population (gefitinib / placebo; both N=132) were nausea (64%/61%) and decreased appetite (49%/34%). No interstitial lung disease was noted, but gefitinib was associated with increased grade 1/2 gastrointestinal toxicities.

IMPRESS is the first randomised Phase III study to confirm that continuation of gefitinib in addition to cisplatin/pemetrexed is of no clinical benefit for patients with acquired resistance to gefitinib. The IMPRESS study confirms that doublet chemotherapy should continue to be the standard of care for patients who develop resistance to first-line gefitinib. First-line EGFR TKI should be continued as long as possible and EGFR TKI should be subsequently rechallenged in the course of the disease. When possible, it is important to re-biopsy the patients when their tumours progress after treatment with tyrosine kinase inhibitors to understand the mechanism that underlies the resistance. New generations of agents are now becoming available for specific mutations with very promising results, enabling further individualization of treatment for these patients.

References

Mok T, Wu Y, Nakagawa K, et al. Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) after progression on first-line gefitinib: the Phase III, randomised IMPRESS study. Presented at ESMO 2014; Abstract LBA2.