IMPRESS trial data on continuing tyrosine kinase inhibitor therapy after resistance development in lung cancer reported

Patients whose lung cancer has developed resistance to the drug gefitinib experience no statistically significant improvement in progression-free survival from continued treatment with the drug in addition to chemotherapy, a phase III trial presented at the ESMO 2014 Congress has shown.

The IMPRESS trial is a randomised phase III study that compared continuation of gefitinib in addition to chemotherapy against chemotherapy alone in patients with lung cancer that carried mutations in the EGFR cell surface receptor.

Gefitinib is a type of drug known as a tyrosine kinase inhibitor, and it targets cells with EGFR mutations. Most patients with EGFR mutation-positive non-small cell lung cancer respond to first-line EGFR tyrosine kinase inhibitors, but later acquire resistance. The primary objective of the trial was to show whether there was a difference in progression-free survival when gefitinib was continued in this situation.

"This study was designed to resolve a greatly debated issue: whether tyrosine kinase inhibitors should be continued beyond progression," said study author Prof Tony Mok, a professor in the Department of Clinical Oncology at the Chinese University of Hong Kong. "As the result demonstrated no difference in progression-free survival, the standard treatment is chemotherapy alone."

This study helps to establish the standard of treatment, and in the future doctors should not prescribe EGFR tyrosine kinase inhibitors in combination with chemotherapy when cancers have progressed after first-line treatment with an EGFR tyrosine kinase inhibitor, Mok said.

The researchers had hoped that the study would show an improvement in progression-free survival, Mok said. "I suspected 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."

The IRESSA Mutation Positive Multicentre Treatment Beyond ProgRESsion Study included 265 patients from 71 centres in Europe and the Asia Pacific region who received chemotherapy plus either gefitinib or a placebo. There was no statistically significant improvement in progression-free survival - the primary endpoint of the study - for gefitinib versus placebo.

The overall survival data is still immature, Mok said, although there is a suggestion of better overall survival in the placebo group. "This needs to be monitored very closely in future," he said.

Commenting on the study, Dr Marina Garassino, a Medical Consultant at the Medical Oncology Division of the National Cancer Institute of Milan, said the results were "very robust and reliable, and they will help clinicians in their daily clinical practice."

"However, 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," Garassino noted.

"New generations of agents are now becoming available for specific resistance mutations with very promising results. It is therefore possible in the future that we will be able to personalise the further treatments for these patients."

Abstract: LBA2_PR

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, T.S.K. Mok, Y. Wu, K. Nakagawa, S. Kim, J. Yang, M. Ahn, J. Wang, J.C. Yang, Y. Lu, S. Atagi, S. Ponce, X. Shi, A. Webster, H. Jiang, J-C. Soria.

Aim: Most patients (pts) with EGFR mutation-positive NSCLC respond to 1st-line EGFR tyrosine kinase inhibitors, but later acquire resistance. The Phase III, double-blind IRESSA Mutation Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS; NCT01544179) evaluated the efficacy/safety of continuing gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in pts with acquired resistance to 1st-line gefitinib.

Methods: Pts (age ≥18 years [Japan ≥20 years], chemotherapy-naïve, locally advanced/metastatic NSCLC with an activating EGFR mutation, prior disease progression on 1st-line gefitinib) from 71 centres (Europe/Asia Pacific) were randomised to G or P (gefitinib 250 mg/day or placebo; plus cis 75 mg/m2/pem 500 mg/m2). Primary endpoint: progression-free survival (PFS). Secondary endpoints included: overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety/tolerability.

Results: 265 pts randomised (G=133; P=132). There was no statistically significant improvement in PFS for G vs P (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.65-1.13, p=0.273; median PFS 5.4 months each).OS was immature (33% of pts had died), with better OS for P vs G suggested (statistically significant difference: HR 1.62; CI 1.05-2.52, p=0.029). No treatment differences were found in ORR/DCR. Most common adverse events (AEs) in the safety population (G/P both n=132): nausea (64%/61%) and decreased appetite (49%/34%); no interstitial lung disease noted. G was associated with increased grade 1/2 gastrointestinal toxicities. AEs with outcome of death reported: with G, 2 casually-related to gefitinib and/or cis/pem; with P, 1 casually-related to cis/pem.

Conclusions: IMPRESS is the first and only randomised Phase III study to confirm continuation of gefitinib in addition to cis/pem would be of no clinical benefit for pts with acquired resistance to gefitinib; thus the standard of care should remain doublet chemotherapy alone. The safety profile for gefitinib plus cis/pem was in line with that known.

Disclosure: T.S.K. Mok: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK Biologicals, Clovis Oncology Inc, Amgen Inc, Janssen, BioMarin Inc, Roche, Eli Lilly, Merck Serono, Amgen International; Y. Wu: Speaker fees from: AstraZeneca, Roche, Eli Lilly, Pfizer, Sanofi, K. Nakagawa: Consultant fees from: AstraZeneca, Eli Lilly; S. Kim: Advisor for: Boehringer Ingelheim; ISS drug supply: AstraZeneca, Boehringer Ingelheim, Eli Lilly; M. Ahn: Advisor/consultant for: AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly; research funding: AstraZeneca, Eli Lilly; J.C. Yang: Advisory fees from: AstraZeneca, Roche, Genentech, Pfizer, Clovis; uncompensated advisor for: Boehringer Ingelheim, Eli Lilly; Y. Lu: Consultant fees from: AstraZeneca, Eli Lilly, Roche, Pfizer; research funding: AstraZeneca, Pfizer; S. Atagi: Honoraria/consultant fees from: Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Taiho Pharmaceutical Co., Boehringer Ingelheim, Pfizer Japan Inc.; X. Shi, A. Webster and H. Jiang: Employee of AstraZeneca and holds shares in AstraZeneca; J-C. Soria: Consultant fees from: AstraZeneca, Eli Lilly.

All other authors have declared no conflicts of interest.