Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation

Eunice L. Kwak, Geoffrey I. Shapiro, Seth M. Cohen, Carlos R. Becerra, Heinz Josef Lenz, Wen Fang Cheng, Wu-Chou Su, Meghan Robohn, Florence Le Maulf, Maximilian T. Lobmeyer, Vikram K. Chand, A. John Iafrate

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

BACKGROUND The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging.

Original languageEnglish
Pages (from-to)3043-3051
Number of pages9
JournalCancer
Volume119
Issue number16
DOIs
Publication statusPublished - 2013 Jun 18

Fingerprint

Epidermal Growth Factor Receptor
erbB-1 Genes
Neoplasms
Gene Amplification
Fluorescence In Situ Hybridization
Mutation
Lung Neoplasms
Biomarkers
Biliary Tract
Appetite
Exanthema
Patient Selection
BIBW 2992
Diarrhea
Pharmacokinetics
Safety
human ERBB2 protein
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kwak, E. L., Shapiro, G. I., Cohen, S. M., Becerra, C. R., Lenz, H. J., Cheng, W. F., ... Iafrate, A. J. (2013). Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation. Cancer, 119(16), 3043-3051. https://doi.org/10.1002/cncr.28120
Kwak, Eunice L. ; Shapiro, Geoffrey I. ; Cohen, Seth M. ; Becerra, Carlos R. ; Lenz, Heinz Josef ; Cheng, Wen Fang ; Su, Wu-Chou ; Robohn, Meghan ; Le Maulf, Florence ; Lobmeyer, Maximilian T. ; Chand, Vikram K. ; Iafrate, A. John. / Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation. In: Cancer. 2013 ; Vol. 119, No. 16. pp. 3043-3051.
@article{4ba4db347dc04c3d84641c205c5b7a08,
title = "Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation",
abstract = "BACKGROUND The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5{\%} (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging.",
author = "Kwak, {Eunice L.} and Shapiro, {Geoffrey I.} and Cohen, {Seth M.} and Becerra, {Carlos R.} and Lenz, {Heinz Josef} and Cheng, {Wen Fang} and Wu-Chou Su and Meghan Robohn and {Le Maulf}, Florence and Lobmeyer, {Maximilian T.} and Chand, {Vikram K.} and Iafrate, {A. John}",
year = "2013",
month = "6",
day = "18",
doi = "10.1002/cncr.28120",
language = "English",
volume = "119",
pages = "3043--3051",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "16",

}

Kwak, EL, Shapiro, GI, Cohen, SM, Becerra, CR, Lenz, HJ, Cheng, WF, Su, W-C, Robohn, M, Le Maulf, F, Lobmeyer, MT, Chand, VK & Iafrate, AJ 2013, 'Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation', Cancer, vol. 119, no. 16, pp. 3043-3051. https://doi.org/10.1002/cncr.28120

Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation. / Kwak, Eunice L.; Shapiro, Geoffrey I.; Cohen, Seth M.; Becerra, Carlos R.; Lenz, Heinz Josef; Cheng, Wen Fang; Su, Wu-Chou; Robohn, Meghan; Le Maulf, Florence; Lobmeyer, Maximilian T.; Chand, Vikram K.; Iafrate, A. John.

In: Cancer, Vol. 119, No. 16, 18.06.2013, p. 3043-3051.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation

AU - Kwak, Eunice L.

AU - Shapiro, Geoffrey I.

AU - Cohen, Seth M.

AU - Becerra, Carlos R.

AU - Lenz, Heinz Josef

AU - Cheng, Wen Fang

AU - Su, Wu-Chou

AU - Robohn, Meghan

AU - Le Maulf, Florence

AU - Lobmeyer, Maximilian T.

AU - Chand, Vikram K.

AU - Iafrate, A. John

PY - 2013/6/18

Y1 - 2013/6/18

N2 - BACKGROUND The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging.

AB - BACKGROUND The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging.

UR - http://www.scopus.com/inward/record.url?scp=84881477255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881477255&partnerID=8YFLogxK

U2 - 10.1002/cncr.28120

DO - 10.1002/cncr.28120

M3 - Article

VL - 119

SP - 3043

EP - 3051

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 16

ER -

Kwak EL, Shapiro GI, Cohen SM, Becerra CR, Lenz HJ, Cheng WF et al. Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation. Cancer. 2013 Jun 18;119(16):3043-3051. https://doi.org/10.1002/cncr.28120