IMPRESS (NCT01544179) evaluated continuation of gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in patients (pts) with acquired resistance to 1st line gefitinib. Primary results (progression-free survival [PFS]) confirmed that continuing gefitinib in addition to cis/pem is of no clinical benefit. We present final OS data.
Pts (age ≥18 years, chemo-naïve, locally advanced/metastatic NSCLC with activating EGFR mutation, progression on 1st line gefitinib) from 61 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: PFS. Secondary endpoints included: OS and safety/tolerability. In pre-planned biomarker analyses, EGFR T790M mutation status was analysed via plasma circulating free tumour-derived DNA.
A total of 265 pts were randomised (G 133; P 132) and followed until 175 (66%) had died (16 Nov 2015); most deaths (G 65%; P 55%) were related to disease progression. Continuation of gefitinib plus cis/pem was detrimental to OS vs P (hazard ratio [HR] 1.44, p = 0.016). Subgroup data by plasma T790M mutation status showed HR 1.49 for T790M-positive and HR 1.15 for T790M-negative (Table). More pts randomised to P vs G (both n = 132; 71% vs 61%) received post-discontinuation therapy, with differing EGFR TKI exposure (36% vs 23%). Gefitinib plus cis/pem continued to be well tolerated, with no new unexpected safety findings.
Final IMPRESS OS data indicate that pts with acquired resistance to 1st line gefitinib should not continue to receive the TKI plus doublet chemotherapy beyond progression, due to the observed detrimental effect on OS. Exploratory plasma biomarker analyses suggest that this effect may be driven by T790M-positive status; inconclusive data in the T790M-negative subgroup warrant further investigation.
|OS||n/N||HR||95% CI||Median OS (months), G vs P|
|Overall||G 94/133; P 82/132||1.44||1.07, 1.94||13.4 vs 19.5|
|Overall with additional covariates|
|Presence/absence of brain metastases and T790M mutation status (positive/negative/unknown) at baseline||G 94/133; P 82/132||1.31||0.97, 1.77||-|
|Subgroup (mutation status by baseline plasma sample)|
|T790M mutation-positive||G 63/81; P 44/61||1.49||1.02, 2.21||10.8 vs 14.1|
|T790M mutation-negative||G 27/46; P 30/59||1.15||0.68, 1.94||21.4 vs 22.5|
|T790M informativea||G 11/19; P 20/31||0.93||0.42, 1.94||18.4 vs 19.5|
|T790M non-informativeb||G 13/24; P 10/28||1.59||0.69, 3.77||25.8 vs NC|
Clinical trial identification
Legal entity responsible for the study
J-C. Soria: Advisor for/honoraria received from: AstraZeneca, Eli Lilly, Genentech-Roche, MSD, Merck Serono, BMS, Pfizer, Taiho, Boehringer Ingelheim, Novartis Pharmaceuticals, GSK, Clovis Oncology Inc, Amgen Inc, Janssen, Servier and Sanofi. Y-L. Wu: Speaker fees from: AstraZeneca, Roche, Eli Lilly, Pfizer, Sanofi. K. Nakagawa: Consultant fees from: AstraZeneca, Eli Lilly. J-J. Yang: Hon. fees: AZ, Boehringer Ingelheim, Eli Lilly, Pfizer, Roche; advisor: Astellas, AZ, Bayer, Boehringer Ingelheim, Celgene, Clovis Oncology, Daiichi-Sankyo, Eli Lilly, Merck, MSD, Novartis, Pfizer, Roche/Genentech; research funding: Boehringer Ingelheim. M-J. Ahn: Advisor/consultant for: AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly; research funding: AstraZeneca, Eli Lilly. J. Wang: Consultant fees from: AstraZeneca, Eli Lilly, Pfizer, Roche, Sanofi. J.C-H. Yang: Advisory board for Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astrazeneca, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene, innopharma, Merrimack. Y. Lu: Consultant fees from: AstraZeneca, Eli Lilly, Roche, Pfizer; research funding: AstraZeneca, Pfizer. S. Atagi: Honoraria/consultant fees from: AstraZeneca, Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Taiho Pharmaceutical Co., Boehringer Ingelheim, Pfizer Japan Inc. Y. Rukazenkov: Employee of AstraZeneca and holds shares in AstraZeneca. R. Taylor: Contractor to AstraZeneca. T.S.K. Mok: Advisor/honoraria:AZ, Roche, Eli Lilly, Merck, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK, Clovis, Amgen, Janssen, BioMarin; speaker bureau:AZ, Roche, Eli Lilly, Boehringer Ingelheim, Merck, Pfizer, Amgen; research funding: AZ. All other authors have declared no conflicts of interest.