Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

Koichi Azuma, Tomonori Hirashima, Nobuyuki Yamamoto, Isamu Okamoto, Toshiaki Takahashi, Makoto Nishio, Taizo Hirata, Kaoru Kubota, Kazuo Kasahara, Toyoaki Hida, Hiroshige Yoshioka, Kaoru Nakanishi, Shiro Akinaga, Kazuto Nishio, Tetsuya Mitsudomi, Kazuhiko Nakagawa

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. Methods This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. Results The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7...months (95% CI 1.4 to 4.2) and 18.0...months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4...months; mOS 20.7 vs 13.9...months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. Conclusions Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. Trial registration number NCT01580735.

Original languageEnglish
Article numbere000063
JournalESMO Open
Volume1
Issue number4
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Mutation
Hepatocyte Growth Factor
Disease-Free Survival
Survival
Erlotinib Hydrochloride
gefitinib
ARQ 197
Protein-Tyrosine Kinases
Neoplasms
Biomarkers
Biopsy
Safety

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib. / Azuma, Koichi; Hirashima, Tomonori; Yamamoto, Nobuyuki; Okamoto, Isamu; Takahashi, Toshiaki; Nishio, Makoto; Hirata, Taizo; Kubota, Kaoru; Kasahara, Kazuo; Hida, Toyoaki; Yoshioka, Hiroshige; Nakanishi, Kaoru; Akinaga, Shiro; Nishio, Kazuto; Mitsudomi, Tetsuya; Nakagawa, Kazuhiko.

In: ESMO Open, Vol. 1, No. 4, e000063, 01.07.2016.

Research output: Contribution to journalArticle

Azuma, K, Hirashima, T, Yamamoto, N, Okamoto, I, Takahashi, T, Nishio, M, Hirata, T, Kubota, K, Kasahara, K, Hida, T, Yoshioka, H, Nakanishi, K, Akinaga, S, Nishio, K, Mitsudomi, T & Nakagawa, K 2016, 'Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib', ESMO Open, vol. 1, no. 4, e000063. https://doi.org/10.1136/esmoopen-2016-000063
Azuma, Koichi ; Hirashima, Tomonori ; Yamamoto, Nobuyuki ; Okamoto, Isamu ; Takahashi, Toshiaki ; Nishio, Makoto ; Hirata, Taizo ; Kubota, Kaoru ; Kasahara, Kazuo ; Hida, Toyoaki ; Yoshioka, Hiroshige ; Nakanishi, Kaoru ; Akinaga, Shiro ; Nishio, Kazuto ; Mitsudomi, Tetsuya ; Nakagawa, Kazuhiko. / Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib. In: ESMO Open. 2016 ; Vol. 1, No. 4.
@article{cae31e22ac574ad2b34d606bfed80385,
title = "Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib",
abstract = "Background Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. Methods This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. Results The ORR was 6.7{\%} (95{\%} CI 1.4{\%} to 18.3{\%}), and the lower limit of 95{\%} CI did not exceed the target of 5{\%}. The median PFS (mPFS) and median OS (mOS) were 2.7...months (95{\%} CI 1.4 to 4.2) and 18.0...months (95{\%} CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4...months; mOS 20.7 vs 13.9...months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. Conclusions Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. Trial registration number NCT01580735.",
author = "Koichi Azuma and Tomonori Hirashima and Nobuyuki Yamamoto and Isamu Okamoto and Toshiaki Takahashi and Makoto Nishio and Taizo Hirata and Kaoru Kubota and Kazuo Kasahara and Toyoaki Hida and Hiroshige Yoshioka and Kaoru Nakanishi and Shiro Akinaga and Kazuto Nishio and Tetsuya Mitsudomi and Kazuhiko Nakagawa",
year = "2016",
month = "7",
day = "1",
doi = "10.1136/esmoopen-2016-000063",
language = "English",
volume = "1",
journal = "ESMO Open",
issn = "2059-7029",
publisher = "BMJ Publishing Group",
number = "4",

}

TY - JOUR

T1 - Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

AU - Azuma, Koichi

AU - Hirashima, Tomonori

AU - Yamamoto, Nobuyuki

AU - Okamoto, Isamu

AU - Takahashi, Toshiaki

AU - Nishio, Makoto

AU - Hirata, Taizo

AU - Kubota, Kaoru

AU - Kasahara, Kazuo

AU - Hida, Toyoaki

AU - Yoshioka, Hiroshige

AU - Nakanishi, Kaoru

AU - Akinaga, Shiro

AU - Nishio, Kazuto

AU - Mitsudomi, Tetsuya

AU - Nakagawa, Kazuhiko

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Background Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. Methods This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. Results The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7...months (95% CI 1.4 to 4.2) and 18.0...months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4...months; mOS 20.7 vs 13.9...months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. Conclusions Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. Trial registration number NCT01580735.

AB - Background Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. Methods This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. Results The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7...months (95% CI 1.4 to 4.2) and 18.0...months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4...months; mOS 20.7 vs 13.9...months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. Conclusions Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. Trial registration number NCT01580735.

UR - http://www.scopus.com/inward/record.url?scp=85019581437&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019581437&partnerID=8YFLogxK

U2 - 10.1136/esmoopen-2016-000063

DO - 10.1136/esmoopen-2016-000063

M3 - Article

VL - 1

JO - ESMO Open

JF - ESMO Open

SN - 2059-7029

IS - 4

M1 - e000063

ER -